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The Modern Treatment of Schizophrenia (Dementia Praecox)
Medical Clinics of North America November, 1938. Philadelphia Number
~
CLINIC OF DRS. EDWARD A. STRECKER FRANCIS J. BRACELAND
AND
INSTITUTE OF THE PENNSYLVANIA HOSPITAL
THE MODERN TREATMENT OF SCHIZOPHRENIA (DEMENTIA PRAECOX)
WE have attempted to give you a clinical and psychological appreciation of schizophrenia, which is unquestionably the gravest disease threat of our civilization. It would appear that the outstanding characteristic of schizophrenic patients is that they tend to live in a world of their own. Practically all of the clinical symptoms are reducible to this phenomenon of psychological isolation. The "splitting" of the mind from which the psychosis derives its name is a lack of unity and parallelism between thought content and emotional accompaniment and it imparts an extremely bizarre expression to schizophrenia, setting it apart from all other behavior reactions, normal or psychotic. From the standpoint of therapy there are at least four important considerations: First, with the much better understanding of the particular type of introverted personality soil in which the psychosis so readily takes root, there is now a much better opportunity for the exercise of preventive measures during childhood. Second, schizophrenia is not only extremely common, but it makes its appearance in about 70 per cent of the patients during the second decade of life. Therefore, effective treatment is unusually important. Third, the chances of successful therapeutic results diminish rapidly as the duration of the psychosis increases. Fourth, prognostic' considerations have been greatly improved by modern pharmacological methods and technics. Preventive Measures.-Prophylaxis must be intensively cultivated during childhood and every child who presents 1747
1748
EDWARD A. STRECKER, FRANCIS
J.
BRACE LAND
schizoid characteristics ("good," "quiet," "shy," "reserved," "difficult," "unsociable," "seclusive," etc.) should be the target for intensive prophylaxis. The objective is to attain a better balance between child and environment and, in some sense, t~ promote socialization. For the child, the home should be first and foremost a place in which there is an atmosphere of harmony and happiness. There should be neither unduly harsh discipline, nor its opposite, spoiling. Competition between brothers and sisters in the home for the favor of the parents, particularly when spurred on by "playing favorites" by the parents, is pernicious. The attempt to stimulate a child by too constantly pointing out the assets in brothers and sisters usually results in the production of inferiority feelings and is a hazardous process. There should be liberal doses of explanation to the child in the parent-child relationship and particularly should punishment contain a generous leaven of explanation. Companionship with other children of both sexes, outdoors, athletics, and all reasonable socializing influences should be encouraged. It should be made easy for the child to bring his playmates into the home and there should be no risk that things would be seen or heard there that would shame him before other children. Sex and particularly the concrete facts of sex are always difficult for the potential schizophrenic and "therefore effort should be made to prevent phantasy by supplying competent knowledge of sex hygiene, and to discourage rumination by always discussing such matters without emotion and with only a modicum of moralization." Sex instruction should be begun comparatively early in childhood, but naturally in a degree and in detail suitable to the age of the child. Children have toward their parents an attitude of idealistic identification. Unconsciously, they supplement their own weakness by identifying themselves in the parents. Here is a strong emotional bond, leading to indiscriminate imitation and containing sources of danger, particularly for the introverted child. The goal of any real psychology of childhood is to obtain for the child a true psychological maturity. If this is not accomplished, the child is destined for a life of slavish imitation of those who become the emotional surrogates for his parents. The parent-child bond must be loosened not too
MODERN TREATMENT OF SCHIZOPHRENIA
1749
abruptly but nevertheless surely, and independence of thought and action must be wisely and continuously encouraged. Introverted children read a great deal and while their reading should not be too rigidly ordered yet, it should be directed toward types of literature that are not too luridly and completely phantastic. Religion supplies an important need and it should be a source of beauty and inspiration but social and practical too, and above all not grimly fear-producing. "The schooling of these children should be carefully scanned and means found to check the tendency to study abtruse and obscure subjects. Rather should socializing subjects be emphasized, that youth may keep close to facts and maintain friendly personal contacts. Primacy in competition of . intellects is a goal to be disparaged . . . the choice and any change of occupation should be given consideration by those interested in order to prevent the development of illness; and any inclination to choose a vocation that merely promises compensation for ill-recognized inferiority feelings should be skillfully handled. The vocation selected should be certainly within the capacity of the individual and of a type to maintain his social life on as broad a scale as may be within his power." (Hamilton.) Treatment of the Psychosis.-Obviously the earlier the actual schizophrenia is treated correctly, the better the chance of adjustment. In combating schizophrenia the psychiatrist needs the inspiration of a workable conception. We know of no better conception than the psychobiological interpretation of Meyer. It views the patient critically in the long section of his life history and particularly surveys the series of maladaptations that preceded the final schizophrenic one. It then asks such pertinent and therapeutically stimulating questions as these: What are the resource~ of the patient? What has he to react with? What is the situation he is called on to meet? Can we modify his resources in order to enable him better to meet the situation, or can we modify the situation so he may better meet it with his resources? Etc. Finally, the psychobiological idea does not court exclusively any single therapeutic mistress and it leaves open the door of every reasonable treatment plan. Psychotherapy.-There are many kinds of psychotherapy
1750
.EDWARD A. STRECKER, FRANCIS
J.
