- Email: [email protected]
Drug Therapy of the Psychoses
Drug Therapy of the Psychoses JACQUES S. GOTTLIEB, M.D.;' GARFIELD TOUHNEY, M.D." PETER G. S. BECKETT, M.B.;t PAUL LOWINGER, M.D.t
THE psychoses present a number of problems to the medical practitioner, in that they arc major disorders of thinking, feeling and behavior which may require immediate management and hospitalization. A part of this problem is certainly concerned with the fact that the concept "psychosis" means different things to different people. Some psychiatrists believe that this term should be disregarded completely, and that the major disturbances in feeling, thinking and behavior should be given a more specific diagnostic classification. The majority of physicians who deal with mental illness, however, believe that the term is a valuable and practical one. In general then, in this review, when the term "psychosis" is used a condition is meant in which one or more of the following difficulties is present. The individual's thinking may be so disturbed that he has difficulty differentiating his own subjective state from the external world; or he may have disturbances in comprehension or intellectual function. Delusions and hallucinations are also important symptoms of this disturbance. Or his emotional responses or feeling states may be quite inappropriate to the actual situation, and also inappropriate to his own thought processes. In addition to these more subtle difficulties, his behavior is frequently disorganized and poorly direeted; this may be manifested either as underactivity or overaetivity, withdrawal or overt antagonistic bchavior. Etiologically, the psychoses are related to a great many different factors. In some eases, definite psychogenic factors are probably most From the LafayeUe Clinic, Detroit, Michigan, and the Wayne University Collf{je of Medicine.
* Director, LafayeUe Clinic; Professor of Psychiatry, Wayne Univers1'ty College of Medicine.
*' Assistant Director in Charge of Educational Programs, Lafayette Clinic; ASbistant Professor of Psychiatry, Wayne University College of Medicine. t Staff Psychiatrist, LafayeUe Clinic; Instructor in Psychiatry, Wayne University Cl'llc(J€ of Medicine. 1385
1386
J. S. Gottlieb, G. l'ourney, P. G. S. Beckett, P. Lowinger
significant, while in other psychoses (such as general paresis, senility and arteriosclerotic brain disease), definite neuropathological changes occur. The psychoses in which the psychogenic element may be significant, and in which there is no structural change in the brain, are referred to as the functional psychoses; these include schizophrenia, manic-depressive psychosis and involutional psychosis. The psychoses in which neuropathologieal changes can be demonstrated are called organic psychoses and include a number of different processes related to infectious, degenerative, toxic, traumatic and neoplastic conditions. Certain drugs have been found to be helpful in the management and treatment of the psychoses. Recently, with the introduction of the tranquilizing drugs, reserpine and chlorpromazine, there has been great enthusiasm for this approach and many remarkable changes in symptomatology have been noted. However, experience shows that these drugs have many limitations. They have not replaced other somatic treatments, e.g., electroconvulsive therapy, in the management of the psychotic patient. It should also be realized that these drug therapies are nonspecific, and that the results obtained from them are purely symptomatic. The fundamental process of the illness generally remains in evidence after treatment. Frequently, however, these drugs contribute greatly to the psychotherapeutic and socialization programs. Their use leads to the patient's establishment of suitable contacts with other people and, frequently, to his understanding of some of the factors in his own illness. This combined therapeutic approach appears to be particularly useful in the management of schizophrenia. The current enthusiasm for the drug treatment of psychoses has led and is leading to the production and investigation of a great number of new substances, some of which are proving to be clinically useful. A great deal more experience is needed with most of these drugs, however, before one can definitely state their value. A number of significant sideeffects have been noted which in many cases may contraindicate their use. Reserpine (Serpasil), the most potent single alkaloid derivative of the Indian plant Rauwolfia serpentina, has been associated with a large number of complications. I These include hypotension, bradycardia, fatigue, listlessness, somnolence, diarrhea, the parkinsonian syndrome, dizziness, nasal congestion, and allergic responses such as dermatoses and the precipitation of asthmatic attacks. Chlorpromazine (Thorazine) presents even more serious problems; these include hypothermia, hypotension, fatigue and dizziness, somnolence, bradycardia, the parkinsonian syndrome, potentiation of the effects of narcotics, sedatives and alcohol, allergic responses, jaundice 2 and agranulocytosis. 3 The number of cases of agranulocytosis reported is increasing, and a number of deaths appeal' to be definitely related to the use of this drug. The cause of the jaundice has been felt to be either on an allergic or a stasis basis, or both. Some authors have minimized
Drug Therapy of the Psychoses
1387
the importance of jaundice and continued treatment. It is interesting to note that a recent case of acute aseptic necrosis of the liver occurred in a patient treated with chlorpromazine. 4 Another danger is the possible masking of infectious processes because of the hypothermia. From the above discussion it becomes apparent that considerable caution must be used with these substances in the treatment of mental illness. TilE FUNCTIONAL PSYCHOSES
Schizophrenia
Schizophrenia remains a disease of essentially unknown ongm, although new evidence as to hereditary, constitutional, physiochemical and psychodynamic factors is rapidly accumulating. It is the belief of many psychiatrists that this condition is a clinical syndrome made up of a number of different illnesses which in turn are related to many factors ranging from eonstitutional to psychological. Patients with this illness show a characteristic dii:lturbanee in the affect or feeling tone. By this is meant that the patient's emotional reaetion to situations is quite inappropriate. There is also a marked abnormality in the asso:;iative aspects of thinking and, with this, behavior may be quite disturbed, in that the patient may become withdrawn, or act out aggressively. Delusions and hallucinations are common symptoms of the illness. The om-let may be acute, but is frequently insidious. The treatment of a schizophrenic cannot be simply defined. The patient may Le acutely disturbed, or he may be easily manageable. At times he may be aggressive and paranoid in his behavior, and at other times he may obey instantly every order. The acuteness of onset, the duration of illness, the particular type of symptomatology, and the exact