http://exhibits.library.stonybrook.edu/mfp/files/original/0cb0657cbbdab38351d56e14b15f8cbf.pdf 7766c5312815a1dcb5171a3528e92d6e PDF Text Text Reprinted from The Journal of the American Medical Association April 12, 1958, Vol. 166 Copyright 1958, by American Medical Association COMPARATIVE STUDY OF CI] LORPROMAZINE AND INSULIN COMA IN THERAPY OF PSYCHOSIS Max Fink, M.D., Robert Shaw, M.D., George E. Gross, M.D. and Frederick S. Coleman, M.D., Glen Oaks, N. Y. With the advent of “newer” drugs for the treatment of psychiatric illnesses and the concomitant awareness that the effectiveness of insulin coma therapy was limited, a control drug therapy—insulin coma study was undertaken. Preliminary trials with various medicaments available in 1954 demonstrated chlorpromazine to be potent and relatively safe. Concurrent reports had noted its value in schizophrenic illnesses, and it was therefore selected as the experimental agent. The study was designed to assess the therapeutic efficacy and indications for intensive chlorproma: zine therapy, compared to classic insulin coma therapy, an in open-ward, voluntarily hospitalized psychiatric population. Subjects and Method All patients referred for insulin coma therapy during the period Sept. 1, 1955, to Dec. 31, 1956, were observed. Supervising psychiatrists made the recommendation for insulin coma therapy independent of the research group. Their criteria for referral were those implicitly held by the hospital administration and were not altered for this study, Randomly selected patients were placed on chlorpromazine therapy instead of insulin coma therapy. This selection was made by the psychiatrist in charge of the insulin therapy unit without prior notice of the referring therapist or the supervising psychiatrist. Sixty patients were referred for insulin coma therapy during the study period, and half of these received chlorpromazine. Insulin Coma.—The standard technique of Sakel for insulin coma was used. All patients received 50 comas, each of a duration of at least one hour, at the physiological level of Babinski reflex, absent lid reflex, or deeper. Recovery was induced by gavage and occasionally by intravenous administration of glucose. Treatments were given five times weekly for a period of three to four months. Chlorpromazine.—To establish an equivalent group, chlorpromazine was given for at least three months. Dosages were determined by the research team and were rapidly increased until well-defined physiological effects were observed. These included rigidity, drooling and fixed facies, seizures, or severe dermatitis. In most instances this was achieved below 1,400 mg. daily, although dosages were increased to 3,600 mg. in one patient. In each instance, the drug dosage was slowly reduced until From the Department of Experimental Psychiatry, Hillside Hospital. The effectiveness of chlorpromazine was compared with that of insulin coma in 60 patients referred for insulin coma therapy. One- half the group, selected on a random basis, received chlorpromazine by mouth for at least three months in doses adjusted so as to fall just short of toxicity in the individual patient,- this dosage varied from 300 mg. to 2,000 mg. daily, with a median of 800 mg. The insulin coma was induced by a standard technique 50 times in each patient. Although many minor differences were noted in comparing the effects of these two methods of treatment, the ultimate results at the time of discharge were essentially the same for the two groups of patients. Neither treatment affected the basic schizophrenic process, but chlorpromazine had the advantage of being safer, easier to administer, and better suited to long-term management. a maintenance dose, just under that producing toxicity, was obtained. This varied from 300 mg. to 2,000 mg. daily with a median of 800 mg. To determine the comparability of the subjects in the random sampling procedures used in this study, the groups were compared as to their psychi— atric diagnoses and ages. Table 1 shows a comparison of the groups as to diagnoses and demonstrates an equal distribution of subjects in each category. In the analysis of the age distribution, the median age for patients subjected to insulin coma was 24 years, with a range of 17 to 38; the median age for patients receiving chlorpromazine was 28, with a range of 19 to 42. Here, too, the distribution shows no significant difference. For both treatment groups, behavioral observations were made by the research staff at weekly intervals. After completion of the treatment period, reports of the patients’ behavior were obtained from the therapist and supervising psychiatrist. The “improvement” rating was determined by the medical director at the patient’s discharge conference and was based on the fourfold scale of recovered, much improved, improved, and unimproved. Neither the authors nor the supervisor of the insulin therapy unit participated in these evaluations. �THERAPY OF PSYCHOSIS—FINK ET AL. Vol. 166, No. 15 Observations Clinical Observations—The following clinical effects were noted in patients who received chlorpromazine and in those subjected to insulin coma therapy. Chlorpromazine: Chlorpromazine induced motor retardation in all subjects. Overactive, destructive behavior rapidly disappeared, and patients became more tractable, less negativistic, and less violent. The nurses’ and therapists’ records noted patients as “less easily excited and frightened,” “cooperating TABLE l.—P.s-ychiatric Psychoneuxosis ....................... Schizophrenia, paranoid ..... Schizophrenia, catatonic ............ Schizophrenia, mixed ................. Schizophrenia, hebephrenic .......... Manic-depressive psychosis ........... Diagnoses Insulin Coma Chlorpromazine 1 2 10 7 10 7 8 3 1 6 2 3 better in ward activities,” and “less restless and less panic-ridden.” One-third of the patients were more sociable and less seclusive and were noted to care for themselves in a more presentable fashion. In instances where severe motor symptoms supervened, however, the patients were less able to care for themselves; they became sloppy and failed to dress themselves. Such periods were usually short and could be significantly modified either by a reduction in drug dosage or by anti-Parkinsonism drugs. Affective changes during chlorpromazine treatment were varied. Four patients became increasingly agitated, tense, and tremulous and either refused to continue on the drug regimen or were induced to do so only with difficulty. Such an affective “storm” appeared early in the treatment and persisted. In four other patients, depressive symptoms were relieved with an increase in affective lability and responsivity. Depressive ideation increased, associated with complaints of insomnia and anorexia in two patients. The medication was continued, however, with an eventual alleviation. In most patients, mood changes were small. Ideation was dramatically altered during the period of chlorpromazine therapy in 12 patients. Eight had a loss or a significant diminution of their psychotic ideation. In five, hallucinatory and referential experiences were no longer reported even on inquiry, and, in three others, delusional ideas were less prominent. In one patient, phobias were relieved and the patient could once again participate in ward activities. In another, hypochondriasis was sufficiently modified to permit a more meaningful relationship between therapist and patient. In one patient, paranoid ideation became more prominent. This was associated with increasing anxiety and panic during drug administration and resulted in discontinuation of the drug regimen. 1847 Insulin Coma: The clinical observations in this group were similar to those reported by others.‘ Alteration in behavior was prominent in all patients once repeated comas were induced. Overactive, hostile behavior rapidly diminished and was replaced by alternating periods of somnolence, irritability, and withdrawal. In most patients, nausea, abdominal distress, belching, sweating, and lassi— tude were common sequelae each afternoon and assumed prominence in the recorded reports. These symptoms often interfered with the patients’ ability to care for themselves, and they became unkempt in their dress. Changes in ideation appeared slowly during the course of therapy. In eight patients, paranoid and delusional thoughts became less prominent, dis— appearing in these on direct inquiry. Suicidal and outWardly directed destructive thoughts were modified in three patients, only to recur in each at the end of the treatment period. Mood changes were small. Increasing agitation, tension, and panic were reported in three patients, leading in two to a refusal of further therapy. In one depressed patient, relief of depressive symptoms was noted early in the treatment and was sustained. In the usual practice of the treatment unit, con— current electroconvulsive therapy was instituted when behavioral control by insulin coma alone was limited. In six patients, such combined treatment was instituted primarily because of a continuation of overactive or delusional ideation. There was, in four instances, a well defined alteration in behavior, but this was unsustained. None of these patients was rated as improved on discharge. Discharge Evaluation—All patients were dis— charged from the hospital within four months of the end of treatment. Table 2 lists the hospital discharge evaluations for patients treated with chlorpromazine and insulin coma. Ratings in Patients Treated with Chlorpromazine and Insulin Coma TABLE 2.-—Discharge Treatment ........................ ........................ Recovered, no. Much improved, no. .................. Improved, no. Iinimproved, no. ..................... Chlorpromazine Insulin Comafi 2 0 4 17 5 15 7 10 Included in the group of patients treated with chlorpromazine who were rated as unimproved were four who received inadequate course of therapy (less than one month) because of complications of the therapy. Of the 10 patients treated with insulin coma who were rated as unimproved, four had inadequate courses of therapy, two because of complications (seizures and prolonged coma), one be— cause she became more disturbed, and one because of administrative transfer to another facility. �‘ THERAPY OF PSYCHOSIS—FINK ET AL. 1848 It apparent that there is no difference in the clinical evaluation at the time of discharge between the group receiving insulin coma and that receiving chlorpromazine. To determine whether this sample was biased because of its small number, we compared these discharge ratings with a similar group treated in this hospital in 1950 and previously reported.2 In table 3, the discharge ratings for both is TABLE 3.-—Discharge Ratings Compared for 1950 and 1956 ............................. ....................... Improved, % ......... .................... Unimproved, % ........................... Recovered, % Much improved, % _ Present Group (30 Subjects) 1950 Group (48 Subjects) 0 14 17 19 42 50 33 ‘25 years are compared. The percentage improvement rates for each category are not significantly different. Toxicity and Complications—Patients receiving chlorpromazine and those subjected to insulin coma therapy were compared as to toxic reactions and complications, with the following effects noted. Chlorpromazine: Inherent in the design of this study were high doses of chlorpromazine, pushed to a level producing symptoms of toxicity. In this context, all patients developed significant drug effects. Rigidity of extremities, accompanied by a decrease in facial expression, drooling, and festination, was frequently observed. In three instances, rigidity appeared as drug dosage was reduced. Most patients became drowsy, retarded, and less active in ward activities. In four patients increased tension, agitation, restlessness, and excitement supervened, leading to a discontinuation of the drug regimen in two. Seizures occurred spontaneously in three patients. Pretreatment electroencephalograms had manifested no dysrhythmia, and no history of seizures had been elicited. In each, the drug medication was reduced, and seizures did not develop at the lower dosages. Dermatitis was a frequent complication. All patients developed a transient erythema to mild solar radiation. Severe intractable skin reactions occurred in three patients, with resultant discontinuation of drug therapy in two. In the third, promazine hydrochloride therapy was substituted for chlorpromazine, with a relief of the dermatitis. The behavioral effect of the promazine was indistinguishable in this patient from that noted in patients receiving chlorpromazine. In this group, no patient developed clinical jaundice. This complication has been variously reported as occurring in less than 0.5% of subjects treated. In the preliminary studies at Hillside Hospital, 3 patients of a group of 20 developed transient clinical jaundice. J.A.M.A., April 12, 1958 Electroencephalograms were obtained in 20 of the patients who received chlorpromazine. With increasing doses, the modulation of the record became more irregular in each. A moderate amount of low-voltage 4-7 cps delta and theta activity was induced, and this activity was exaggerated by hyperventilation. There was a suggestive relationship between the degree of the induced slow-wave activity and the drug dosage. Insulin Coma: The complications of insulin coma therapy in this series were not unusual. Insulin resistance was noted only once and was eventually overcome by the method of alternating dosages. Prolonged reactions occurred in three patients. In each, neurological examination and electroencepha— lography demonstrated signs of persistent central nervous system dysfunction for at least 10 days. Aphasia, hemiparesis, and paresthesias were frequent in five patients and transient in eight others. Seizures occurred in five patients and were recurrent in three. Frequent secondary reactions, nausea, vomiting, abdominal distress, sweating, pallor, lassitude, and generalized weakness occurred in all patients with varying frequencies. The complications of both forms of treatment are listed in table 4. Certain effects, such as dermatitis and hypotension, secondary reactions, and prolonged coma are individual for each therapy, and seizures, agitation, and refusal of therapy were noted with both regimens. The frequencies of these are not significantly different. Effects on Psychotherapeutic Relationship—Pa— tients were referred for insulin coma therapy after a period of verbal relationship therapy. Such referral implies a failure of interpersonal communication. TABLE 4.-C0mplicati0ns of Treatment with Chlorpromazine and Insulin Coma Treatment _______./\—————5 Agitation and panic .................. Dermatitis, severe ..................... ............................... Refusal of further therapy .......... Hypotension .......................... Secondary reaction, frequent ........ Prolonged coma (>6 hr.) ............ Insulin resistance ..................... Seizures Chlorpronmzine Insulin Coma 4 3 3 3 2 5 2 2 6 3 . . . 1 Chlorpromazine: During the period of effective drug action, 15 of the patients treated with chlorpromazine were described by the therapist in response to an inquiry as “more accessible,” “speaking more freely,” and “more amenable to psychotherapy.” The behavioral changes could be classified in two groups: subjects in whom tension and preoccupation with somatic symptoms became much less, and those in whom hallucinatory or delusional preoccupations ended. Such changes in �I Vol. 166, No, 15 THERAPY OF PSYCHOSIS—FINK ET AL. in— described as an we1e frequuitly '.*‘-1;welationship stww‘arease in “contact In 13 subjects, psychotherapy either was still‘not feasible” or had become less feasible because of increasing uncontrolled tension, anxiety, or preoccupation with the side-effects of wthe drug regimen. Insulin Coma: Similar observations were made in the patients treated with insulin. Of the 30 patients, 7 were noted to be less tense and less anxious during therapeutic sessions. The theiapists noted that the patient “verbalized more freelv” and was more aware of his environment.” Four patients were specifically treated with a “modified anaclitic” approach. In each instance, this relationship was unsustained during treatment and the therapists resorted to more conventional tactics. In the remaining patients (19), while supportive, educational, and environmental manipulating techniques were applied, the therapists were no more successful than prior to insulin therapy. In 11 patients, the physiological effects of the treatments (secondary reactions, sweating, nausea, vomiting, and weight gain) were reported as interfering with psychotherapeutic attempts. Comment Clinical Considerations—In these patients, nei— ther chlorpromazine in high therapeutic doses nor insulin coma specifically modified the psychotic had of 88% these Since a diagpatients process. nosis of schizophrenic illnesses, we concluded that neither treatment has a specificity in altering the schizophrenic process. When given in adequate dosage, however, both treatments are potent methods for the alteration of behavior. In the discharge evaluations, the treatments are similar. In only 20% of the patients were induced behavioral patterns persistent, with the rating “much improved” or “recovered.” For the others, the induced behavioral changes were transient or minimal. Since these therapies fail to induce a recovery from the psychotic process, consideration should be given to their ameliorative, palliative, and supportive aspects. Symptomatic relief was frequent but generally limited to the treatment period. Patients were made uncomfortable by both therapies, however, and the complications and toxic effects have already been noted. In assessing the role of concomitant psychotherapy, there is little advantage in either therapy. Both methods were said to enhance relationship therapy, although the therapists’ evaluations favored chlorpromazine therapy. Excluding those who deveIOped increased agitation, patients were more comfortable, more alert, and physically better able to discuss their feelings and experiences while on chlorpromazine treatment. It is clear that“interpretive” psychotherapy is not enhanced, rather, 1849 supportive, educative, reorienting, and directive types of therapy are. When there is a modification of agitated, hallucinatory, depressed, manic, or aggressive behavior, both the therapist and the patient are more comfortable and better able to discuss the reality aspects of the life situation. Therefore, in this context, the ease of administration and the possibility of continued maintenance of chlorpromazine in an outpatient setting assume decisive significance. To maintain such therapy after discharge and continue thereby the relationship established in the hospital setting may be an important element in sustaining the behavioral changes induced by hospitalization. Other Studies.