BRACE LAND
and we believe the more individualistic the approach the better. Generally speaking the psychiatrist will find his patient living on the plane of unreality or dangerously close to it. Between this and the reality which is possible for the patient and which varies for each patient there is a gulf which must be bridged if adjustment is to be secured. The steps between phantasy and reality cannot be forced too abruptly but must be taken, psychologically speaking, slowly and gradually. The building up of confidence, persuasion, suggestion, particularly the indirect suggestion that skilfully and not too obviously puts forth the claims of reality, are helpful. All this implies some degree of accessibility on the part of the patient but so is this a requisite for any form of psychotherapy and in the bulk of early cases some degree of accessibility is at hand. Once a bit of insight is secured and there is some beginning of the process of viewing the symptoms objectively, then this advantage should be pressed and expanded. There is much difference of opinion concerning that specialized form of psychotherapy known as psychoanalysis. Some authorities feel that dangerous panics result from the inability of the patient to face the probable incestuous significance of the phantasies, and that the physician becomes a part of the phantasy. Others think that this is merely a difficult place in the treatment plan and that it can be won through. It is obvious that in any event psychoanalysis must be modified if it is to be used in the treatment of the schizophrenic. General Management.-In well-established schizophrenia the majority of the patients must be treated in suitable mental hospitals or sanatoria. In this way the medical interests of the patient, his safety, the safety of the community and the welfare and efficiency of the family are best protected and conserved. Under skilful supervision and, if satisfactory conditions are available, a number of patients may be cared for in the home, particularly during the "quiet" periods of the psychosis. In some instances farm or ranch life is a good solution. In early or mild cases, the out-patient clinic or private physician can satisfactorily direct the care of the patient in the home. The placement of the patient in suitable homes and the community plan as it is followed at Gheel,
MODERN TREATMENT OF SCHIZOPHRENIA
1751
Belgium, deserve wider recognition. Whether the patient be in hospital or at home, adequate nursing, occupational therapy and proper social service are important. The nurse is the representative of the psychiatrist and, if well trained, she will know how to attempt to check the inroads of phantasy and how to set forth in theory and practice the claims and advantages of reality. The social service worker if not too fanciful is especially valuable in the "follow-up" of adjusted patients and in the instances where patients are kept in the home, she should combat the danger of family disorganization. Occupational therapy is an extremely valuable and a necessary treatment adjunct. It is constantly symbolic of reality rather attractively garbed, and it produces the concrete fruits of work. Treatment of Special Symptoms.-The good nurse will know how necessary it is to see that the patient has sufficient nourishment; that he is tube fed when necessary; that he is kept clean, bathed frequently, changed when he wets or. soils himself; that dangerous and sharp objects with which the patent might mutilate himself or others are not available; that the patient has enough exercise, sunshine and fresh air; that the chronic patient is taught useful habits and some routine, at least, in the care of the bodily functions and the nurse, too, will minimize and control the physical dilapidation of appearance which is such an early result of the shutting out of reality. The prolonged bath, wet packs, etc., sometimes quiet the excited states. Apathy must be often the target of special measures: walks, calisthenics, physical culture apparatus, athletic games, indoor games, cards, other diversions, suitable motion pictures, and the theatre, music, dancing, garden work, arts and crafts especially basketry and weaving, etc., are all helpful. Sometimes in stupor visiting by relatives is beneficial. Pharmacological Therapy.-Until comparatively recently the treatment which has been outlined constituted the extent of our therapeutic resources. A therapeutic renaissance has appeared, which boldly and rather successfully attempts to strike directly at certain chemical factors which may be causal of schizophrenia, or which, at least, may provide conditions under which the psychosis becomes chronic.
175:2
EDWARD A. STRECKER, FRANClS
J.
BRACE LAND
NEWER FORMS OF THERAPY IN SCHIZOPHRENIA
Insulin.-Among the newer forms of therapy in use in schizophrenia insulin shock therapy and treatment with metrazol rank first in importance. The present form of insulin shock therapy was first used by Manfred Sake! of the WagnerJauregg Clinic ·in Vienna, and to him goes the credit for having discovered it. While Sakel was the first actually, to use hypoglycemic shock in the treatment of schizophrenia he was not the first to use insulin in the treatment of psychotic patients. Other investigators had tried it as a means of increasing the appetite and promoting nutrition in mental patients. As early as 1928, Haack in Germany had reported improvement in the mental status of patients being treated with insulin. Steck in Switzerland reported the same results but both men buffered the injection and warned against hypoglycemia. In America, Appel, Farr and Marshall of the Pennsylvania Hoppital began work with insulin in 1928 and 1929 as did Strecker and Palmer. The first mentioned group gave up to 70 units a day in an attempt to improve the patient's nutrition. They noted improvement in one patient who had a hypoglycemic reaction but did not follow it through. Therefore Sakel fathered the present type of treatment and was the first to devise a safe technic and elaborate a successful method of treatment on that basis. He announced the results of his five years' observation at a meeting of the Vienna Medical Society in November of 1933. He reported that 58 patients who had been ill six months or less had been under treatment and that 70.7 per cent responded with a full remission and a further 17.3 per cent responded with a good social remission, a total of 88 per cent positive results. His reports were soon confirmed by Max MUller of Munsing Hospital in Bern, Switzerland, who reported that out of 136 patients who had been ill less than six months 89 per cent had improved, 73 per cent being full remissions. Among those patients whose illness had lasted six to eighteen months 82 per cent were improved, 50 per cent being full remissions. A third major series of cases was reported from Jugoslavia in November of 1936 and the investigators noted 70.58 per cent remissions but there was 1 fatality.
MODERN TREATMENT OF SCBIZOPHRENIA
1753
In America, credit for precedence in the actual beginning of insulin shock therapy no doubt goes to Cameron and Hoskins of the Worcester State Hospital. Glueck's glowing account of his visits to Munsing and Vienna was published in September of 1936 and stimulated great interest in the work in this country. Wortis had been active with the treatment in Bellevue Hospital in New York and very soon the therapy was begun in the Pennsylvania Hospital, Philadelphia General Hospital, and· in many of the larger clinics of the United States. It was apparent that any form of therapy which showed such excellent results in a psychosis which had had such poor prognosis would attract a great deal of attention. Bond and Braceland had reported in a five-year follow-up study that only 11 per cent of all patients who had been treated and then followed for five years had shown good remissions. This included the cases in which the remissions were spontaneous and those which were brought about by any type of therapy. The disparity between the recoveries reported is apparent. If the new figures were to be really correct, a great deal of good would be expected from this type of therapy. Essentially the treatment consists of the production of consecutive daily insulin shocks. This is accomplished with the injection of graded doses of insulin, usually starting with 20 or 30 units or less and increased by 5 or 10 units until the shock dose is reached. The insulin usually produces somnolence and coma accompanied by profuse perspiration, giving a clinical picture which was formerly regarded as being alarming. Sakel calls these "wet shocks." Occasionally a severe epileptiform seizure is produced and he calls this "dry shock." Sakel divides the treatment into four phases: 1. Preparatory or introductory. 2. Shock phase. 3. Rest phase. 4. Transitional, polarization, or terminal stage. The first stage simply consists in the preparation of the patient for shock. Few symptoms are seen. The patient's skin is usually moist and he may complain of hunger. As the dosage increases the patient shows more severe symptoms; he may become quiet, perspire profusely, exhibit forced blinking,
1754
EDWARD A. STRECKER, FRANCIS
J.