subclassification in many ways determines the treatment. In most cases, particularly the acute ones, treatment in a psychiatric hospital is indicated, where adequate safeguards, skilled nursing and a suitable social environment are present. In the hospital management of the acutely disturbed patient seclusion may be needed, but the use of drugs can be of considerable help. The intravenous injection of 0.5 gram (7% grains) of amobarbital sodium (Sodium Amy tal) will often result in very satisfac·tory control. The dosage can be repeated within four hours if necessary. Scopolamine given in doses of 0.6 mg. (1/100 grain) may also work well in the management of the acute schizophrenic patient. This medication can be repeated after a thrcp-hour period. It has a very useful sedative and hypnotic effect for the schizophrf'nic, but it cannot be utilized in prolonged therapy. Other sedatives alld hypnotics, such as barbital and chloral hydrate, can be used, but frequently largPr doses than the standard U.S.P. recommendations are needed. Since its introduction, reserpine has proved effpctive in the manage-
1388
J. S. Gottlieb, G. Tourney, P. G. S. Beckett, P. Lowinger
ment of the psychomotor excitement and many other acute symptoms of schizophrenia.)' 5-8 It can be administered intramuseularly in doses of 2.5 to 5 mg., which are repeated to give a total of 12.5 to 15 mg. during a 24 hour period. Over a period of four to seven days, as the patient becomes more cooperative, the total dose can be gradually redw:ed and parenteral medication discontinued, with the patient being maintained on 3 to 6 mg. of oral preparation per day. After seven to 14 days the patient can often be managed on :i mg. per day. Even with adequate drug medication, many patients remain disturbed and other measures must be uEed, such as eleetroconvulsive therapy and insulin hypoglycemic therapy. Reserpine has a useful function in the treatment of the schizophrenia but it has not replaced other approaehes, somatic or psychotherapeutie. Instead, it complements them. Chlorpromazine has been used by a number of investigators 7, 9-12 and has been regarded as a valuable medication in the control of psychomotor excitement and anxiety of acute schizophrenia. Use of initial doses of 50 mg. by deep intramuscular injection two to six times daily has been reported. In addition, an oral dose of 50 to 100 mg. was given three to four times a day. Parenteral and oral doses may be increased, so that the total dosage may be as high as 800 mg. a day. This dosage has been continued for up to four weeks and longer as part of a treatment program. Other investigators have used mueh higher dosages ranging as high as 4000 mg. a day, but there is good evidenee that the lower doses reeommended are equally satisfaetory in providing the remissions. In our experienee, because of the serious toxicity deseribed pn~viously from both high and low doses of chlorpromazine, this medication has been used infrequently. There is reason to believe that chlorpromazine treatment of schizophrenia is more hazardous than the use of electrotherapy ill terms of patirmt morbidity and mortality. Less disturbed schizophrenic patienes often can be managed, sometimes on an outpatient basis, with smaller doses of reserpine. These doses are in the range of 1 to 6 mg. a day given orally. In these patients, mild agitation and anxiety symptoms are reduced, and often there is much less concern about delusions and hallucinations. However, on careful examination, the primary symptoms of schizophrenia remain including both the association disturbance as also the affective changes. Individuals respond much better in their interpersonal relationships, begin to enter ward or social activities, and are able to talk about many of their problems in psychotherapy. Manic-Depressive Psychosis
Depressions
The term "depression" is a descriptive one. Depression presents itself as a symptom in a number of psychiatric disorders including psychoneurosis and functional and organic psychoses. Some of these reactions
Drug Therapy of the Psychoses
1389
are definitely of psychotic proportions, but a large number are not. Only by a thorough examination and possibly by a period of observation can one define the type and depth of depression. The principal types of depression are the reactive depression or neurotic depression; manicdepressive psychosis, depressed type; involutional psychosis, depressed type; and depression associated with organic brain disease. The discussion here is concerned only with the psychotic depressions. In these conditions there is characteristically depressed mood, retardation of speech and psychomotor antivity, difficulty in sleeping (particularly with early morning awakening), loss of appetite, loss of interest, fatigue, suicidal preonnupation, and thoughts of self-blame and self-abnegation. The illness usually occurs between the ages of 18 and 40 years. Typically, the depressions occur periodinally, but some individuals may have only one attack in a lifetime. Oncasionally, there are alternating periods of depression and elation. Each episode of depression may last from three months to two years, but suicide is always a risk. In the more severe depressions of this type, hospitalization is definitely indicated. Because of appetite and weight loss there may be dehydration and nutritional deficiencies, hence it is advisable to supplement the diet with vitamins and provide a high calorie intake and adequate fluids. Hypnotics are needed for the sleep disturbances. In our experience, chloral hydrate has been more useful than the barbiturates and is usually given in doses of 0.5 to 1 gram. Amobarbital sodium (Sodium Amy tal) in doses of 200 to 300 mg. (2 to 5 grains) has also been used. In mild depressions, hospitalization is usually not indicated, although some supervision in the home may be necessary to guard against suicide. For these mild cases, onc may u"e amobarbital sodium and racemic amphetamine sulfate (Benzedrine), given together. 13 These drugs have a synergistic antidepressive action, and therefore are more effective when used together than singly. They should be given on rising in the morning and at noon. Ordinarily, amobarbital sodium in doses of 60 to 100 mg. is given with 5 to 10 mg. of racemic amphetamine sulfatc. If somnolence or drowsiness tends to occur with this regimen, the amobarbital sodium is decreased and the amphetamine may be increased. If excitement and restlessness occur, the opposite change in dosage is made. In the late afternoon (for instance, at 4 P.M.), the dose of amobarbital sodium may be given alone in order to produce a certain amount of sedation if needed. Those depressions of moderate and severe degree which require hospitalization usually do not respond to the above management. A number of new experimental drugs, such as Ritalin and Meretran, are being evaluated at the present time, but their efficacy has not yet been proved. Most moderate and scvcr<~ dppressions require electroconvulsive therapy. M anic Episodes