—While many reports of the treatment of psychosis by chlorpromazine have appeared, we are aware of only one similar comparative study. Boardman, Lomas, and Markowe,3 after a review of the problem, reported a study of 100 patients randomly divided into two groups of 50 and treated with either insulin coma or chlorpromazine. The chlorpromazine dosage was lower than that used in the present series (average 300 mg), but the drug period (three months) was the same. Their observations are directly comparable to this study. They reported no difference either in discharge evaluations or in symptom assessments for either treatment group. The patients treated with chlorpromazine, however, remained in the hospital an average of 6.2 weeks less than the subjects treated with insulin. This was a significant difference between the groups. They concluded, “There is inconclusive evidence that chlorpromazine has advantages over insulin in the treatment of schizophrenia [but] insulin has disadvantages in the form of greater danger and more unpleasantness for the patients and greater strain on the nurses. Chlorpromazine is the first treatment of choice in schizophrenia, but this conclusion is based on the immediate results of treatment and has not yet been confirmed by an adequate follow-up study.” Boardman and his co-workers emphasize the problem of evaluating the therapeutic efficacy of insulin coma. They note a number of reports that raise doubts as to the efficacy of insulin coma therapy in schizophrenia. Bourne,4 in an extensive review of the merits of insulin therapy in schizophrenia, concluded, “There is no proof of any specific therapeutic effect, and the long term prognosis is in no way influenced.” The recent observations of insulin treatment of 5 schizophrenia by Ackner, Harris, and Oldham are relevant. In a carefully controlled study, young schizophrenic patients were randomly treated either by insulin or by barbiturate coma in the same ward and under similar conditions. Evaluations of results were made by psychiatrists without knowl- �1850 THERAPY OF PSYCHOSIS—FINK ET AL. edge of which treatment the patients received. The authors noted a similar outcome, whether the loss of consciousness was induced by a barbitufate or by insulin, and concluded that insulin was not a specific therapeutic agent in the outcome. In the follow-up studies done in this hospital,2 the therapeutic results of insulin coma therapy were disappointing. Patients referred for insulin coma had the longest period of hospitalization (6.5 months, as against 6.04 with'psychotherapy and 4.95 with electroshock), the poorest discharge‘ rating (33% recovered and much improved as against 63% with psychotherapy and 67% with electro— shock), and, within four years, a 50% rehospitalization rate (compared to 33% with psychotherapy and 29% with electroshock). While these observa— tions reflect the idea that the more severely ill patients are referred for insulin coma, they also support the belief that insulin coma is not a specific treatment for the patients referred. From these reports we would conclude that, despite considerable study and the passage of many years, insulin coma therapy has not been shown to induce persistent behavioral changes more frequently than other nonspecific, less dangerous, and less expensive therapies. To the list of alternate therapies of limited value in the management of psychosis we may now add Chlorpromazine, not— ing, however, its advantage of lesser risk and ease of administration. Dosage of Chlorpromazine.—F0r the purpose of assuring an adequate level of Chlorpromazine dosage for evaluation, the amount of medicament given was increased in all subjects to t0xic levels. This level was too high for its behavioral effects, as evidenced by the reduction in all responsive cases to maintenance levels of 300 to 2,000 mg. It is our impression that Chlorpromazine affects the function of the central nervous system (as evidenced by changes in modulation and per cent time delta in the electroencephalogram and the systemic phenomena of rigidity and lassitude) and results in a nonspecific alteration in behavior.6A Such behavioral change is varied and is dependent on a variety of factors, of which the personality organization and the expectancy of the milieu are significant. In this context, the induction of a state of altered cerebral function is a necessary prerequisite to behavioral change. The only assurance of achieving a therapeutic level, therefore, is the appearance of toxicity and a lowering of dosage from that level to a maintenance dose. The effects of rigidity, drowsiness, and lassitude, therefore, are necessary concomitants of the therapy and should be induced in all patients in whom a therapeutic effect is desired. In instances where an affective “storm” supervenes, continuation of therapy at ].A.M.A., April 12, 1958 higher levels, with concomitant administration of trihexyphenidyl hydrochloride (Artane) and benztropine (Cogentin) methanesulfonate should be considered. Such an attitude in therapy is comparable to the application of digitalis in cardiology and to the present concept of the mode of action of electroshock therapy.6 Summary In a.study of patients referred for insulin coma therapy in an open-ward, voluntary psychiatric hospital, patients received randomly either insulin coma therapy or intensive Chlorpromazine therapy. Chlorpromazine was found to be as effective in modifying psychotic behavior as insulin coma therapy. There was no difference in the improvement rating on discharge, incidence of complications, or effects on the psychotherapeutic relationship for either therapy. In comparison to insulin coma, Chlorpromazine is safer, easier to administer, and lends itself to long—term management. Patients receiving chlorpromazine therapy are more comfortable than those receiving insulin coma. No evidence has been educed that either therapy has altered the basic schizophrenic process, nor is there any evidence that there is greater specificity of either form of therapy for schizophrenic illnesses. 75—59 263rd St. (Dr. Fink). This study was supported by the Board of Directors" search Fund of the Society of the Hillside Hospital. Re— The chlorpromazine used in this study was supplied as Thorazine by Smith, Kline & French Laboratories, Philadelphia. The promazine hydrochloride used in this study was supplied as Sparine by Wyeth, lnc., Philadelphia. References and Hoch, P. H.: Shock Treatments, Psychosurgery, and Other Somatic Treatments in Psychiatry, ed. 2, New York, Grune and Stratton, lnc., 1952. 2. Rachlin, H. L., and others: Follow-up Study of 317 Patients Discharged from Hillside Hospital in 1950, J. Hillside Hosp. 5:17-40 (Jan) 1956. 3. Boardman, R. H.; Lomas, J.; and Markowe, M.: Insulin and Chlorpromazine in Schizophrenia: Comparative Study in Previously Untreated Cases, Lancet 2:487—494 (Sept. 8) 1. Kalinowsky, L. B., 1956. 4. Bourne, H.: Insulin Myth, Lancet 2:964—968 (Nov. 7) 1953. 5. Ackner, B.; Harris, A.; and Oldham, A. J.: Insulin Treatment of Schizophrenia: Controlled Study, Lancet 2: 607-611 (March 23) 1957. 6. Fink, M., and Kahn, R. L.: Relation of EEG Delta Activity to Behavioral Response in Electroshock: Quantitative Serial Studies, A. M. A. Arch. Neurol. 81 Psychiat. 78:516— 525 (Nov.) 1957. 6A. Fink, M.: Unified Theory of Action of Physiodynamic Therapies, J. Hillside Hosp. 6:197-206 (Oct.) 1957. �Printed in U. S. A. �Cjéz,,4./rv./¢ COMPARATIVE STUDY OF CHIDRPROMAZINE AND INSULIN COIvIA IN THE THERAPY 0}”? PSYCHOSIS *- Max ColemanAM.D. Fink M.D., Robert Shaw M.D., George E. Gross M.D., and Frederick S. * From the Department of Experimental Psychiatry, Hillside Hospital, Glen Oaks, N.Y. Supported by the Board of Directors' Research Fund of the Society of the Hillside Hospital. 7-22-57: IV �Comparative Study of Chlorpromazine and Insulin Coma in the Therapy of Peychosis for the treatment of psychiatric illnesses, and the concomitant awareness that the effectiveness of insulin With the advent of "newer" drugs limited, a control drug therapy-insulin coma study was undertaken. Preliminary trials with various medications available in l95h demonstrated chlorpromazine to be potent and relatively safe. Concurrent reports coma therapy had noted was its value in schizophrenic illnesses, and it was therefore selected as the experimental agent. study was designed to assess the therapeutic efficacy and indications for intensive chlorpromazine therapy compared to classical insulin coma therapy in an openaward, voluntary hospitalized psychiatric population. The Subjects and Method All patients referred for insulin coma therapy during the period September 1, 1955 to December 31, 1956 were observed. Supervising psychiatrists made the recommendation for insulin group. Their criteria for referral coma therapy independent of the research were those implicitly held by the beepital administration, and were not altered for this study. Randomly selected patients were placed on chlorpromazine therapy instead of insulin psychiatrist in charge of the insulin therapy unit, without prior notice of the referring therapist or the super- coma. This selection was made by the vising psychiatrist. Sixty patients were referred for insulin during the study period, and half received chlorpromazine. coma therapy �.2... a) Insulin Coma: The patients received standard technique of Sakel was used. All 50 comes, each of a duration of at least one hour at the physiologic level of Babinski reflex, absent lid reflex, or deeper. Recovery was induced by gavage and occasionally by intravenous glucose. Treatments were given five times weekly, b) Chlorpromazine: was given team and To for a period of B-h months. establish an equivalent group, chlorpromaziner for at least three months. Dosages were determined by the research were rapidly increased until well defined physiologic effects were observed. These included rigidity, drooling and fixed facies, seizures or severe dermatitis. In most instances this was achieved below lhOO mgm daily patient. In each instance, slowly reduced until a maintenance dose, just under although dosages were increased to 3600 the drug dosage toxicity, was was obtained. a median of 800 mgm in This varied from 300 one mgm to 2000 mgm daily with mgm. To determine the comparability of the subjects resulting from the in this study, the groups were compared as to their psychiatric diagnoses and ages. Table I compares both groups as to diagnoses, and demonstrates an equal distribution of subjects in random sampling procedures used each category. ‘M% c: such-on .m & Chlorpromazine supplied as "Thorazine" through courtesy of Smith, Kline 3 French, Inc. �.3TABLE I PSYCHIATRIC DIAGNOSES Insulin Psychoneuresis Coma Chlorpromazine 1 2 10 10 Schizophrenia, Catatonic 7 7 Schizophrenia, Mixed 8 6 Schizophrenia, Hebephrenic 3 2 HaniooDepressive Psychosis l 3 Schizophrenia, Paranoid In the analysis of the age distribution, the patients was 21; for the insulin with a range of 17 to 38 ; while the chlorpromazine patients had a