BRACE LAND
twitching of the lips and facial muscles and drowsiness progressing to stupor. When this stuporous stage progresses to coma the preparatory stage is at an end and the patient is regarded as being in the shock phase. Typically, the shock starts with profuse perspiration, proceeds with increasing somnolence and finally goes over into coma. It might be interrupted temporarily by psychotic excitement. The patient is in true coma when he does not respond to stimulus. Sakel uses the loss of the swallowing reflex as the criterion of coma. There is usually drooling from the corners of the mouth. The pupils are small at the onset of coma and dilate as it deepens. It has been found that once the shock dose is reached and is established, invariably it is possible to lower the dosage and yet produce coma. The patient may show minor twitches, that is, transient perioral or periorbital twitches which are not rhythmic. There is no cause for alarm in these minor twitches; they simply indicate that the patient is going into coma. The patient recovers from them spontaneously. During this stage no stimulus of any kind should be permitted lest perhaps it bring on major twitches. Major twitches are characterized by a rhythmic clonic jerking involving facial and somatic musculature. If allowed to progress these major twitches increase in both frequency and severity until they approximate a clonic convulsion. The stage in which the twitches are present is sometimes called "restless stupor." Either restless or quiet stupor usually precedes the coma. As the hypoglycemia deepens the pulse usually becomes slower. Respiration deepens but the rate increases slightly. The temperature drops. Perhaps the most difficult thing of all is to decide when the opportune time has arrived to interrupt. As Sakel says the therapeutic effect does not depend on the amount of insulin or on the duration or depth of the coma. It depends on the accurately timed moment of interruption of the hypoglycemic state. Experience is the essential factor here and there are no known criteria which direct one when the hypoglycemic state should be terminated. The shock phase is interrupted by sugar solution given through a nasal tube or by an intravenous injection of glucose. Intravenous glucose is of course used in any case of emergency. The immediate period following the interrup-
MODERN TREATMENT OF SCHIZOPHRENIA
1755
tion is a time of mental clarity and alertness. At first ihis period is of relatively short duration but the time lengthens as treatment proceeds. Late in the treatment in those patients who are improved the psychotic symptoms are removed and the normal personality can again achieve complete dominance. Sakel believed that in schizophrenia the cortical cells were continuously exposed to an adrenalin-like substance and that insulin was its antagonist. He therefore felt that the effectiveness of hypoglycemic treatment was due to the action by insulin directly on the cell itself. He assumed that the products of the adrenalin substance sensitized the cells excessively so that normal adequate stimuli produced pathological effects. Insulin opposes the action of the products of the adrenaiin substance so that excessive stimuli are muffled and the cells kept relatively quiescent with benefit to the individual. He believes that this occurs in phase 1. Sakel continues that this stimulating hormone not only stimulates the activity of the individual cell but also revives forgotten phylogenetically ancient and infantile nerve pathway patterns which are normally latent and subdued in healthy waking thought. In the pathologic conditions were described all of these old patterns and called into action again they interfere with each other and produce what Stransky calls "intrapsychic ataxia." The nerve pathway patterns are shattered by phase 2 which is the shock phase and the normal pathways take precedence. In the convalescent period he feels that pathological nerve pathways remain subdued and the normal pathways remain inactive. In the last phase the normal cellular relations are reinforced by further injections and are said to be polarized. At present the Pennsylvania Hospital statistics show the following. Seventy-two cases have been treated. At the end of treatment 45 per cent showed either clinical or social recovery. Within a period of weeks or months 15 per cent had relapsed, giving us a present recovery rate of 30 per cent. These statistics are at marked variance with the high recovery rates reported on the continent. One of the reasons for this disparity is probably that 15 of our cases were chronic and of long standing, a few of the 15 having been here for fifteen years. We are able to agree that the newer the patient's ill-
1756
EDWARD A. STRECKER, FRANCIS
J.
BRACELAND
ness, the more hopeful the prognosis under insulin therapy. It is interesting to note that in a recent review of the cases done in the State Psychiatric Institute of New York they reported 58 patients treated. Out of the first 47 it was found that 26 per cent had recovered, 17 per cent were much improved, and 17 per cent were improved. Apparently the paranoid patients do better under insulin than do other types of schizophrenia. No doubt as the number of cases treated increases the recovery rate will average about 35 or 40 per cent. We should mention that due to the rigors of insulin therapy any gross lesion especially of the cardiovascular system should be considered a barrier to the initiation of treatment. The older the patient the more care must be taken in gauging the dosage and in carrying out the technic. Metrazol.-Ladislaus von Meduna of the Royal Hungarian Hospital in Budapest was the first to utilize metrazol for the treatment of schizophrenia. In July of 1935 he reported the results of his experiments with convulsive agents. The idea of treating schizophrenics by inducing convulsive states was based upon observations by Nyiro and Jablonszky, G. MUller, A. Glaus and others who had studied the few cases of schizophrenia which were accompanied by epilepsy. They concluded that epilepsy militated against the development of schizophrenia and on the basis of these observations formulated the following hypothesis: "Between schizophrenia and epilepsy there is a biological antagonism. Should it be possible to induce epileptic attacks in schizophrenic patients, such epileptic attacks would change the chemical, humoral, haematological and other aspects of the organism in such a manner that thereby-since the organism so changed would represent an unfavorable basis for the development of schizophrenia-a biological possibility is given for a remission of the disease." They experimented with several convulsants. Camphor was more successful than the others but they found they were unable to fix the dosage. Metrazol was selected as it was more consistent in its action and readily soluble in water. Also, it is absorbed completely and rapidly even in large doses and it has no injurious effect upon the heart. Von Meduna started to treat schizophrenic patients with this drug; he began
MODERN TREATMENT OF SCHIZOPHRENIA
I757
by injecting 5 cc. of a 10 per cent solution into the veins. As a rule, there was a convulsive attack immediately after the injection. As long as the amount sufficed and a convulsion resulted the dosage was not increased. After the patient developed a tolerance, however, the dosage was increased by 1 cc. of a 10 per cent solution daily until in some cases as much as 15 cc. was given. Von Meduna treated the patients twice weekly. Other investigators, notably Friedman in America, treated the patients every second day. The number of treatments vary with the investigator, usually averaging 2 or 3 weekly. At first the convulsion is tonic in character but within a few seconds it becomes clonic. The convulsions simulate epilepsy including the aura and automatisms. Before the onset of the convulsion there is always a tonic yawning movement which allows insertion of the gauze pad to protect the patient's mouth. During this latter phase the patients often urinate, the pupils are dilated and do not react to light and there is a positive Babinski. As mentioned before, it simulates an epileptic attack. After the attack, the patients in most cases are confused and dizzy and fall into a deep coma-like sleep which lasts from five t6 ten minutes. They again regain consciousness but are quite exhausted and fall asleep again and five to six hours after the attack they are allowed to take nourishment and move around. No definite number of convulsive seizures has been fixed as the curative number. In some cases the patients were better after 2 or 3 attacks; other required 25 treatments. As a general rule 15 attacks are induced even in patients who are not improving. If the patient has had an apparent remission it is well to give 3 or more convulsions despite this. Von Meduna pointed out that the blood picture changes under metrazol therapy. The lymphocytes are reduced and the neutrophiles are increased. This was particularly so in patients who showed a remission. Also, the urinary acidity is increased about 25 per cent while the phosphates are increased 10 per cent. The chlorides are decreased 25 per cent. The investigators called our attention to the fact that in epilepsy these findings have been observed by various authors. Even though the attack seems to be appalling, the workers feel that there is no inherent danger in this type of
1758
EDWARD A. STRECKER, FRANCIS
J.