In the manic episodes of manic-depressive illness the subject feels elated, becomes overactive, overenthusiastic, jovial, grandiose and un-
1390
J. S. Gottlieb, G. Tourney, P. G. S. Beckett, P. Lowinger
realistic in his thinking. He becomes so engrossed in his own t.houghts and activities that he frequently refuses to eat. and as a result nutritional disturbances, such as dehydration and electrolyte imbalance, are common. Close dietary supervision, as outlined under depreiolsion, is necessary. Sedation is oftpll needed to reducp the overactivity and to aid in the avoidance of exhaustioll which can })(' a very real problem. The nse of intravenouiol amobarbital sodium may be necessary to combat the patient's resistance and uncooperation. It is given as for the acutely disturbed sehizophrenic patient. Hmvevcr, this type of sedation can be used only for a short period of time to handle the immediate excitement. Chlorpromazine has reeently been suggested for the treatment of mania. 14 On occasion it redueeiol the overaetivity quite readily. Ordinarily, such patients are giv(,l1 up to 500 mg. a day in doses of 100 mg. orally every four to iolix hours. If the patients arc noncooperative, one can give 100 mg. by deep intramuscular injection. The parenteral administration is often needed early in the course of the disease but can be supplemented by oral medieat.ion later. Chlorpromazine, hmvever, has definite limitations in th(' management of mania, not only because of its toxic side effects but becam,e its effects arp often temporary. A more rapid recovery may be obtained by the use of electroconvulsive t.herapy. Involutional Psychosis
Involutional psychosis occurs after the age of 4.5 years, and is characterized by depression, somatic concern and paranoid thoughts. Again, thoughts of self-blame and self-abnegation, suicidal tendencies, agitation and restlessness, severe insomnia, appetite loss and weight loss arc prominent symptomiol. The illness accounts for a large number of suicides in this age group. The physical state of the patient with involutional psychosis may be severely depleted, hence treatmpnt for dehydration and undernourishment must be carried out. As with manic-depressive illness, various hypnotics may be needed to produce sleep and reduce agitation; again chloral hydrate is the preferred drug. Estrogenic hormones in the female and testosterone in the male have been of little or no value in the treatment of involutional psychosiiol, although these drugiol may relieve some of the symptoms of the menopausal syndrome. Amphetamine and amobarbital sodium when used as described above may be helpful, but in moderate and severe depressions these drugs are really of little value. As with the manic-depressive illneRs, electroconvuliolive therapy is indieated. Conclusions
Before pro('eeding further it should llf' pointed out that the use of drugs for the funetional psychoses have symptomatic value only and must be considered aiol one aspect of a total therapeutic approach.
Drug Therapy of the Psychoses
1391
As has been mentioned, electroconvulsive therapy is the most specific treatment for the patients with depressive psychoses. The new tranquilizing drugs are of importance because of the symptomatic improvement which allmvs the applicatiOll of the very important socialization and psychotherapeutic technique:,;. TIlE ORGANIC PSYCHOSES
In these conditions the psychosis is related to organic brain disease. The characteristic symptomatology involves thinking, feeling and behavior, often reflects the premorbid personality patterns, and may be of any degree of severity. The organic psychoses may be acute or chronic. Ordinarily the acute organic psychoses are not associated with structural brain disease and are reversible, while the chronic organic psychoses are part of an irreversible organic process. Both the acute and chronic psychoses may be due to or a:,;sociated with infectious processes, intoxication, trauma, circulatory disturbances, disturbances of metabolism, nutrition, neoplasm, or to uncertain causes. Characterizing the organic psychoses are a number of symptoms often referred to as the organic: syndrome. Typically there is a memory disturbance, with recent memory and retention being involved more severely. With this is associated anxiety, confusion and disorientation. Impairment of the critical faculties and judgment occurs. The emotions bec:ome quite labile; there is easy laughter and crying. Attention difficulties are common. Finally one may observe delusions and hallucinations. Physical and neurological symptoms such as tremor, speech difficulties, poor coordination, and ataxia are often present. Acute Deliria and Toxic Reactions
Acute deliria probably account for the greatest number of psychotic reactions seen in medic:al prac:tice. Such deliria oc:cur in association with aieoholism, drug intoxicatioll, infectious diseases, cardiovascular disease, injuries, and postoperative ('omplications.
Delirium Tremens The most common alc:oholic psychosis is delirium tremens. Although this may vary considerably in severity of symptoms, it should be recognized as a serious illness that needs energetic treatment. Incipient delirium tremens, characterized by anxiety and tremors, may occur in a chronic alcoholic who has continued to drink heavily, but is also precipitated by the sudden withdrawal from alcohol. The condition may progress to an overt psychosis with such symptoms as marked psyc:homotor excitement, overactivity and vivid visual halluninations. Hospitalization then becomes nec:essary. Various drugs play an important role in the treatmmlt of delirium tremens. Such treatment ineludes the use of the "Bellevue Cocktail"
1392
J. S. Gottlieb, G. Tourney, P. G. S. Beckett, P. Lowinger
given intravenously as frequently as three to four times a day. This is a mixture of 50 cc. of 50 per cent glucose, 20 units of regular insulin, thiamine 50 mg., nicotinic acid 100 mg., and ascorbic acid 100 mg. The oral administration of paraldehyde in doses of 8 to 16 cc. every four to six hours reduces excitement, anxiety and concern over hallucinations. Other management should inelude liberal amounts of oral fluids ineluding water, fruit juices and milk in amounts of 3000 to 4000 cc. per day, 2 grams of sodium chloride three times a day, high calorie, high vitamin diet, and oral as well as parenteral vitamins of the B complex group. In the more severe cases of delirium tremens, parenteral fluids may be required. An occasional complication of delirium tremens is an infeetious process which may increase the degree of delirium and should be treated appropriately. Other associated illnesses include cardiac decompensation, head injury, and grand mal convulsions. To forestall or treat the convulsions, Dilantin 0.1 gram may be given three times a day. More recently, newer drugs such as chlorpromazine 15 and reserpine 16 have been advocated for the control of excitement and overactivity of these patients. However, because chlorpromazine potentiates the effect of alcohol and also has led to repeated eases of jaundice, we have felt that this drug is not indicated.