median age of 28 and a range of 19-122. shows no median age Here, too, the distribution significant. difference. For both treatment groups, behavioral observations were made by the research staff at weekly intervals . Following completion of the treatment period, reports of the patients' behavior were obtained from the therapist and supervising psychiatrist. Medical Director The "improvement" at the patient's Discharge four~fold scale of recovered, rating was determ‘ned by the Conference and was based on the much improved, improved and unimproved. None of the authors, nor the supervisor of the insulin therapy unit, participated in these evaluations. �Observatigns 1. Clinical Observations all subjects. Overactive, destructive behavior rapidly disappeared, patients in ghlgrpromazine: Chlorpromazine induced motor retardation a) became more tractable, less negativistic and less violent. and The therapists' records note patients as "less easily excited and frightened," "cooperates better in ward activities," and "less restless and less panic ridden." One-third of the patients were more sociable and less nurses' and seclusive, and were noted fashion. In instances patients were to dress. modified to care for themselves in a more presentable where severe motor symptoms supervened, however, the less able to care for themselves; Such periods were usually short, became sloppy and significantly and could be either by a reduction in drug dosage or by anti-Parkinson drugs. Affective changes during chlorpromazine were varied. became failed increasingly agitated, tense continue on and tremulous and patients either refused to the drug regimen or were induced only with difficulty. affective "storm" appeared early in the treatment other patients, depressive affective lability and symptoms were medication was persisted. In four relieved, with an increase in patients. The continued, however, with an eventual alleviation. In most mood changes were Ideation and Such an reaponsivity. Depressive ideation increased, assoc- iated with complaints of insomnia patients, Fbur was and anorexia, in two small. dramatically altered during the period of chlorpromazine therapy in twelve patients. Eight had a loss or a significant diminution of their psychotic ideation. In five, hallucinatory and referential experiences �.5. inquiry were no longer reported even on once in three others, delusional patient, phobias were relieved and the again participate in ward activities. In another, ideas were less prominent. In patient could and One hypochondriasis was sufficiently modified to permit a more meaningful relatedness of therapist became more prominent. and patient. In one patient, paranoid ideation This was associated with increasing anxiety and panic during drug administration, and resulted in discontinuation of the drug regimen. b) Insulin similar to those reported prominent in all patients clinical observations in this group'were others (1). Alteration in behavior was The Coma: by once repeated comes were induced. hostile behavior rapidly diminished, of somnolence, irritability and and was replaced by Overactive, alternating periods withdrawal. In most patients, nausea, distress, belching, sweating and lassitude were common sequellae each afternoon, and assumed prominence in the recorded reports. These abdominal symptoms often interfered with the patient's ability to care for themselves, and fliey became unkempt in their dress. in ideation appeared slowly during the course of therapy. In eight patients, paranoid and delusional thoughts became less prominent, disappearing in these on direct inquiry. Suicidal and outwardly directed destructive thoughts were modified in three patients, only to recur in each Changes at the end of the treatment Mood period. changes were small. Increasing agitation, tension and panic were reported in three patients, leading in two to a refusal of further therapy. In one depressed patient, relief of depressive symptoms were noted early in �-6the treatment, and was sustained. In the usual practice of the treatment unit, concurrent electroconvulsive therapy was instituted when behavioral control by insulin limited. In six patients, such combined treatment was coma alone was instituted primarily because of a continuation of overactive or delusional ideation. There was, in four instances, a well defined alteration in behavior, but this sustained. None was un- of these patients was rated as improved on discharge. 2. Discharge Evaluation All patients were discharged from the hospital within four months of the end of treatment. Table for both the chlorpromazine and II lists the hospital discharge evaluations insulin coma TABLE treated patients. I}; DISCHARGE RATINGS Chlorpromazine Insulin 1. Recovered 2 O 2. much Improved h 5 3. Improved 17 15 h. Uhimproved 7 10 Coma Included in the unimproved group of chlorpromazine patients are four who received inadequate course of therapy (less than one month) because of complications of the therapy. four Of the ten unimproved insulin had inadequate courses of therapy (seizures, prolonged - coma patients, two because of complications coma), one because she became more fourth by administrative transfer to another facility. disturbed, and the �-7. It is apparent that there is no difference in the clinical evaluation at the time of discharge between the insulin coma treated groups. To determine whether this sample and the chlorpromazine its was biased because of small number, we compared these discharge ratings with a similar group treated in this hospital in 1950 and previously reported (2). In Table III, the discharge ratings for both years are compared. TABLE Present Group 1950 Group (30 subjects) (h8 subjects) 0 1h% 17% 19% Improved 50% h2% Ikrhmproved 33% 25% Recovered Much The III Improved percent improvement rates for each category are not significantly different. 3. Toxicitx and Complications a) ghlorpromazine: Inherent in the design of this study were high doses of chlorpromazine, pushed to symptoms of toxicity. In this context, all patients developed significant drug effects. Rigidity of extremities, accom— in facial eXpression, drooling and festination was frequently observed. In three instances, rigidity appeared as drug dosage was reduced. Host patients became drowsy, retarded, and less active in ward panied by a decrease activities. In four patients increased tension, agitation, restlessness and excitement supervened, leading in two. to a discontinuation of the drug regimen �-8Seizures occurred spontaneously in three patients. Pre-treatment electroencephalograms had manifested no dysrhythmia and no history of elicited. In seizures did not develop at the seizures each, the drug medication was reduced, and had been lower dosages. Dermatitis was a frequent complication. All patients developed a transient erythema ato mild solar radiation. Severe intractable skin reactions occurred in three patients, with resultant discontinuation of drug therapy in two. In dze third, promazine* therapy was substituted for chlorpromazine, with a was relief of the dermatitis. The indistinguishable in this patient behavioral effects of the promazine from that noted for the chlorpromazine group. In this group, no patient developed clinical jaundice. This complication has been variously reported as occurring in less than %% of subjects treated **. Electroencephalograms were obtained in twenty of the chlorpromazine patients. With increasing doses, the modulation of the record irregular in each. activity A became more moderate amount of low voltage h-7 cps delta and theta was induced, and this activity was exaggerated by hyperventilation. There was a suggestive relationship between the degree of the induced slow wave activity b) series were and the drug dosage; Insulin Coma: The complications of insulin not unusual. Insulin resistance eventually overcome by the method of coma therapy in this was noted only once, and was alternating dosages. Prolonged reactions * Supplied as "Sparine" through courtesy of Uyeth & Co. as In the preliminary studies at Hillside Hospital, three patients of a group of twenty developed transient clinical jaundice. �-9occurred in three patients. In each, neurologic examination and electroencephalography demonstrated signs of persistent central nervous system dysfunction for paresthesias at least ten days. Transient aphasia, hemiparesis, were frequent transient in eight others. were recurrent in three. Frequent in five patients, Seizures occurred in five patients, and and secondary reactions, nausea, vomiting, abdominal lassitude and and generalized weakness occurred distress, sweating, pallor, in all patients in varying frequencies. The complications of both forms of treatment are listed in Table IV. Certain effects, as dermatitis and hypotension, secondary reactions and prolonged coma are individual for each therapy, and seizures, agitation and refusal of therapy were noted in both regimens. The frequencies of these are not significantly different. TABLE IV COMPLICATIONS Chlorpromazine Insulin Agitation and Panic h 3 Dermatitis, severe 3 - Seizures 3 5 Refusal of further therapy 2 2 Hypotension 2 — Secondary reaction, frequent - 5 Prolonged Coma ( + Insulin Resistance 6 hours) 3 l Coma �.10.