BRACE LAND
treatment. Several thousand convulsions have been induced without any serious complications. Dislocation of the jaw has occurred and occasionally a dislocation of the shoulder. In von Meduna's report he chronicles the results of treatments in 110 patients, of whom 54 had a remission. This is roughly about 50 per cent. As stated above, the remissions in patients untreated range around 11 to 15 per cent. If we were to take the patients who were ill less than one year, von Meduna's figures would show a remission as high as 90 per cent. Von Meduna's experiments have been corroborated by many other investigators. In America, Finkelman, Steinberg and Liebert of Elgin, Illinois, reported on the treatment of 66 patient's with dementia praecox by the administration of metrazol. They reported that 85 per cent of the patients whose symptoms were . less than six months in duration had a remission. The rate of remission, they felt, was invariably proportionate to the duration of the psychosis. They say that if the psychosis has lasted more than three years, the anticipation of a remission is slight. Patients who had been ill longer than eighteen months required larger doses of metrazol and more treatments. The type of dementia praecox that has the greatest tendency to remit with this therapy is the catatonic followed closely by the paranoid. It will be remembered that the paranoid type responds best to insulin shock. The following contraindications to metrazol therapy are listed: Failing or decompensating cardiovascular system, acute infectious diseases, and pulmonary diseases. Other investigators claim that severe anemia or cachexia, menstruation, history of cranial injury with subsequent unconsciousness should be added to the list of contraindications. The rate of injection of the metrazol is also important. It should be given at the rate of 0.1 cc. every ten seconds. The same dose of the drug given rapidly will produce convulsions which will not occur if the injection is given slowly. Wahlmann in Germany remarks that in hebephrenic cases it is difficult to judge improvement, but 3 of these patients were apparently improved and discharged from the hospital and at the time of writing had not returned. He also noted that the patients who reacted more severely to metrazol showed a greater degree of improvement, that is, that im-
MODERN TREATMENT OF SCHIZOPHRENIA
1759
provement seemed to depend directly on the degree of convulsions produced. In recent literature we find that von Meduna and Sakel both claim credit for priority in the use of convulsions in the treatment of schizophrenia. Von Meduna points out that Sakel very carefully avoided allowing his patients to go into convulsions and that other investigators warned about it also. Sakel contends that he also used camphor and metrazol to provoke epileptic convulsions as far back as 1933. Sakel says his article was written in order to avoid an unfavorable schism in the pharmacological shock therapy. Ziskind reviews some of this quarrel and says that Sakel regards convulsions in insulin therapy as "heavy artillery" and prefers to use "light artillery" even though he recognizes that favorable effects sometimes follows major seizures. He points out that according to Grayzel convulsive paroxysms in rabbits cause cerebral damage. When no convulsions followed the insulin injections there were no microscopic pathological changes in the brain; after slight convulsions there were minimal changes; after one or more severe convulsions there were definite anatomic lesions. The greater the number and the more prolonged the convulsions the more severe were the lesions and among other changes there were small zones of focal necrosis in the cerebral cortex. The dose of insulin was comparable to that used in schizophrenia. Individual reactions with insulin should preferably be avoided. Ziskind remarks: "What bearing these histopathologic observations have on convulsant therapy with camphor or Metrazol can only be a matter of conjecture. The question is worthy of further study." While we have been using metrazol therapy in the treatment of dementia praecox, as yet we do not have a sufficient number of cases to speak with any authority. BIBLIOGRAPHY GENERAL
Strecker and Ebaugh: Practical Clinical Psychiatry, 4th ed., P. Blakiston's Son and Co., Inc., Philadelphia, 1937. INSULIN
Sakel, Manfred: Neue Behandlungsmethode der Schizophrenie, Moritz PerIes, Wien and Leipzig, 1935.
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EDWARD A. STRECKER, FRANCIS J. BRACE LAND
Sakel, Manfred: Section on Neurology and Psychiatry, New York Academy of Medicine, Jour. Nerv. and Ment. Dis., Vo!. lxxxv, May, 1937, pp. 561-580.
Braceland and Hastings: Insulin Shock Therapy in Schizophrenia, Penna. Med. Jour., Vol. 41, No. 1, pp. 7-14, October, 1937. Wortis, J oseph: Sakel's Hypoglycemic Insulin Treatment of Psychoses, Jour. Nerv. and Ment. Dis., Vo!. lxxxv, May, 1937, pp. 581-594. Glueck, Bernard: Jour. Amer. Med. Assoc., 107: 1029-1031, Sept. 26, 1936. Sakel, Manfred: A New Treatment of Schizophrenia, Amer. Jour. Psychiatry, 93 (No. 4): 829-841, June, 1937.
METRAZOL von Meduna: The Convulsive Therapy of Schizophrenia, Psych. Neuro!. Wchnschr., 37: 317, July, 1935. Wahlmann: The Treatment of Psychoses with Metrazol, Psych. Neuro!. Wochenschr., 38: 78, Feb. 15, 1936. Kriiger: The Treatment of Schizophrenia by von Meduna's Method, Psych. Neuro!. Wochenschr., 38: 135, 1936. Friedman: Irritative Treatment of Schizophrenia (Review of 20 Cases), Amer. Jour. Psych., Sept., 1937, Vo!. 94, No. 2. Finkelman et al... The Treatment of Schizophrenia with Metrazol by the Production of Convulsions, Amer. Jour. Med. Assoc., 110 (No. 10): March 5, 706, 1938.