Barbiturate Delirium Various barbiturates may produce a wide variety of psychiatric syndromes. The coma of acute barbiturate poisoning is well recognized. Barbituratps may also produce many of the same symptoms as alcohol, and frequently the clinical picture elosely resemhles delirium tremens. Many patients have been consuming large quantities of hoth alcohol and barbiturates for prolonged periods, so that the exact etiology of the subsequent reaction may not be entirely dear. The treatment of delirious reactions related to barbiturates elosely resembles the treatment of alcoholic: delirium tremens. Fluid administration and sedation are the most important measures. Also, on(~ mU8t realize that ehlorpromazine potentiates barbituraks as well as alc:ohol, hence this drug should be used eautiously, if at allY The withdrawal of barbiturates from patients long habituated to them should be done gradually, so that anxiety, convulsions and psychotic symptoms may be minimized. This withdrawal is often necessary in the deliriou8 patient, consequently the patient should be placed on a gradually decreasing maintenance dose of the barbiturate, given at regular intervals. If the previous dose is unknown, the standard D.S.P. dosage of any of the barbiturates may be used three to four times daily. Proportionate reduction of this dose over a five to 15 day period usually proves suitable. For the sedation of an excited barbiturate patient, who may be suffering from marked tremors and hallucinations, paraldehyde is preferable in
Drug Therapy of the Psychoses
1893
oral doses of 8 to 16 cc. given every four to six hours for symptomatic relief.
Bromide Intoxication Bromides, commonly used in patent medicines, may lead to the development of psychosis if taken over a long period of time. The bromide replaces the chloride of the blood, and psychosis is usually associated with a blood bromide level of 150 mg. per 100 cc. In the bromide psychosis there is confusion, disorientation, hallucinations, paranoid thoughts, and often an acneform rash. In the treatment of such reactions, one should immediately stop the ingestion of the drug and give 6 to 8 grams of sodium chloride in enteric-coated capsules in divided doses, and 4000 to 5000 cc. of fluids a day as long as there is no evidence of cardiac or renal disease. Such psychotic reactions usually clear in two to six weeks.
Deliria Associated with Systemic Disease Toxic psychoses are commonly seen during an infectious illness, following injury or surgery, and in cardiovascular renal disease. These reactions may have many and various precipitating factors. In some cases psychological stress seems to be an important factor, which includes fears and misconceptions concerning surgery, guilt over circumstances of the injury, difficulties in the emotional acceptance of illness, and similar types of experiences. It is interesting to note that psychotic reactions not uncommonly occur following surgical procedures on the genitalia and the eyes, these organ systems having considerable emotional significance for each individual. In other circumstances, more purely physical factors may be significant. Such factors include fluid and electrolyte imbalance, toxic reactions to various drugs, toxic factors associated with infectious diseases, uremia, anoxia, other metabolic disturbances, and cerebral arteriosclerosis. Most often there is a combination of various stresses, some obvious and others not so obvious, which lead to a disturbed patient on a general hospital ward. Symptoms which these patients show may be many and varied. There is often confusion and disorientation, especially at night, with the patient behaving as if he were not in a hospital at all. He may have hallucinations of friends or relatives in his room or in the hall. Often he becomes overactive and wants to leave his room and the hospital. The patient may be quiet, retarded, depressed, or even logical and rational most of the time, but highly suspicious that he is being poisoned and persecuted. The management of such a problem will depend primarily on a thorough investigation of all the factors involved. It will be necessary to know as much as possible about the extent of physical disease and whether it is systemic or intracranial. Heart failure, myxedema, Cushing's syndrome and lupus erythematosus are examples of diseases that may present
1394
J. S. Gottlieb, G. Tourney, P. G. S. Becketl, P. Lowinger
predominantly psychotic symptoms before the physical manifestations are readily apparent. Another point for early consideration in the management of these cases is a careful check on the medication that the patient has been receiving. It may sometimes happen that there has been a continuation of large doses of narcotics, barbiturates or other drugs which, especially in elderly people, may not be necessary. These drugs complicate any underlying confused or delirious state and should be reduced in amount or discontinued in so far as possible. A convenient hypnotic which may be substituted is chloral hydrate, 0.5 to 1 gram, given orally at night and repeated if necessary. Regular treatment of the underlying physical disease must be continued and special attention paid to fluid and electrolyte balance. The possibility of intracranial complications and complicating infectious processes should be considered. A light left on in the room at night may help considerably in orienting the confused patient. Once the current status of the patient has been thoroughly evaluated, the restlessness, anxiety and bewilderment so frequently present can be treated effectively by such new drugs as reserpine or chlorpromazine. Chlorpromazine may be given by deep intramuscular injection in doses beginning with 25 or 50 mg. three or four times a day, later supplemented by oral medication, 50 mg. four to six times a day. Dosage may be increased to a total of 400 to 500 mg. per day if necessary. Reserpine has also been helpful in managing these reactions and is given intravenously or intramwlcularly in doses of 2.5 to 5 mg. and repeated once or twice during the first day. Oral medication can be given to replace the parenteral medication ill doses of 2 to 6 mg. per day in three to four divided doses. With thiH approach to the acute toxic reactions, one usually sees marked improvement in a matter of several days, and recovery not infrequently within a period of a week. These eases are often treated effectively in a general hospital in which there is good nursing care, which may at first need be on a 24 hour basis for the disturbed patient to avoid the possibility of self-injury or even suicide.