- h. Effects on the Psychotherapeutic Relationship In.this setting, patients are referred for insulin coma therapy after a period of verbal relationship therapy. Such referral implies a failure of interpersonal communication. During the period of effective drug action, treated patients were described by the fifteen of the chlorpromazine— therapist in re6ponse to an inquiry as "more accessible," "Spoke more freely" and were "more amenable to psychotherapy." subjects in The behavioral changes could be classified into two groups: whom tension and preoccupation with somatic symptoms became much hallucinatory or delusional preoccupations ended. Such changes in relationship'were frequently described as an increase in "contact." In thirteen subjects, psychotherapy was either still "not feasible" less, and those in whom less feasible because of increasing, uncontrolled tension, anxiety or preoccupation with the side effects of the drug regimen. Similar observations were made in the insulin treated patients. Of the thirty patients, seven were noted to be less tense and less anxious during or had become therapeutic sessions. more freely" The therapists noted that the patient "verbalized and "was mere aware of his environment." Four patients were specifically treated with a "modified anaclitic" approach. In each instance, this relationship was unsustained during treatment and the therapists resorted to more conventional ive, educational therapists tactics. In the remaining patients (19), while support- and environmental manipulating techniques were were no more successful than applied, the prior to insulin therapy. In eleven patients, the physiologic effects of the treatments (secondary reactions, sweating, nausea, vomiting and'weight gain) were reported as interfering with psychotherapeutic attempts. �-11Discussion 1. Clinical Considerations In these patients neither chlorpromazine in high therapeutic doses nor insulin specifically modified the psychotic process. Since 88% of these patients were diagnosed as suffering from schizophrenic illnesses, we concluded thatiieither treatment has a specificity in altering the schizocoma phrenic process. shen given in adequate dosage, however, both treatments are potent methods for u1e alteration of behavior. the treatments are similar. ioral patterns persistent In only and others, the induced behavioral Since these therapies 20% rated as of the patients were induced behav- much improved or recovered. For the transient or minimal. Chang 5 were fail to In the discharge evaluations, induce a recovery from the psychotic process, then consideration should be given to their ameliorative, palliative and supportive aSpects. Symptomatic to the treatment period. Patients relief was frequent, but generally limited were made uncomfortable by both therapies, however, and the complications and toxic effects have already been noted. In assessing the role of concomitant psychotherapy, there is advantage of either therapy. Both methods were said to enhance little relationship therapy although the therapists' evaluations favored chlorpromazine therapy. Excluding those who developed increased agitation, patients were more comfortable, more alert and physically better able to discuss their feelings and experiences while on chlorpromazine, than on insulin coma. It is clear that "interpretive" psychotherapy is not enhanced, but rather supportive, educative, re-orienting and directive types of therapy. When there is a modification of agitated, hallucinatory, depressed, manic or aggressive behavior, than both the therapist and the patient arernore comfortable and able to discuss �-12the reality aspects of the life situation. Therefore, in this context, the ease of administration and the possibility of continued maintenance of chlorpromazine in an outpatient setting assumes decisive significance. To maintain such therapy after discharge continue thereby the relationship established in the hospital setting an important element in sustaining the behavioral changes induced by and may be hospital- ization. 2. Other Studies While many appeared, we reports of the treatment of psychosis by chlorpromazine have are aware of only one similar comparative study. Boardman, Lomas and Harkowe one hundred (3), after a review of the problem, report their study of patients randomly divided into two groups of SO and treated either insulin coma or chlcrpromazine. The chlorpromazine dosage was lower than that in this series (average 300 mgm) but the drug period (3 months) was the by Their observations are directly comparable to same. no difference in the discharge evaluations, nor in this study. They reported assessments for symptom either treatment group. The chlorprcmazine treated patients, box-raver, remained in the hoslaital less than the insulin treated subjects. This was a significant difference between the groups. They concluded that: "There is inconclusive evidence that chlorpromazine has advantages over insulin in the an average of 6.2 weeks treatment of schizophrenia," but "that insulin has disadvantages in the form of greater danger and more unpleasantness on the nurses. Chlorpromazine is the phrenia, but this conClusion and has is for the patients first and greater strain treatment of choice in schizo- based on the immediate results of treatment not yet been confirmed by an adequate follow-up study." �«n13- his co-workers emphasize the problem of evaluating the Boardman and therapeutic efficacy of insulin coma. They note a number of raise doubts as to the efficacy of insulin coma reports that therapy in schizophrenia. (h), in an extensive review of the merits of insulin therapy in Boume is no proof of any Specific therapeutic the long term prognosis is in no way influenced." schizophrenia concluded that "there effect, he and recent observations of insulin treatment of schizophrenia by Harris and Oldham ( S) Aclmer, are relevant. In a carefully controlled study, young schizophrenic patients were randomly treated either by insulin or by barbit- urate coma results in the same ward and under were made by patients received. similar conditions. Phraluations of psychiatrists without The knowledge of which medication the authors noted a similar outcome whether the loss of consciousness was induced by a barbiturate or by insulin, and concluded that insulin was not a specific therapeutic agent in the outcome. In the fol] oar-up studies in this hospital (2), the therapeutic results for insulin coma therapy were disappointing. In that report, patients ferred for insulin coma had re— the longest period of hospitalization (6.50 months for electroshock), poorest discharge rating (3325 recovered. and much improved, 1?. 63:5 for psychotherapy and 67% for electroshock), and within four years, a 5015 re-hospitalization rate (compared to 33% for psychotheram and 29% for electroshock). while these observations reflect 1g 6.0).: for psychotherapy and 14.95 the observation that the more severely coma, it also ill patients are referred. for insulin supports the belief that insulin coma is not a specific treatment for the patients referred. From these reports and the passage of many we would conclude years, insulin that, deepite considerable study coma therapy has not been shown to �.mpersistent behavioral changes more frequently than other non~specific, less dangerous and less expensive therapies. To the list of alternate induce therapies of limited value in the chlorpromazine, noting, however, management of psychosis we may now add its advantage of lesser risk and ease of adninis tration . 3. Dosage of Chlorpromazine for For the purpose of assuring an adequate level of chlorpromazine evaluation, the medication This level was too high duction in was increased in all subjects to toxic levels. fox-its behavioral effects, as evidenced by the re- all responsive cases to maintenance levels of 300 to 2000 mgm. our impression that chlorpromazine affects the function of the central nervous system (as evidenced by changes in.modulation and percent time delta in the electroencephalogram and systemic phenomena of rigidity It is results in a non-Specific alteration in behavior. Such behavioral change is varied and is dependent upon a.variety of factors, of which the personality organization and the expectancy of the milieu are sigand lassitude) and nificant. In this context, the induction of a state of altered cerebral function is a necessary prerequisite to behavioral change. The only assurance of achieving a therapeutic level, therefore, is the appearance of toxicity, and a lowering of dosage from that level to a maintenance dose. The effects of rigidity, drowsiness and lassitude, therefore, are necessary concomitants of the therapy and should be induced in all patients in whom a therapeutic effect is desired. In instances uhere an affective "storm" supervenes, continuation of the drug at higher levels, with concomitant artane and cogentin, should be considered. Such an attitude in therapy is comparable to the application of digitalis in cardiology, and to the present concept of the action of electroshock therapy (6). mode of �.15Conclusions 1. In a study of patients referred for insulin open ward, voluntary insulin coma psychiatric hospital, patients coma therapy in an randomly received either therapy or intensive chlorpromazine therapy. 2. Chlorpromazine was as effective in modifying psychotic behavior as insulin coma therapy. There was no difference in the improvement rating on discharge, incidence of complications or effects on the psychoflaerapeutic relationship for either therapy. 3. In comparison to insulin administer, and lends itself to coma, dilorpromazine long term management. is safer, easier to Patients receiving chlorprcmazine therapy arernore comfortable than those receiving insulin coma. that either therapy has altered the basic schizophrenic process; nor is there any evidence that there is greater specificity of either form of therapy for schizophrenic illnesses. b. No evidence has been educed �REFERENCES l. Kalinousky, L.B. and Hoch, P.H.: Shock Treatments, Psychosurgery, and. other Somatic Treatments in Psychiatry, Grune and Stratton, 13.15. 3 1952. Rachlin, H.L., Goldman, (3.5., Gurvitz, $1., Lurie, A. and Rachlin, L.: Follow-up Study of 317 Patients Discharged from Hillside Hospital in 1950, J. Hillside Hosp. §_: 174.0, 195 6. 