Ziskind, E.: Convulsions During Insulin Therapy in the Psychoses, Jour. Amer. Med. Assoc., 110 (No. 12): 915, March 19, 1938. von Meduna vs. Sakel: Jour. Nerv. and Ment. Dis., 87 (No. 2): 133-155, Feb., 1938.
~
CLINIC OF DRS. EDWARD A. STRECKER FRANCIS J. BRACELAND
AND
INSTITUTE OF THE PENNSYLVANIA HOSPITAL
THE MODERN TREATMENT OF SCHIZOPHRENIA (DEMENTIA PRAECOX)
WE have attempted to give you a clinical and psychological appreciation of schizophrenia, which is unquestionably the gravest disease threat of our civilization. It would appear that the outstanding characteristic of schizophrenic patients is that they tend to live in a world of their own. Practically all of the clinical symptoms are reducible to this phenomenon of psychological isolation. The "splitting" of the mind from which the psychosis derives its name is a lack of unity and parallelism between thought content and emotional accompaniment and it imparts an extremely bizarre expression to schizophrenia, setting it apart from all other behavior reactions, normal or psychotic. From the standpoint of therapy there are at least four important considerations: First, with the much better understanding of the particular type of introverted personality soil in which the psychosis so readily takes root, there is now a much better opportunity for the exercise of preventive measures during childhood. Second, schizophrenia is not only extremely common, but it makes its appearance in about 70 per cent of the patients during the second decade of life. Therefore, effective treatment is unusually important. Third, the chances of successful therapeutic results diminish rapidly as the duration of the psychosis increases. Fourth, prognostic' considerations have been greatly improved by modern pharmacological methods and technics. Preventive Measures.-Prophylaxis must be intensively cultivated during childhood and every child who presents 1747
1748
EDWARD A. STRECKER, FRANCIS
J.
BRACE LAND
schizoid characteristics ("good," "quiet," "shy," "reserved," "difficult," "unsociable," "seclusive," etc.) should be the target for intensive prophylaxis. The objective is to attain a better balance between child and environment and, in some sense, t~ promote socialization. For the child, the home should be first and foremost a place in which there is an atmosphere of harmony and happiness. There should be neither unduly harsh discipline, nor its opposite, spoiling. Competition between brothers and sisters in the home for the favor of the parents, particularly when spurred on by "playing favorites" by the parents, is pernicious. The attempt to stimulate a child by too constantly pointing out the assets in brothers and sisters usually results in the production of inferiority feelings and is a hazardous process. There should be liberal doses of explanation to the child in the parent-child relationship and particularly should punishment contain a generous leaven of explanation. Companionship with other children of both sexes, outdoors, athletics, and all reasonable socializing influences should be encouraged. It should be made easy for the child to bring his playmates into the home and there should be no risk that things would be seen or heard there that would shame him before other children. Sex and particularly the concrete facts of sex are always difficult for the potential schizophrenic and "therefore effort should be made to prevent phantasy by supplying competent knowledge of sex hygiene, and to discourage rumination by always discussing such matters without emotion and with only a modicum of moralization." Sex instruction should be begun comparatively early in childhood, but naturally in a degree and in detail suitable to the age of the child. Children have toward their parents an attitude of idealistic identification. Unconsciously, they supplement their own weakness by identifying themselves in the parents. Here is a strong emotional bond, leading to indiscriminate imitation and containing sources of danger, particularly for the introverted child. The goal of any real psychology of childhood is to obtain for the child a true psychological maturity. If this is not accomplished, the child is destined for a life of slavish imitation of those who become the emotional surrogates for his parents. The parent-child bond must be loosened not too
MODERN TREATMENT OF SCHIZOPHRENIA
1749
abruptly but nevertheless surely, and independence of thought and action must be wisely and continuously encouraged. Introverted children read a great deal and while their reading should not be too rigidly ordered yet, it should be directed toward types of literature that are not too luridly and completely phantastic. Religion supplies an important need and it should be a source of beauty and inspiration but social and practical too, and above all not grimly fear-producing. "The schooling of these children should be carefully scanned and means found to check the tendency to study abtruse and obscure subjects. Rather should socializing subjects be emphasized, that youth may keep close to facts and maintain friendly personal contacts. Primacy in competition of . intellects is a goal to be disparaged . . . the choice and any change of occupation should be given consideration by those interested in order to prevent the development of illness; and any inclination to choose a vocation that merely promises compensation for ill-recognized inferiority feelings should be skillfully handled. The vocation selected should be certainly within the capacity of the individual and of a type to maintain his social life on as broad a scale as may be within his power." (Hamilton.) Treatment of the Psychosis.-Obviously the earlier the actual schizophrenia is treated correctly, the better the chance of adjustment. In combating schizophrenia the psychiatrist needs the inspiration of a workable conception. We know of no better conception than the psychobiological interpretation of Meyer. It views the patient critically in the long section of his life history and particularly surveys the series of maladaptations that preceded the final schizophrenic one. It then asks such pertinent and therapeutically stimulating questions as these: What are the resource~ of the patient? What has he to react with? What is the situation he is called on to meet? Can we modify his resources in order to enable him better to meet the situation, or can we modify the situation so he may better meet it with his resources? Etc. Finally, the psychobiological idea does not court exclusively any single therapeutic mistress and it leaves open the door of every reasonable treatment plan. Psychotherapy.-There are many kinds of psychotherapy
1750
.EDWARD A. STRECKER, FRANCIS
J.