Traumatic Delirium An acute delirious reaction to head trauma may appear as the patient emerges from stupor or coma. The underlying cause may be concussion, contusion, laceration, hemorrhage or increaHed intracranial pressure. However, in most cases the actual cerebral damage is mild and no focal lesion is elicitable. It is far more common in children than adults. In any such ease, thorough neurological and neurosurgical investigation is necessary. There is often confusion, di~;orientation, marked irritability and very vivid and terrifying. hallucinations. This reaction often requires hospitalization in a psychiatric setting. Chlorpromazine and reserpine, used in dosages described for the toxic deliria, may be of aid in the man-
Drug Therapy of the Psychoses
1395
agement of this illness, which will usually clear within one to three weeks if no serious organic disease is present. Other Alcoholic Psychoses
Delirium tremens, the most common alcoholic psychosis, was discussed previously. Chronic psychotic reactions associated with alcoholism include chronic hallucinosis, paranoid alcoholic psychosis and simple deterioration. With these conditions there is little or no response to drug therapy and care is largely institutional in nature. Two less common alcoholic reactiolls are Korsakoff's psychosis and Wernicke's encephalopathy. Treatment consists of improving the nutritional state with the utilization of multiple vitamins as des(:ribed under "Delirium Tremens." Vitamin Deficiencies
Cerebral symptoms oceur with vitamin deficiencies, particularly those of the vitamin B complex group which play a very integral role in cerebral metabolism. Wernicke's encephalopathy may be associated with such deficiency states. Psychoses with pellagra arc characterized by dementia and delirium. These, too, are often associated with alcoholism. These cases respond very well to ni(:otinic acid. 18 However, deficiencies involving the other B groups are usually present, and so B complex medication should be given. One hundred milligrams of nicotinic acid amide every two hours, given parenterally or orally, may be valuable. Subsequently the dosage may be reduced to 100 mg. given orally four times a day, Psychosis Associated with Metanic Poisons
A psychotic picture may follow the ingestion of heavy metals. A few examples will be discussed with emphasis on the use of drugs and their treatment. BAL (British anti-lewisite) is useful in promoting the excretion of certain metallic poisons. This is particularly true of arsenic, mercury, thallium and cadmium. A 5 per cent solution in peanut oil and benzyl benzoate, given by the intramuscular route in amounts of 2 cc. every four hours, should be given during the first day. During eaeh of the second, third and fourth days, two doses of 2 cc. each are given, and for the fifth and sixth days, only one dose of 2 cc. is administered each day.19 The encephalopathy, delirium or convulsions of lead poisoning, especially as they occur in children or after poisoning by tetraethyllead vapor, respond less well to BAL. This reaction may need a sedative program similar to that discussed under toxic psychosis and such symptomatic measures as may be necessary to eontrol convulsions and excitability. In the initial stages, a high calcium diet, including 2 quarts of milk daily and 5 gram;; of calcium lactate three times a day, promotes fixation of lead in the bones. 19 Whpll the toxic symptoms have disappeared, a low calcium diet and careful use of ammonium chloride, 1 gram
1396
J. S. Gottlieb, G. Tourney, P. G. S. Beckett, P. Lowinger
eight to ten times a day for as long as three weeks, will help to promote lead excretion. Ammonium chloride should not be given in the presence of symptoms of encephalopathy. * Chronic Psychotic Reactions Associated with Central Nervous SysteDl Disease
Another common problem in practice is presented by a patient with a chronic central nervous system disease associated with psychosis, severe behavioral disturbances, mental deficiency or dementia. Here, again, the new tranquilizing drugs are useful. In hyperactive retarded children, 25 to 100 mg. or more of chlorpromazine intramuscularly per day is effective. 2o In seriously disturbed adult psychotic epileptic patients, reserpine in initial dose of 2.5 to 5 mg. intramuscularly plus 3 mg. orally with gradual tapering off of the intramuscular dose, and continuance of the oral dose, has given good results. 21 However, with both reserpine and chlorpromazine seizures may increase, hence anticonvulsant medication should always; be used. In Huntington's chorea reserpine, used as described above, has been of considerable value in controlling motor behavior. Convulsive Disorders
Other patients in whom psychotic behavior accompanies psychomotor or temporal lobe epilepsy and in whom a surgical treatable lesion has been excluded, are more difficult to control. When surgical therapy is not indicated, a specific antieonvulsant should be given. Epilepsy may lead to an acute confusional state and psychosis in some cases following grand mal convulsions, as well as states of chronic epileptic deterioration. Severe epileptic episodes of confusion and continuously uncontrolled behavior often require hospitalization of the patient and immediate sedation. A useful drug is amobarbital sodium given in doses of 0.5 to 1 gram intravenously and followed by sodium phenobarbital 0.1:3 to 0.25 gram intramuscularly every four to six hours. Paresis
General paresis, a disease of the central nervous system associated with syphilis, ordinarily results in psychotic behavior. Other forms of neurosyphilis do not usually lead to a definite psychotic pattern of behavior. Typical organic symptoms, such as gradual intellectual deterioration as well as depression, manic behavior, delusions and hallucinations, and paranoid behavior, may occur in the paretic. With the introduction of penicillin in the treatment of paresis, fever therapies and the use of heavy metals have largely been replaced. The usual treatment of paresis consists of penicillin, 300,000 units, twice a day to total at least 12 million units. * Calcium versenate (Ca EDT A) is also being used suecessfully in the treatment of children with lead encephalopathy.--Ej.