3. Insulin and Chlorpromazine Comparative Study in Previously Untreated Cases, Lancet, Sept. 8, 1956, pp. 1:87—1:91. Boardman, R.H., Lamas, J. in Schizophrenia - and liarkma‘e, M.: A Boume, H.: The Insulin Myth, Lancet, Nov. 7, 1953, pp. 961;~968. Ackner, B. , Harris, A. and Oldham, A.J.: Insulin Treatment of Schizophrenia - A Controller} Study, Lancet, March 23, 1957, pp. 607-6110 Fink, 1-1. and Kahn, R.L.: Relation of ETTG Delta Response in Electroshock: Quantitative Arch. Neurol. and Psychiat. (in Activity to Behavioral Serial Studies, AJ'LA. press). �January 31, 1957 Subject: Drs. From: To: - Insulin Control Chlorpromazine Max Study: Interim Report Fink, Robert Shaw, George Gross and Fred Coleman Dr. Joseph S. A. Miller, Dr. Simon Kwalwasser and the Research Committee of Medical Board Following insulin During is a summary of the observations in the control chlorpromazine- study, instituted September 1, 1955 and completed January 1, 1957. coma this period, 59 patients were referred for insulin coma Half therapy. of the group was placed, by random sampling, on chlorpromazine * therapy in- stead of insulin coma. Four patients received both insulin and chlorpromazine therapy. of the patients of therapy of less than who received chlorpromazine, seven received courses one month. patients, three had an of the 29 insulin inadequate course of therapy. I. During the period l95h—1955, preliminary PROHLEH: azime resulted in the awareness and safe. In view of the unusually poor trials of that the drug showing of was the insulin chlorpromp both potent coma populat- ion in the 1950 Fbllowaup Study (1), and the appearance of numerous articles in the psychiatric literature recommending chlorpromazine as a therapy schizophrenia, a comparative study of chlorpromazine taken. The a) - insulin for coma was under- following questions were postulated: What b) What is the clinical effect of adequate doses of chlorpromazine? is its therapeutic efficacy'when compared to insulin coma therapy? 0) ‘Ehat are the indications (and contraindications) for the use of chlorpromazine and/or insulin coma? * Chlorpromazine supplied as "Thorazine" through the courtesy of Smith, Kline and French 00., Philadelphia. Rachlin, H,L., Goldman, G.S., Gurvitz, M., Lurie, A., and Rachlin, L.: Follow—up Study of 317 Patients Discharged from Hillside Hospital in 1950, J. Hillside HOSp., _5_: 17-ho, 1956. (1) �«2. II. All patients referred for insulin SUBJECTS: coma therapy during the period September 1, 1955 and December 31, 1956 were observed. Supervising psychiatrists made the recommendation independent of the research group. Their by the hospital administration, patients made by coma therapy criteria were those implicitly held and were not were placed on chlorpromazine for insulin altered for this study. Selected therapy. selection The was random and the supervising psychiatrist of the physical therapy unit, without prior notice of the referring therapist. III. a.) Insulin nga; EETEQQ: standard technic of Sakel was used. The All patients received 50 comes, each of a duration of one hour or longer at the physiologic level flex or deeper. Recovery ous glucose. of Babinski reflex or absent was induced by gavage and lid re- occasionally by intraven- Treatments were given five times weekly, for a period of 3-h months. b.) Chlorpromazin : To establish a complementary therapeutic group, chlorpromazine was given for at least three months. Dosages were determined by the research team and were rapidly increased clear-cut physiologic effects ifest rigidity, drooling, ere dermatitis. were observed. These included and fixed clinically mans facies; or toxicity, as seizures or sev- In each instance, the drug dosage was slowly reduced a maintenance dose, until just under toxicity, was obtained. until This was maintained for the duration of the observation period. Laboratory blood counts, tests were carried out at irregular intervals liver function tests, glucose tolerance tests and included and electroenceph- alogramS. In both experimental groups, behavioral observations were made at'weekLy intervals. Following completion of the treatment period, reports of the ther- �4-3- apist and supervising psychiatrist were obtained. The rating of "improvement" Conwas that established by the Medical Director at the patient's Discharge ference. IV: RESULTS: Chlorpromazine A. l. until signs creased rapidly of was achieved in daily dosages to 3600 in mgm. 2000 mgm. one patient. of chlorpromazine was in- The dosage QEEEEE.22.22EQEEEEEEEEEEF rigidity appeared. In most instances this below lhOO mgm. although dosages were increased The maintenance dose varied from 300 mgm. to daily. 2. Clinical effects of chlorpromazine: motor retardation in all subjects. Chlorpromazine induced a Overactive, destructive behavior rapidly disappeared, and the patients were more tractable, less negativistic and less violent. The nurses' and therapists' records relate that patients are "less easily excited and frightened," "cooperates better in "less restless and less panic-ridden." ward activities," and One-third of the patients were more sociable and less seclusive, and were noted to care for themselves in a more presentable fashion. In the instances where severe parkinsonism supervened, however, the patients were less able to care for themselves; became sloppy and failed to dress. by Such periods were short or could be significantly modified anti-parkinson drugsn Affective changes during chlorpromazine were varied. In four instances, the patients became increasingly agitated, tense, tremnlous and either refused to continue on the drug regimen or were induced only with difficulty. Such an persisted. In four other instances, depressive symptoms were significantly relieved, with an increase in affective lability and responsivity. In two patients, deaffective "storm" appeared early in the therapy and �.u. pressive ideation increased and was associated with complaints of insomnia. The medication was continued, however, with an eventual alleviation. In most patients, mood changes were small. Ideation was dramatically altered during the period of-chlorpromazine therapy in twelve of the patients. Eight patients had a loss or a significant diminution of psychotic ideation. In five, the hallucinatory and referential xperiences were no longer reported even on inquiry; and in three others, delusional ideation was less prominent. In one patient, phobias were relieved to a degree that the patient could participate in ward activities. In another, hypochondriasis was sufficiently modified to permit of a more meaningful latedness of therapist and re— patient. In one patient, paranoid ideation became more prominent. This was associated with increasing anxiety and panic during drug administration, with resultant discontinuation of the drug regimen. 3. Effects en the psychotherapeutic relationship; Patients are referred for insulin coma therapy after a period of verbal relationship therapy. Such referral implies a failure of interpersonal communication. During the period of effectiwadrug activity, ten of the patients were described by the therapist in reSponse to an enquiry as "more accessible," "spoke more freely" and were "more amenable to psychotherapy." The responses could be classified into two groups: the subjects whose tension and pre— occupation with somatic symptoms became much less and those in whom halluc- inatory or delusional preoccupations ended. In each instance, the therapist described the change in relationship as an increase in "contact". In twelve subjects, psychotherapy was either still "not feasible" or "less so because of increasing, uncontrolled tension." �-5. In no instance did the problem of drug addiction or drug dependence play a role, nor was there an appreciation that drug therapy altered the therapeutic relationship adversely. h. §g§igg§ twenty four have left the hospital. thirty patients in this series, or the 93 "improvement": Table I lists the number of patients evaluated by the Discharge Conference, according to the four-fold classification in use in the hospital. For comparison, the discharge ratings of the insulin coma therapy patients, following the TABLE same criteria, have been included. I DISCHARGE RATINGS Chlogpromazine Insulin l. Recovered 1 O 2. Much Improved 3 1 3. Improved 15 10 h. Unimproved S 8 Coma Included in the unimproved group of chlorpromazine patients are four who received inadequate courses of therapy (less than one month) because of complications of the therapy. or the eight unimproved insulin coma patients, four had inadequate courses of therapy - two because of complications (seiz- ures, prolonged coma), one because she was a severe the fourth by administrative transfer to the V. A. 5. Toxicity g£_chlorpromazine: management problem; and Inherent in the design of were the high doses of chlorpromazine, pushed to symptoms of this study toxicity. In this context, all patients developed significant drug effects. In all, rigidity of extremities appeared; frequently accompanied by a decrease in facial expression, drooling and festination. In a number of patients the pafkinsona. �~6— ian features appeared as the drug dosage was reduced. symptoms were became drowsy, relieved when retarded, the drug and was discontinued. less active in ward In.each patient the Almost all patients activities. In four pat- ients, increased tension, agitation, restlessness and excitement supervened, to a degree that led to a discontinuation of the drug regimen. Seizures occurred in three patients. Ineaach, the drug medication was reduced, and seizures did not develop at the lower dosages. Dermatitis was a frequent complication. Severe, intractable skin reaction occurred in three patients, with resultant discontinuation of drug therapy in two. In the third, promazine * therapy was substituted for chloru promazine, with a relief of the dermatitis. The behavioral effect of the promazine was indistinguishable in this patient from the chlorpromazine group. All patients developed a skin photosensitivity so that on exposure to sun, transient erythema developed. Refusal of further medication because of drug effects occurred in two patients. Both developed severe tension and agitation. In two other instances, agitation resulted in the therapist insisting upon a change in treatment regimen. Table II lists the complications of both treatments. Certain effects are individual to the type of therapy, as dermatitis for chlorpromazine; and prolonged coma, severe secondary reactions and nausea and vomiting in insulin coma. 0there, as seizures, fainting spells, and increased are seen in both. *- Surplied as "Sparine" by the courtesy of Hyeth and Co. states of agitation �'77“ II TABLE COMPLICATIONS Insulin _Chlorpromazine Coma “ Agitation h and Panic 2 - Dermatitis, severe 3 Seizures 3 3 Refusal of further therapy 2 2 Hypotension 2 - Secondary reaction, frequent - 5 - 3 ~ 1 Prolonged Coma (+ 6 hours) Insulin Resistance In this chlorpromazine series, no patients developed clinical jaundice. This complication has been variously reported as occurring in less than %% of the subjects treated.