BRACE LAND
and we believe the more individualistic the approach the better. Generally speaking the psychiatrist will find his patient living on the plane of unreality or dangerously close to it. Between this and the reality which is possible for the patient and which varies for each patient there is a gulf which must be bridged if adjustment is to be secured. The steps between phantasy and reality cannot be forced too abruptly but must be taken, psychologically speaking, slowly and gradually. The building up of confidence, persuasion, suggestion, particularly the indirect suggestion that skilfully and not too obviously puts forth the claims of reality, are helpful. All this implies some degree of accessibility on the part of the patient but so is this a requisite for any form of psychotherapy and in the bulk of early cases some degree of accessibility is at hand. Once a bit of insight is secured and there is some beginning of the process of viewing the symptoms objectively, then this advantage should be pressed and expanded. There is much difference of opinion concerning that specialized form of psychotherapy known as psychoanalysis. Some authorities feel that dangerous panics result from the inability of the patient to face the probable incestuous significance of the phantasies, and that the physician becomes a part of the phantasy. Others think that this is merely a difficult place in the treatment plan and that it can be won through. It is obvious that in any event psychoanalysis must be modified if it is to be used in the treatment of the schizophrenic. General Management.-In well-established schizophrenia the majority of the patients must be treated in suitable mental hospitals or sanatoria. In this way the medical interests of the patient, his safety, the safety of the community and the welfare and efficiency of the family are best protected and conserved. Under skilful supervision and, if satisfactory conditions are available, a number of patients may be cared for in the home, particularly during the "quiet" periods of the psychosis. In some instances farm or ranch life is a good solution. In early or mild cases, the out-patient clinic or private physician can satisfactorily direct the care of the patient in the home. The placement of the patient in suitable homes and the community plan as it is followed at Gheel,
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Belgium, deserve wider recognition. Whether the patient be in hospital or at home, adequate nursing, occupational therapy and proper social service are important. The nurse is the representative of the psychiatrist and, if well trained, she will know how to attempt to check the inroads of phantasy and how to set forth in theory and practice the claims and advantages of reality. The social service worker if not too fanciful is especially valuable in the "follow-up" of adjusted patients and in the instances where patients are kept in the home, she should combat the danger of family disorganization. Occupational therapy is an extremely valuable and a necessary treatment adjunct. It is constantly symbolic of reality rather attractively garbed, and it produces the concrete fruits of work. Treatment of Special Symptoms.-The good nurse will know how necessary it is to see that the patient has sufficient nourishment; that he is tube fed when necessary; that he is kept clean, bathed frequently, changed when he wets or. soils himself; that dangerous and sharp objects with which the patent might mutilate himself or others are not available; that the patient has enough exercise, sunshine and fresh air; that the chronic patient is taught useful habits and some routine, at least, in the care of the bodily functions and the nurse, too, will minimize and control the physical dilapidation of appearance which is such an early result of the shutting out of reality. The prolonged bath, wet packs, etc., sometimes quiet the excited states. Apathy must be often the target of special measures: walks, calisthenics, physical culture apparatus, athletic games, indoor games, cards, other diversions, suitable motion pictures, and the theatre, music, dancing, garden work, arts and crafts especially basketry and weaving, etc., are all helpful. Sometimes in stupor visiting by relatives is beneficial. Pharmacological Therapy.-Until comparatively recently the treatment which has been outlined constituted the extent of our therapeutic resources. A therapeutic renaissance has appeared, which boldly and rather successfully attempts to strike directly at certain chemical factors which may be causal of schizophrenia, or which, at least, may provide conditions under which the psychosis becomes chronic.
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EDWARD A. STRECKER, FRANClS
J.
BRACE LAND
NEWER FORMS OF THERAPY IN SCHIZOPHRENIA
Insulin.-Among the newer forms of therapy in use in schizophrenia insulin shock therapy and treatment with metrazol rank first in importance. The present form of insulin shock therapy was first used by Manfred Sake! of the WagnerJauregg Clinic ·in Vienna, and to him goes the credit for having discovered it. While Sakel was the first actually, to use hypoglycemic shock in the treatment of schizophrenia he was not the first to use insulin in the treatment of psychotic patients. Other investigators had tried it as a means of increasing the appetite and promoting nutrition in mental patients. As early as 1928, Haack in Germany had reported improvement in the mental status of patients being treated with insulin. Steck in Switzerland reported the same results but both men buffered the injection and warned against hypoglycemia. In America, Appel, Farr and Marshall of the Pennsylvania Hoppital began work with insulin in 1928 and 1929 as did Strecker and Palmer. The first mentioned group gave up to 70 units a day in an attempt to improve the patient's nutrition. They noted improvement in one patient who had a hypoglycemic reaction but did not follow it through. Therefore Sakel fathered the present type of treatment and was the first to devise a safe technic and elaborate a successful method of treatment on that basis. He announced the results of his five years' observation at a meeting of the Vienna Medical Society in November of 1933. He reported that 58 patients who had been ill six months or less had been under treatment and that 70.7 per cent responded with a full remission and a further 17.3 per cent responded with a good social remission, a total of 88 per cent positive results. His reports were soon confirmed by Max MUller of Munsing Hospital in Bern, Switzerland, who reported that out of 136 patients who had been ill less than six months 89 per cent had improved, 73 per cent being full remissions. Among those patients whose illness had lasted six to eighteen months 82 per cent were improved, 50 per cent being full remissions. A third major series of cases was reported from Jugoslavia in November of 1936 and the investigators noted 70.58 per cent remissions but there was 1 fatality.
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In America, credit for precedence in the actual beginning of insulin shock therapy no doubt goes to Cameron and Hoskins of the Worcester State Hospital. Glueck's glowing account of his visits to Munsing and Vienna was published in September of 1936 and stimulated great interest in the work in this country. Wortis had been active with the treatment in Bellevue Hospital in New York and very soon the therapy was begun in the Pennsylvania Hospital, Philadelphia General Hospital, and· in many of the larger clinics of the United States. It was apparent that any form of therapy which showed such excellent results in a psychosis which had had such poor prognosis would attract a great deal of attention. Bond and Braceland had reported in a five-year follow-up study that only 11 per cent of all patients who had been treated and then followed for five years had shown good remissions. This included the cases in which the remissions were spontaneous and those which were brought about by any type of therapy. The disparity between the recoveries reported is apparent. If the new figures were to be really correct, a great deal of good would be expected from this type of therapy. Essentially the treatment consists of the production of consecutive daily insulin shocks. This is accomplished with the injection of graded doses of insulin, usually starting with 20 or 30 units or less and increased by 5 or 10 units until the shock dose is reached. The insulin usually produces somnolence and coma accompanied by profuse perspiration, giving a clinical picture which was formerly regarded as being alarming. Sakel calls these "wet shocks." Occasionally a severe epileptiform seizure is produced and he calls this "dry shock." Sakel divides the treatment into four phases: 1. Preparatory or introductory. 2. Shock phase. 3. Rest phase. 4. Transitional, polarization, or terminal stage. The first stage simply consists in the preparation of the patient for shock. Few symptoms are seen. The patient's skin is usually moist and he may complain of hunger. As the dosage increases the patient shows more severe symptoms; he may become quiet, perspire profusely, exhibit forced blinking,
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EDWARD A. STRECKER, FRANCIS
J.