Drug Therapy of the Psychoses
1397
Psychoses Associated with Arteriosclerosis and Senility
With increased life expectancy, it is not surprising that a larger number of psychotic reactions of an organic nature related to senility and arterioscleroti(~ changes are seen by the medical practitioner. It is difficult to differentiate between pure senile and arteriosclerotic reactions, and these may often occur concomitantly. Since the symptomatic pictures and the treatment methods are similar, they are described together. Both of these illnesses occur late in life, and are characterized by a gradual impairment of brain tissue function. The symptoms develop insidiously and often consist of a gradual breakdown in high cultural and ethical standards, impairment in skills, disturbances of memory and judgment, and often delusions and hallucinations. Eventually the individual becomes quite deteriorated in his intellectual function, personal care and behavior. Acute cerebral syndromes developing later in life are confused with chronic brain reactions in this age group, and may lead to unnecessary custodial care. The aging person with beginning senile and arteriosclerotic changes is more susceptible to mild injuries, infections, small doses of alcohol, drugs, and other stressful stimuli. Such toxic reactions can be managed by reducing drug or alcohol intake, treating injuries and infections and the initiation of measures to improve the nutritional state of the patient. The specific methods described for treatment of the acute toxic psychoses are applicable here. Drug doses should be made proportionately lower for the elderly individual. Milder cases of senile and arteriosclerotic brain syndromes may be cared for in the home where the patient has a routine and familiar environment. However, problems frequently occur, such as nocturnal restlessness and delirium. It is best to avoid much sedation, particularly the use of the barbiturates. Small doses of chloral hydrate, 0.5 to 1 gram, may be helpful when sedation is needed. When delusions, hallucinations or agitation become prominent, small oral doses of reserpine, 1 to 3 mg. per day, or chlorpromazine, 100 to 300 mg. a day, may be used. 22 Many of these patients are depressed and may require hospitalization and electroconvulsive therapy. Amphetamine and amobarbital sodium, used in doses of 5 mg. and 60 mg. respectively, with adjustment of dose as described in the discussion of depressiolls, may be useful. An important aspect of treatment is to maintain the nutritional state since many arterioseierotic and senile patients become quite capricious about their appetites and refuse to eat many foods. Supplementary vitamins arc usually helpful. ~icotinic acid is used as a vasodilator to augment cerebral circulation. It is given in large oral doses, usually 50 to 100 mg., one to three times a day. An initial flushing reaction and dizziness may occur, which is usually transitory. The use of pentylenetetrazol (Metrazol) orally, as a measure to overcome fatigue and mental confusion and stimulate the patient, has been of some help.23 It is given in 100 to 200 mg. doses, three times a day. Although I-glutamic acid has
1398
J. S. Gottlieb, G. Tourney, P. G. S. Beckett, P. Lowinger
also been advocated in the treatment of the aging patient, there is no evidence that it passes the blood brain barri('!' or has any effect Oil a(~tual cerebral metabolism. It must be re(:ognized that the psy(:hoses associated with arteriosclerosis and senility have a uniformly poor prognosis and frequently custodial or nursing home care is eventually indicated. Drug therapy is purely a symptomatic and temporary measure. SUMMARY ANn CONCLUSIONS
The aim of this contribution has been to present briefly the corwcpt of psychosis, classify the various psychoses, and describe their drug therapies. It has been pointed out that the psychoses usually require hospitalization, and that drug therapies are purely a symptomatic rather than a specific etiologie approach to their management. Other measures beside the use of drugs are required, including other somati(~ therapies, special nursing care, socialization and psy(:hotherapy. Treatment in each of the psychoses is dependent upon the diagnosis, which may require an extensive history, observation, and elillical and laboratory studies. 1'\ ot infrequently, ('ven after a diagnosis is made, considerable individualization of treatment depending OIl the severity of symptoms, premorbid personality and available facilities is indicated. The role of the new tranquilizing drugs, chlorpromazine and reserpine, in the treatment of the psychoses has been discussed. Their toxic symptoms, with which anyone using them must be familiar, have) been outlined. These drugs and similar products need further study to delineateearefully their proper use in the trpatmellt of emotional and mental disturbances. REFERENCES 1. Tourney, G., Tsi>erg, E. M. and Gottlieh, .1. H.: Use of Reserpine in an Aeutf.) Psychiatrie Treatment Setting. A.M.A. Arch. Neurol. & Psy(:hiat.. '14: 32.~, 1955. 2. Cohen, I. M. and Areher, J. D.: Liver Function and Hcpatie Complications in Patients Receiving Chlorpromazill() ..I.A.M.A. 15.9: un, 195f). 3. Council on I'h:mmwy and Chemistry: Blood DYRcrasias AS30ei,c\{'d with Chlorpromazine Thempv. J.A.M.A. WO: 287, 1\)55. 4. Elliott, R. N., Hchrut, A. H. and Marra. J ..1.: Fatal Acu'e As~ptie Nerosis of the Liver Associated with Chlorpromw ine. Am. J. Psychiat. 112: 940, 1956. 5. Kline, H. S.: Use of Rauwolfia Herpentina Benth. in NeJropsyehiatrie Conditions. Anll. Nc:w York Aead. Se. 5U: 107, 1954. 6. N oce, R. H., Willi:tms, D. B. and Rapaport, VI.: Reserpine (Herpasil) in lV:anagement of Mentally III and Ment~.lly Eet.:mj(,(1. J.A.lV'.A. 1517: 821, 1!l54. 7. Kline, N. H. and Htanley, A. M.: Use of R()sc:rpine in a Keuropsychiatrie Hospital. AIIIl. New York Aead. Se. 61: 8fi, Il1.55. 8. Lowinger, 1'.: Rauwolfia Serpentina ill Control of Anxiety. SubrniUc:d for publication. n. Winkelman, N. W . .Jr.: Chlorproma7,ine in Treatment of Neuropsychiatric Disorders. J.A.M.A. 155: 18, 1\).54. 10. Bird, E. G., Goss, J. D. Jr. and Denbpr, H. C.: Chlorpromazine in Tr(' ,tl'~():\L of Mental Illness: Study of 750 Pati()nts. Am ..1. Psychiat. 111: U"", El;);).