* Liver function and blood element studies were done in this group of patients. Changes were small, and at the recommendation of the medical consultant, the studies were discontinued. Electroencephalograms were obtained patients. and On in fifteen of the chlorpromazine adequate doses, a moderate amount of low voltage theta activity was induced. This activity h—7 cps.delta was exaggerated by hypervent- ilation. There was a suggestive relationship between the degree of the induced slow wave activity and the drug dosage. 6. Adjuvants tg_Chlorpromazine: With the development of rigidity, festination, and drooling, patients received cogentin or artane medication. Both drugs relieved the symptoms, and in a few instances, to a significant * In the initial studies at Hillside twenty developed Hospital, three patients of a group of transient clinical jaundice. �-8degree. Concomitant with the relief of the rigidity a feeling of euphoria and wellabeing was occasionally noted. In one of the patients who developed effect. therapy, anti- an affective "storm" the administration of artane had a salutary In patients who developed seizures during insulin coma convulsant medication (dilantin, phenobarbital) has been routinely employed. Such agents were on lowered not used with chlorpromazine as the seizures did not recur dosages. Insulin B. Coma Theragz clinical effects, complications, the treatment results of insulin ccma therapy have been exhaustively reported. In this series, twenty-nine patients began insulin coma therapy. Of these, nineteen have completed their period of hOSpitalization and ten are either completing their treatment perThe iod or are awaiting discharge. The over-all ratings of "improvement" are listed in Table I. When comp pared with the Hillside HOSpital Follow-up Study of 1955, the percent improve— ment in each category is not significantly different, although the trend is less optimistically than the 1950 group. In Table III the percentages are listed for each evaluation category of this to rate the present series somewhat group compared to the 1950 populatidn. TABLE INSULIN III COMA THERAPY Present Group E 1. Recovered 0% 2. Much h% 19% 3. Improved 52% h2% h. Unimproved hh% 25% Such a Improved difference in trend, if sustained, 1h% may reflect a variety of factors, including changes in criteria of "improvement;" prior administration �.9... tranquillizing agents exerting a selectivity on the population admitted to the hOSpital; and changes in staff criteria for referral for in» of the newer Sulin coma therapy. complication rate in this insulin group is comparable to published studies. No unusual complications, and no deaths were observed. The role of psychotherapy in patients undergoing insulin coma therapy The is complex. In this group, four patients were treated with a "modified anaclitic" approach and an effort at establishing a working psychotherapeutic relationship was made. In the remaining patients, no unusual efforts at psychotherapy were made, with the consensus that a supportive, educative, enviru onmental-manipulative, reassuring type of therapy was achieved, to varying degrees. Therapists reported (in 7 instances) that patients were less tense less anxious during sessions while in coma therapy. In eight patients the physiologic effects of the treatment (secondary reactions, sweating, nausea, vomiting, weight gain) interfered with relationship therapy to a significant and degree. C. Therapeutic Results in Relation to Final Diagnosis Table IV lists the final diagnostic categories for the patients in each group. All diagnoses were represented in each series with an equivalent distribution. TABLE IV EBYCHIATRIC DIAGNOSES Insulin Coma Chlorpromazine Psychoneurosis l 2 Schizophrenia, Paranoid 0\ we U1 O\ U1 \n \» to +4 DD Schizophrenia, Catatonic Schizophrenia, Mixed Schizophrenia, Hebephrenic Manic Depressive Psychosis �~10— No diagnostic group had a significantly better treatment response than any other with either form of therapy. V. DISCUSSION: A. Comparison of Chlorpromazine and Insulin Coma Therapies: Neither chlorpromazine in high therapeutic doses, nor insulin are Specific treatments for schizophrenia. The discharge evaluations both treatments are not significantly different. There is, coma, for however, a def- inite tendency for more patients in the chlorpromazine group to be rated in the better classifications than in the insulin coma group. The trend assumes significance when both the type of sampling and the qualitative aspects of the treatments are taken into account. the The random sampling is exemplified by resultant matching of diagnoses. Since these treatments have not resulted in a recovery from the psychotic process, then their ameliorative, palliative and supportive aSpects must be considered. The insulin coma patients are usually uncomfortable throughout their treatment period. Nausea, vomiting, secondary reactions, are Prolonged coma common. loss of is a and drowsiness realistic threat; as well as the threat to life. The chlorprcmazine patients also suffered considerable disagreeable side effects. Parkinsonism, drowsiness, and skin reactions are significant, must be considered as concomitant management problems. and Seizures and jaundice are the most severe reactions, and to date, have not been permanent. It is possible to modify the significance of these side effects to a considerable extent by anti-parkinson and anti-convulsant medication. There is no question, furthermore, as to the ease with which chlorprom- azine can be administered, in contrast to insulin coma. A significant element in the use of these agents in the therapy of schiz- �.11... ophrenia is concomitant psychotherapy. Such relationship therapy by both It was therapies. apparent in the therapist's evaluations, however, that the chlorpromazine regimen was apy. Patients, excluding those comfortable, alert iences while on and was enhanced more conducive to concomitant verbal who developed ther- increased agitation, were more physically able to discuss their feelings and exper- chlorpromazine, than insulin coma. In another respect, the ease of administration of chlorpromazine advantage. Patients who respond to drug therapy can is of be maintained on such therapy for as long as needed, even on an outpatient basis, while the "course" of insulin coma is limited. Are these treatments equivalent? Can one be substituted for the other? While these questions cannot be answered by the data the negative can be denied. groups are not The in a positive assertidn, results of these treatments in equivalent different with regard to the discharge evaluation. The changes in behavior noted and the symptoms alleviated are not significantly different. In this series, three patients had adequate courses of both regimens. Two have been discharged"improved," and the third is still in the hospital. There has been no significant differences in their reSponse to either form of therapy. Comparison With Other Studies: B. While many studies of chlorpromazine in schizophrenia have appeared, only one report of a controlled study is available. gt_al_ (2) after an excellent review of the problem, report their results in one hundred patients, coma randomly divided into two groups of SO and Boardman, treated either by insulin or chlorpromazine. Their chlorpromazine dosage was lower than in this series (average 300 mgm) but the drug period ( 3 months ) was the same. Their observations are directly comparable to this series. They noted that the over(2) et a1: Insulin and Chlorpremazine in Schizophrenia — Study of Previously Untreated Cases, Lancet g5 h87-h9l, Comparative (September) 1956. Boardman, R.H. A �all clinical results were slightly more favorable in the chlorpromazine group than in the insulin group judging both by interview status and by a rating scale of difference was not of high statistical signif- The symptom change. state, however, that the chlorpromazine patients remained in the hospital an average of 6.2 weeks less; and that this difference was statistically significant. They concluded that: "There is inconclusive evidence icance. They did that chlorpromazine has advantages over insulin in the treatment of schizophrenia," but "that insulin has disadvantages in the form of greater danger and more unpleasantness for the patients and greater strain on the nurses. Chlorpromazine is the first treatment of -choice in schizophrenia, but this conclusion is based on the immediate results of treatment and has not yet been confirmed by an adequate follow-up study." In Boardman‘s review, due cognizance therapeutic efficacy of insulin come. He is given to the problem of the notes the number of'dissident re- ports that raise doubts as to the role of insulin In this regard, for insulin it is therapy in schizophrenia. important to note the results of the Hillside Follow-up in which patients referred for coma, coma such therapy had the period of hOSpitalization, poorest discharge ratings, and a ization rate (compared to 33% for psychotherapy and 29% 50% longest rehosPital- for the electroshock therapy groups). Two other control studies of chlorpromazine in psychoses are relevant to this report. "blind" study ment at Feldman gjgggp (5) Topeka reporting the observations in a controlled, State HOSpital