BRACE LAND
twitching of the lips and facial muscles and drowsiness progressing to stupor. When this stuporous stage progresses to coma the preparatory stage is at an end and the patient is regarded as being in the shock phase. Typically, the shock starts with profuse perspiration, proceeds with increasing somnolence and finally goes over into coma. It might be interrupted temporarily by psychotic excitement. The patient is in true coma when he does not respond to stimulus. Sakel uses the loss of the swallowing reflex as the criterion of coma. There is usually drooling from the corners of the mouth. The pupils are small at the onset of coma and dilate as it deepens. It has been found that once the shock dose is reached and is established, invariably it is possible to lower the dosage and yet produce coma. The patient may show minor twitches, that is, transient perioral or periorbital twitches which are not rhythmic. There is no cause for alarm in these minor twitches; they simply indicate that the patient is going into coma. The patient recovers from them spontaneously. During this stage no stimulus of any kind should be permitted lest perhaps it bring on major twitches. Major twitches are characterized by a rhythmic clonic jerking involving facial and somatic musculature. If allowed to progress these major twitches increase in both frequency and severity until they approximate a clonic convulsion. The stage in which the twitches are present is sometimes called "restless stupor." Either restless or quiet stupor usually precedes the coma. As the hypoglycemia deepens the pulse usually becomes slower. Respiration deepens but the rate increases slightly. The temperature drops. Perhaps the most difficult thing of all is to decide when the opportune time has arrived to interrupt. As Sakel says the therapeutic effect does not depend on the amount of insulin or on the duration or depth of the coma. It depends on the accurately timed moment of interruption of the hypoglycemic state. Experience is the essential factor here and there are no known criteria which direct one when the hypoglycemic state should be terminated. The shock phase is interrupted by sugar solution given through a nasal tube or by an intravenous injection of glucose. Intravenous glucose is of course used in any case of emergency. The immediate period following the interrup-
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tion is a time of mental clarity and alertness. At first ihis period is of relatively short duration but the time lengthens as treatment proceeds. Late in the treatment in those patients who are improved the psychotic symptoms are removed and the normal personality can again achieve complete dominance. Sakel believed that in schizophrenia the cortical cells were continuously exposed to an adrenalin-like substance and that insulin was its antagonist. He therefore felt that the effectiveness of hypoglycemic treatment was due to the action by insulin directly on the cell itself. He assumed that the products of the adrenalin substance sensitized the cells excessively so that normal adequate stimuli produced pathological effects. Insulin opposes the action of the products of the adrenaiin substance so that excessive stimuli are muffled and the cells kept relatively quiescent with benefit to the individual. He believes that this occurs in phase 1. Sakel continues that this stimulating hormone not only stimulates the activity of the individual cell but also revives forgotten phylogenetically ancient and infantile nerve pathway patterns which are normally latent and subdued in healthy waking thought. In the pathologic conditions were described all of these old patterns and called into action again they interfere with each other and produce what Stransky calls "intrapsychic ataxia." The nerve pathway patterns are shattered by phase 2 which is the shock phase and the normal pathways take precedence. In the convalescent period he feels that pathological nerve pathways remain subdued and the normal pathways remain inactive. In the last phase the normal cellular relations are reinforced by further injections and are said to be polarized. At present the Pennsylvania Hospital statistics show the following. Seventy-two cases have been treated. At the end of treatment 45 per cent showed either clinical or social recovery. Within a period of weeks or months 15 per cent had relapsed, giving us a present recovery rate of 30 per cent. These statistics are at marked variance with the high recovery rates reported on the continent. One of the reasons for this disparity is probably that 15 of our cases were chronic and of long standing, a few of the 15 having been here for fifteen years. We are able to agree that the newer the patient's ill-
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EDWARD A. STRECKER, FRANCIS
J.
BRACELAND
ness, the more hopeful the prognosis under insulin therapy. It is interesting to note that in a recent review of the cases done in the State Psychiatric Institute of New York they reported 58 patients treated. Out of the first 47 it was found that 26 per cent had recovered, 17 per cent were much improved, and 17 per cent were improved. Apparently the paranoid patients do better under insulin than do other types of schizophrenia. No doubt as the number of cases treated increases the recovery rate will average about 35 or 40 per cent. We should mention that due to the rigors of insulin therapy any gross lesion especially of the cardiovascular system should be considered a barrier to the initiation of treatment. The older the patient the more care must be taken in gauging the dosage and in carrying out the technic. Metrazol.-Ladislaus von Meduna of the Royal Hungarian Hospital in Budapest was the first to utilize metrazol for the treatment of schizophrenia. In July of 1935 he reported the results of his experiments with convulsive agents. The idea of treating schizophrenics by inducing convulsive states was based upon observations by Nyiro and Jablonszky, G. MUller, A. Glaus and others who had studied the few cases of schizophrenia which were accompanied by epilepsy. They concluded that epilepsy militated against the development of schizophrenia and on the basis of these observations formulated the following hypothesis: "Between schizophrenia and epilepsy there is a biological antagonism. Should it be possible to induce epileptic attacks in schizophrenic patients, such epileptic attacks would change the chemical, humoral, haematological and other aspects of the organism in such a manner that thereby-since the organism so changed would represent an unfavorable basis for the development of schizophrenia-a biological possibility is given for a remission of the disease." They experimented with several convulsants. Camphor was more successful than the others but they found they were unable to fix the dosage. Metrazol was selected as it was more consistent in its action and readily soluble in water. Also, it is absorbed completely and rapidly even in large doses and it has no injurious effect upon the heart. Von Meduna started to treat schizophrenic patients with this drug; he began
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by injecting 5 cc. of a 10 per cent solution into the veins. As a rule, there was a convulsive attack immediately after the injection. As long as the amount sufficed and a convulsion resulted the dosage was not increased. After the patient developed a tolerance, however, the dosage was increased by 1 cc. of a 10 per cent solution daily until in some cases as much as 15 cc. was given. Von Meduna treated the patients twice weekly. Other investigators, notably Friedman in America, treated the patients every second day. The number of treatments vary with the investigator, usually averaging 2 or 3 weekly. At first the convulsion is tonic in character but within a few seconds it becomes clonic. The convulsions simulate epilepsy including the aura and automatisms. Before the onset of the convulsion there is always a tonic yawning movement which allows insertion of the gauze pad to protect the patient's mouth. During this latter phase the patients often urinate, the pupils are dilated and do not react to light and there is a positive Babinski. As mentioned before, it simulates an epileptic attack. After the attack, the patients in most cases are confused and dizzy and fall into a deep coma-like sleep which lasts from five t6 ten minutes. They again regain consciousness but are quite exhausted and fall asleep again and five to six hours after the attack they are allowed to take nourishment and move around. No definite number of convulsive seizures has been fixed as the curative number. In some cases the patients were better after 2 or 3 attacks; other required 25 treatments. As a general rule 15 attacks are induced even in patients who are not improving. If the patient has had an apparent remission it is well to give 3 or more convulsions despite this. Von Meduna pointed out that the blood picture changes under metrazol therapy. The lymphocytes are reduced and the neutrophiles are increased. This was particularly so in patients who showed a remission. Also, the urinary acidity is increased about 25 per cent while the phosphates are increased 10 per cent. The chlorides are decreased 25 per cent. The investigators called our attention to the fact that in epilepsy these findings have been observed by various authors. Even though the attack seems to be appalling, the workers feel that there is no inherent danger in this type of
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EDWARD A. STRECKER, FRANCIS
J.