Drug Therapy
(~l
the Psychoses
1399
11. Killl'oss-Wright. Y.: Chlorpromazine ill Treatment of Mental Disorders. Am ..J. Psychiat. 111: 007, 1\J55. 12. Ayd, F. J . .1r.: Large Doses of Chlorpromazine in Treatment of Psychiatric Patients. Dis. J\Terv. System 16: 146, lOSS. 13. Gottlieb, .1. S.: Use of Sodium Amy tal and Benzedrine Sulfate in Symptomatic TreatnlPllt of Depressions. Dis. Nerv. System 10: 50, 1949. 14. Lehmann, H. K and Hanrahan, G. E.: Chlorpromazine: New Inhibitory Agent for Psy<,homotor Excitement and Manic States. A.M.A. Arch. Neurol. & Psychiat. 71: 227, 1\J54. 15. Sehultz, .1. D., Rea, E. L., Fazekas, .J. F. and Shea, J. C.: Chlorpromazine in ManagmllPnt of Acute Alcoholic States. Quart. J. Stud. Alcohol 16: 245, 1055. \(i. Avol, M. and Yogel, P. J.: Treatment of Delirium Tremens with Reserpine (Serpasil) ..I.A.M.A. 159: 1516, l055. 17. Broob, W., Deutsch, L. and DickeR, R.: Use of Chlorpromazine Hydrochloride in Treatment of Barbiturate Addiction with Acute Withdrawal Syndrome Am ..1. l's.vchi~t. 111: 6!)6, 1\J.~5. 18. Spies, T. D., Aring, C. D., Gelperin, J. and Bean, W. E.: Mental Symptoms of Pellagra and Their Relief with Nicotinic Acid. Am. J. M. Se. 196: 461, 1\J38. ID. Wilson, S. A.K. :tlld Eruee, A. N.: Neurology. 2d Ed. Baltimore, Williams & Wilkills Co., lOSS. 20. Bail', I!. V. and Herold, W.: Eflicaey of Chlorpromazine in Hyperactive Mentally Retarded Children. A.M.A. Arch. Neurol. & Psychiat. 7-4: 363, 1\155. 21. Bat'sa, .1. A. and Kline, N. S.: R<,sm-pinc in Treatment of Psychotics with Convulsivp Disorders. A.M.A. Ardl. Neurol. & I's.v<,hiat. 7-4: 31, 1(J.~fi. :l2. Kurland, A. A.: Chlorpromazine in Managempnt of Institutionalized Aged l'sydliatric Patient with Chronic Brain Syndrome. Dis. N erv. System 16: 360, UJ55. 23. Scidel, H., !-lilvcr, A. A. and Nagel, H.: Effects of Metrazol and Nicotinamide on Psychic and Mental Disorders in Geriatric Patient; Preliminary Report.. J. Am. Geriat. Soc. 1: 280, 1\)53. !)fil E. LafayeU,e Street lJdroit 7, Michig:tn
THE psychoses present a number of problems to the medical practitioner, in that they arc major disorders of thinking, feeling and behavior which may require immediate management and hospitalization. A part of this problem is certainly concerned with the fact that the concept "psychosis" means different things to different people. Some psychiatrists believe that this term should be disregarded completely, and that the major disturbances in feeling, thinking and behavior should be given a more specific diagnostic classification. The majority of physicians who deal with mental illness, however, believe that the term is a valuable and practical one. In general then, in this review, when the term "psychosis" is used a condition is meant in which one or more of the following difficulties is present. The individual's thinking may be so disturbed that he has difficulty differentiating his own subjective state from the external world; or he may have disturbances in comprehension or intellectual function. Delusions and hallucinations are also important symptoms of this disturbance. Or his emotional responses or feeling states may be quite inappropriate to the actual situation, and also inappropriate to his own thought processes. In addition to these more subtle difficulties, his behavior is frequently disorganized and poorly direeted; this may be manifested either as underactivity or overaetivity, withdrawal or overt antagonistic bchavior. Etiologically, the psychoses are related to a great many different factors. In some eases, definite psychogenic factors are probably most From the LafayeUe Clinic, Detroit, Michigan, and the Wayne University Collf{je of Medicine.
* Director, LafayeUe Clinic; Professor of Psychiatry, Wayne Univers1'ty College of Medicine.
*' Assistant Director in Charge of Educational Programs, Lafayette Clinic; ASbistant Professor of Psychiatry, Wayne University College of Medicine. t Staff Psychiatrist, LafayeUe Clinic; Instructor in Psychiatry, Wayne University Cl'llc(J€ of Medicine. 1385
1386
J. S. Gottlieb, G. l'ourney, P. G. S. Beckett, P. Lowinger
significant, while in other psychoses (such as general paresis, senility and arteriosclerotic brain disease), definite neuropathological changes occur. The psychoses in which the psychogenic element may be significant, and in which there is no structural change in the brain, are referred to as the functional psychoses; these include schizophrenia, manic-depressive psychosis and involutional psychosis. The psychoses in which neuropathologieal changes can be demonstrated are called organic psychoses and include a number of different processes related to infectious, degenerative, toxic, traumatic and neoplastic conditions. Certain drugs have been found to be helpful in the management and treatment of the psychoses. Recently, with the introduction of the tranquilizing drugs, reserpine and chlorpromazine, there has been great enthusiasm for this approach and many remarkable changes in symptomatology have been noted. However, experience shows that these drugs have many limitations. They have not replaced other somatic treatments, e.g., electroconvulsive therapy, in the management of the psychotic patient. It should also be realized that these drug therapies are nonspecific, and that the results obtained from them are purely symptomatic. The fundamental process of the illness generally remains in evidence after treatment. Frequently, however, these drugs contribute greatly to the psychotherapeutic and socialization programs. Their use leads to the patient's establishment of suitable contacts with other people and, frequently, to his understanding of some of the factors in his own illness. This combined therapeutic approach appears to be particularly useful in the management of schizophrenia. The current enthusiasm for the drug treatment of psychoses has led and is leading to the production and investigation of a great number of new substances, some of which are proving to be clinically useful. A great deal more experience is needed with most of these drugs, however, before one can definitely state their value. A number of significant sideeffects have been noted which in many cases may contraindicate their use. Reserpine (Serpasil), the most potent single alkaloid derivative of the Indian plant Rauwolfia serpentina, has been associated with a large number of complications. I These include hypotension, bradycardia, fatigue, listlessness, somnolence, diarrhea, the parkinsonian syndrome, dizziness, nasal congestion, and allergic responses such as dermatoses and the precipitation of asthmatic attacks. Chlorpromazine (Thorazine) presents even more serious problems; these include hypothermia, hypotension, fatigue and dizziness, somnolence, bradycardia, the parkinsonian syndrome, potentiation of the effects of narcotics, sedatives and alcohol, allergic responses, jaundice 2 and agranulocytosis. 3 The number of cases of agranulocytosis reported is increasing, and a number of deaths appeal' to be definitely related to the use of this drug. The cause of the jaundice has been felt to be either on an allergic or a stasis basis, or both. Some authors have minimized