noted a significant degree of improve- for chlorpromazine. They<eoncluded that "thorazine was found to be useful in converting acutely disturbed psychotics into tractable, accessible patients who could (S) Feldman, P.E. then participate more actively in the hOSpital rehabili- et al: A Controlled, Blind Study of Effects of Thorazine Clinic, a9; 25-h7, 1956. on Psychotic Behavior, Bull. Men. �.13... tatidn program." Tenenblatt and Spagno (6), describing the St. Elizabeth's Hospital eXperience, in another control study, noted significant behavioral effects in psychotic illnesses other than involutional psychoses. Effect of Study D. An on Staff: inherent factor in a control study of any therapeutic modality is the effect that the knowledge of random selection of patients or the use of placebos has on the therapist in his choice of therapy. sulin coma referrals were to be given Knowledge that in- either chlorpromazine or insulin coma created a feeling of insecurity and impotence in the therapist. Their control of the therapeutic situation was in a decrease in the drug effects, and number of felt as severely constricted. This resulted referrals, an exaggeration of the physiologic in the patients expressing doubts as to the therapeutic efficacy of the drug despite significant changes in ward behavior. On numer- therapists called to enquire which therapy their patient, referral for ICT had not yet been made, would get. Prior prejudice ous occasions, ‘whose suitability of either therapy resulted in the therapist's expressing disappointment at the modality used. In two instances, such preabout the judices led to early discontinuation of chlorpromazine therapy, when the pat~ ient experienced eanLy signs of drug effects. E. Dosage of Chlorpromazine: For the purposes of assuring an adequate level of chlorpromazine for evaluation, the medication was "pushed" in level in was too high all all subjects to toxicity. This for its behavioral effects, as evidenced responsive cases to maintenance levels of by the reductidn hOO-lOOO mgm. The effects of parkinsonism, drowsiness and lassitude are prdbably necessary concomitants (6) Tenenblatt, 3.8. and Spagno, A.: A Controlled Study of Chlorpromazine Therapy in Chronic Psychotic Patients, Quart. Rev. Peych. & Neurol., �1":114- of the therapy; and should be induced effect is desired. In instances where in all patients in an whom a therapeutic affective "storm" supervenes, con- inuation of the drug at higher levels, with concomitant artane or cogentin, should be considered. VI. CONCLUSIONS: In a control study of patients referred for insulin coma therapy, chlorprcmazine therapy was found to be as effective in modifying psychotic behavior patterns as insulin charge ratings to be coma therapy. is There better for the chlorpromazine a tendency for the group than dis- for the insulin coma group. In comparison to insulin coma to administer, more controllable in therapy, chlorpromazine is safer, easier its effects, and has fewer side effects. that either therapy has altered the basic schizophrenic process; nor is there any evidence that there is greater specificity for either form of therapy for schizophrenic illnesses. No evidence has been educed �February 3, 1958. that at a bucuti 1.. t :1 1251 : or EEG Dona Maturity to Bohuioml Quaint-Adv. 801-111 Studiu, “Hg, . kaponn in metro-hock: a: Arch. chhnt. 18; 516-525. 1957. Fink, H. and Kuhn, my a.L.s 3818321511 . Mime flux-spin, Units.“ Theory of the Action of 1957. 197-306. g. Hillside 3032. 9: ILL: Significance of Individual Variability in ma human to moctmlhock, g. Bullio- Raga. Q: 229-21“), 1957. link, 91.: A 3. m, h. Join, 5. Kuhn, 3.1.. and $. him, 8.1... J. «In An abacus.” Study of Went-.1031 £111.16. Hog. 9,: 207.215, 1957. link, In blink, PchhiaMc Interview, Figural Artur Induced mm (1957). g: Perception of m5. Puma)... mum, Altered Bruin 1n 361 H. and Pink, 15.: Social Salaam of Factorl 1n 216-228, 1957. 7. 3. and Pink, Ha Role or Stimulus Intensity 1n Pomcpuan tom, ' Simultaneous Gunman: Electrical Stimuli, 1. munch Hog). 9" 2181.250; 195?. at ‘ mama“ 8. Karin, 8. (With Tameka, 8. and Friedman, 8.): Pomeptim Stw o: Ambit-lanai, mg, hard, I: inching.. 1Q: 1&7-176, 19 7. 9. Punter. in; H. (with Geldfarb, Lgflé. knack, H. LE. 322‘ E a g Md it): gaunt. fl! (with‘marb, m): Test in Schilophrcnic 0111mm, 6354-6132, 1957. htum of Orientation in Childm in 303.1de Instant. for 8mm Bonnier Daemon, her. J. Mama . 213538-552, 195?. n. (with Battarnby, v.3. and Radar, 14.3.): Tnchia’wteopic hunk, “minimum of Contour 1n fluent: with Brain mange, J, Cog. algal. gm 61° fl. 3’ 220.227, 1957. Pollack, K. (with Battersw, $1.3. and War, 11.3.): Visual Deficit After Brain Damage in Man as Hammad with Rupidlyakpoud chromatic Stimn, mr. BIS-“2.9;. £2} 7’ 1‘68, 19570 0 13. Pollack, u. (with 00161111), in): cum-a1 ma Ehviromntal Factors attracting Complex Exception in the Institutionaliud Aged, ,1. Gomntolu l2“: ’1, “374‘38’ 19570 �Wf— ,. . , , . ~v-wwwavw—wmvwwnw—wu—va . «m <-~w—-~ uv-v—r rvs—«wv flv‘w—I-‘V n V'Wuzwr- may, mm "—31-— "Wu Flbmuy 3, 1958. Imagination! in Pro”: 1. 3., Mfo, J. humor, with mantra-hook 2. Pink, 3. Pink, IL, Shut, R... Grass, 0. and Colo-Inn, F.3d and Kuhn, Yuma“, J, 3.1.: chhomompenuc Techniques Hang. (in press). was 8.. [$11, 3.1.. tad anon, 14.1.: fluctuahook Prone-l, m, luv. “perinatal M. mama). J. r ‘mo (in Phi.)i and Insulin Cm in the Studio: of the (in press). Omani» Study of Therapy of Psychosis, * h. Pink, 5. ma, LL. 11.: 2E8 Laura}. Gnu Gun. In macaw. a u m- Indu a! the Sedation Munch}, in press). W. and Pink, 24.: humanity Factors (in nutmnhock Therapy, in Buhuioral mu). name to .- v- w. 1r, ,mrnv .7 w K, - �Luvzuv-amwnvww «7,. w—nwrruwm...»~.\,..—... W. WA R .. ran n-«cmvrrme—u»:‘v' February m. »u r’er’I-‘vs 3 , 1958 . many: in m Rayon-buy. Inflow“ York, Pom-my 1957. 1. Fink, IL: Individual 2. fink, Mu cut-m 3. Pink, 3., Kuhn, 8.1:. 1nd km :1; the Sociow no scanty, In 1n Enluation of Clinical Bolivian}. physiologie Alp-ct... Presented at LBJ... at Motropoutan Band Change: Neuro- ma tabla, Chicugo, by 1957. Exporiunm Gm, LL: of Biological Pm“. Juno 1957. Studio: of the msctmahock Psychiatry, Atlantic City, H. and Kuhn, R.L.I mum of amt-wean: Role of Alteration in Brain Function in Bah-dot. Pnsented at. Int. Congas: of Pnychntry, Zurich, Sept. 1957. h. fink, S. I!” xfin, 3.14. ”d “an, 3.! “ICC“ Qt 01:!qu “tend 3w m’Function on Pomaption. Pruemad at the 17 Int. Congrats of Psycholog, Ema-1c, August 1957. ' 6. Fink, II. and him, 3.1“: Random Pattoml in Induced Stat» of Aland Road at w. New Ion Divisional Hating, A.P.A. 1m. 1957. Brain 7. Pink, Mu 8. on m ma sumnwm tar hoary of Le Enact. or M,Pmaou of Conwlaivo Thu-um. Read It. Mom “Inflation of manna mum. of m quancy Shirt for Plychintz-y. Simian“SOQCW‘ HoY: 30'. 1957- ”Mum EEG 13101313511). anecphalographm, Nov 9. 10. Road at. M30, 4.: 1621:, Doc. 1957. Bahamian). chug” Plyohomum in Evaluation of Clinical Round Tabla, Chicago, Hay 1957. lingnhuc “pom. Fromm at A.P.A., in hymn-Le Interview. NationA.P.A.. Nov. 1957. MIC, J.: Lu Obj-«tin Study of had at um How Iork Divisions). Mating, in Buhuioral Euponu to metre-hock Thonpy. haunted at meta-omen}: Research “mention, [11:21, 3.1.. and Pink, 11.: Pomonality Factor! Chicago, Ram, New 1957. LL. and link, Aland Brain Mu Pompticn or Function. Road We! Figures Arte:-InInduood Ierk, August 1957. at Ann. Plyehol. Luau” Karin, H. (with runabout, S. and Friedman, 84): Pomption Expouunu in a Study of Allah-Amen. End at Suction on lourolog I: Plychintry of Ed. of Kodiak)! and LY. Roux-01. Socioty, NJ. Jm. 1957. low �__. _.__ .7...._—M wvwwfiwww «V . ., m«m1.1m: 1. _ (5....»“1 .._ _ w. ....,._-,_..,..._.. «1...; .I.-....._.L,,.r..». w“ynw-WMW r‘m-vnr—Vwfltnflw’all ' 7 I-vrn" “rm” ‘ nun—mm.—.,.m~ I2 (Iith Italahau; s. and lhindnan, 3.): th- Relation a: Ambasulnneo Mansion and Monty 1n Wan-antic mum... and at Amt. Mabel. Ame. Sept. 1957. (New Kerk). 15. Karin, B. (with Tarmac»: and Mama, 8.): Stun” in “bitumen. 1h. lbrin, H. to Pnlantad boron Sahildar Sociew, M York, 00%. 1957. 16. Pamak, H. (with Galena), W. and Dam, 14.): Pain mucus in Schumann 02:11am. Haunted at Mr. Orthapaychntrio mac. Chicago, Marah 1957. 17. ‘ M.‘(v1th Integer, H.P.)I.Oan1mtor'and Bantam Put-m 1n o: lamina, Sahisophnnia Wldran. P's-mug! at Mr. knack, Am 18. Pollack, H. (with Butterfly, v.3. and Bond-r, 11.8.): figure-mane! Pamphlet: Tumor. But! *Enmm Payahol. uses... In York in Plunges with 13111 0“.an 19 7o it Pollack, K. (with Batu-thy, H. 3. and Bondar, 3.3.): Datum in Visual Phraoption in Brain mm:- Patten“. Flaunt-d baton Int. Congrats or ngcha1., aux: 1957. (Brunloll). .20. anuok, K. (with Battarnby, v.3. and Bondar, 14.3.): Visual M1611: After with Rapidly-kpand Chmtia 9mg. a Mutant! Assoc" Nu Int-k, Sept. 1957. Pmud at Ann. PaychoI. Brain 1:: Man Stimuli. Pollack, H. (with Goldhrb, A.): Cultural and Environ-um Factor: Aged. Presented “hating (De-plan: Pox-caption in tin Institutiamliud at the “analogical Society, Cleveland, 00%. 1957. 22. Pollack, 11.: Brain Dung... Pmanud It. Nil mm Inhalation and Childhood Sauomania. Hating, MPJ. new. 1957. York Divisions). � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Published Works Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Comparative study of chlorpromazine and insulin coma in therapy of psychosis. J Am Med Assoc. 1958 Apr 12;166(15):1846-50. Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-02-01-002-31-008 Date A point or period of time associated with an event in the lifecycle of the resource 1958 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a>; Shaw, Robert; Gross, George E.; Coleman, Frederick S. Subject The topic of the resource Published Works -- Articles and Reviews Relation A related resource The Max Fink Collection Description An account of the resource [Preprint and reprint]. Reprint from The Journal of the American Medical Association April 12, 1958, Vol. 166. Observation letter. Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Published