BRACE LAND
treatment. Several thousand convulsions have been induced without any serious complications. Dislocation of the jaw has occurred and occasionally a dislocation of the shoulder. In von Meduna's report he chronicles the results of treatments in 110 patients, of whom 54 had a remission. This is roughly about 50 per cent. As stated above, the remissions in patients untreated range around 11 to 15 per cent. If we were to take the patients who were ill less than one year, von Meduna's figures would show a remission as high as 90 per cent. Von Meduna's experiments have been corroborated by many other investigators. In America, Finkelman, Steinberg and Liebert of Elgin, Illinois, reported on the treatment of 66 patient's with dementia praecox by the administration of metrazol. They reported that 85 per cent of the patients whose symptoms were . less than six months in duration had a remission. The rate of remission, they felt, was invariably proportionate to the duration of the psychosis. They say that if the psychosis has lasted more than three years, the anticipation of a remission is slight. Patients who had been ill longer than eighteen months required larger doses of metrazol and more treatments. The type of dementia praecox that has the greatest tendency to remit with this therapy is the catatonic followed closely by the paranoid. It will be remembered that the paranoid type responds best to insulin shock. The following contraindications to metrazol therapy are listed: Failing or decompensating cardiovascular system, acute infectious diseases, and pulmonary diseases. Other investigators claim that severe anemia or cachexia, menstruation, history of cranial injury with subsequent unconsciousness should be added to the list of contraindications. The rate of injection of the metrazol is also important. It should be given at the rate of 0.1 cc. every ten seconds. The same dose of the drug given rapidly will produce convulsions which will not occur if the injection is given slowly. Wahlmann in Germany remarks that in hebephrenic cases it is difficult to judge improvement, but 3 of these patients were apparently improved and discharged from the hospital and at the time of writing had not returned. He also noted that the patients who reacted more severely to metrazol showed a greater degree of improvement, that is, that im-
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provement seemed to depend directly on the degree of convulsions produced. In recent literature we find that von Meduna and Sakel both claim credit for priority in the use of convulsions in the treatment of schizophrenia. Von Meduna points out that Sakel very carefully avoided allowing his patients to go into convulsions and that other investigators warned about it also. Sakel contends that he also used camphor and metrazol to provoke epileptic convulsions as far back as 1933. Sakel says his article was written in order to avoid an unfavorable schism in the pharmacological shock therapy. Ziskind reviews some of this quarrel and says that Sakel regards convulsions in insulin therapy as "heavy artillery" and prefers to use "light artillery" even though he recognizes that favorable effects sometimes follows major seizures. He points out that according to Grayzel convulsive paroxysms in rabbits cause cerebral damage. When no convulsions followed the insulin injections there were no microscopic pathological changes in the brain; after slight convulsions there were minimal changes; after one or more severe convulsions there were definite anatomic lesions. The greater the number and the more prolonged the convulsions the more severe were the lesions and among other changes there were small zones of focal necrosis in the cerebral cortex. The dose of insulin was comparable to that used in schizophrenia. Individual reactions with insulin should preferably be avoided. Ziskind remarks: "What bearing these histopathologic observations have on convulsant therapy with camphor or Metrazol can only be a matter of conjecture. The question is worthy of further study." While we have been using metrazol therapy in the treatment of dementia praecox, as yet we do not have a sufficient number of cases to speak with any authority. BIBLIOGRAPHY GENERAL
Strecker and Ebaugh: Practical Clinical Psychiatry, 4th ed., P. Blakiston's Son and Co., Inc., Philadelphia, 1937. INSULIN
Sakel, Manfred: Neue Behandlungsmethode der Schizophrenie, Moritz PerIes, Wien and Leipzig, 1935.
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Sakel, Manfred: Section on Neurology and Psychiatry, New York Academy of Medicine, Jour. Nerv. and Ment. Dis., Vo!. lxxxv, May, 1937, pp. 561-580.
Braceland and Hastings: Insulin Shock Therapy in Schizophrenia, Penna. Med. Jour., Vol. 41, No. 1, pp. 7-14, October, 1937. Wortis, J oseph: Sakel's Hypoglycemic Insulin Treatment of Psychoses, Jour. Nerv. and Ment. Dis., Vo!. lxxxv, May, 1937, pp. 581-594. Glueck, Bernard: Jour. Amer. Med. Assoc., 107: 1029-1031, Sept. 26, 1936. Sakel, Manfred: A New Treatment of Schizophrenia, Amer. Jour. Psychiatry, 93 (No. 4): 829-841, June, 1937.
METRAZOL von Meduna: The Convulsive Therapy of Schizophrenia, Psych. Neuro!. Wchnschr., 37: 317, July, 1935. Wahlmann: The Treatment of Psychoses with Metrazol, Psych. Neuro!. Wochenschr., 38: 78, Feb. 15, 1936. Kriiger: The Treatment of Schizophrenia by von Meduna's Method, Psych. Neuro!. Wochenschr., 38: 135, 1936. Friedman: Irritative Treatment of Schizophrenia (Review of 20 Cases), Amer. Jour. Psych., Sept., 1937, Vo!. 94, No. 2. Finkelman et al... The Treatment of Schizophrenia with Metrazol by the Production of Convulsions, Amer. Jour. Med. Assoc., 110 (No. 10): March 5, 706, 1938.
Ziskind, E.: Convulsions During Insulin Therapy in the Psychoses, Jour. Amer. Med. Assoc., 110 (No. 12): 915, March 19, 1938. von Meduna vs. Sakel: Jour. Nerv. and Ment. Dis., 87 (No. 2): 133-155, Feb., 1938.