Drug Therapy of the Psychoses
1387
the importance of jaundice and continued treatment. It is interesting to note that a recent case of acute aseptic necrosis of the liver occurred in a patient treated with chlorpromazine. 4 Another danger is the possible masking of infectious processes because of the hypothermia. From the above discussion it becomes apparent that considerable caution must be used with these substances in the treatment of mental illness. TilE FUNCTIONAL PSYCHOSES
Schizophrenia
Schizophrenia remains a disease of essentially unknown ongm, although new evidence as to hereditary, constitutional, physiochemical and psychodynamic factors is rapidly accumulating. It is the belief of many psychiatrists that this condition is a clinical syndrome made up of a number of different illnesses which in turn are related to many factors ranging from eonstitutional to psychological. Patients with this illness show a characteristic dii:lturbanee in the affect or feeling tone. By this is meant that the patient's emotional reaetion to situations is quite inappropriate. There is also a marked abnormality in the asso:;iative aspects of thinking and, with this, behavior may be quite disturbed, in that the patient may become withdrawn, or act out aggressively. Delusions and hallucinations are common symptoms of the illness. The om-let may be acute, but is frequently insidious. The treatment of a schizophrenic cannot be simply defined. The patient may Le acutely disturbed, or he may be easily manageable. At times he may be aggressive and paranoid in his behavior, and at other times he may obey instantly every order. The acuteness of onset, the duration of illness, the particular type of symptomatology, and the exact subclassification in many ways determines the treatment. In most cases, particularly the acute ones, treatment in a psychiatric hospital is indicated, where adequate safeguards, skilled nursing and a suitable social environment are present. In the hospital management of the acutely disturbed patient seclusion may be needed, but the use of drugs can be of considerable help. The intravenous injection of 0.5 gram (7% grains) of amobarbital sodium (Sodium Amy tal) will often result in very satisfac·tory control. The dosage can be repeated within four hours if necessary. Scopolamine given in doses of 0.6 mg. (1/100 grain) may also work well in the management of the acute schizophrenic patient. This medication can be repeated after a thrcp-hour period. It has a very useful sedative and hypnotic effect for the schizophrf'nic, but it cannot be utilized in prolonged therapy. Other sedatives alld hypnotics, such as barbital and chloral hydrate, can be used, but frequently largPr doses than the standard U.S.P. recommendations are needed. Since its introduction, reserpine has proved effpctive in the manage-
1388
J. S. Gottlieb, G. Tourney, P. G. S. Beckett, P. Lowinger
ment of the psychomotor excitement and many other acute symptoms of schizophrenia.)' 5-8 It can be administered intramuseularly in doses of 2.5 to 5 mg., which are repeated to give a total of 12.5 to 15 mg. during a 24 hour period. Over a period of four to seven days, as the patient becomes more cooperative, the total dose can be gradually redw:ed and parenteral medication discontinued, with the patient being maintained on 3 to 6 mg. of oral preparation per day. After seven to 14 days the patient can often be managed on :i mg. per day. Even with adequate drug medication, many patients remain disturbed and other measures must be uEed, such as eleetroconvulsive therapy and insulin hypoglycemic therapy. Reserpine has a useful function in the treatment of the schizophrenia but it has not replaced other approaehes, somatic or psychotherapeutie. Instead, it complements them. Chlorpromazine has been used by a number of investigators 7, 9-12 and has been regarded as a valuable medication in the control of psychomotor excitement and anxiety of acute schizophrenia. Use of initial doses of 50 mg. by deep intramuscular injection two to six times daily has been reported. In addition, an oral dose of 50 to 100 mg. was given three to four times a day. Parenteral and oral doses may be increased, so that the total dosage may be as high as 800 mg. a day. This dosage has been continued for up to four weeks and longer as part of a treatment program. Other investigators have used mueh higher dosages ranging as high as 4000 mg. a day, but there is good evidenee that the lower doses reeommended are equally satisfaetory in providing the remissions. In our experienee, because of the serious toxicity deseribed pn~viously from both high and low doses of chlorpromazine, this medication has been used infrequently. There is reason to believe that chlorpromazine treatment of schizophrenia is more hazardous than the use of electrotherapy ill terms of patirmt morbidity and mortality. Less disturbed schizophrenic patienes often can be managed, sometimes on an outpatient basis, with smaller doses of reserpine. These doses are in the range of 1 to 6 mg. a day given orally. In these patients, mild agitation and anxiety symptoms are reduced, and often there is much less concern about delusions and hallucinations. However, on careful examination, the primary symptoms of schizophrenia remain including both the association disturbance as also the affective changes. Individuals respond much better in their interpersonal relationships, begin to enter ward or social activities, and are able to talk about many of their problems in psychotherapy. Manic-Depressive Psychosis
Depressions
The term "depression" is a descriptive one. Depression presents itself as a symptom in a number of psychiatric disorders including psychoneurosis and functional and organic psychoses. Some of these reactions
Drug Therapy of the Psychoses
1389
are definitely of psychotic proportions, but a large number are not. Only by a thorough examination and possibly by a period of observation can one define the type and depth of depression. The principal types of depression are the reactive depression or neurotic depression; manicdepressive psychosis, depressed type; involutional psychosis, depressed type; and depression associated with organic brain disease. The discussion here is concerned only with the psychotic depressions. In these conditions there is characteristically depressed mood, retardation of speech and psychomotor antivity, difficulty in sleeping (particularly with early morning awakening), loss of appetite, loss of interest, fatigue, suicidal preonnupation, and thoughts of self-blame and self-abnegation. The illness usually occurs between the ages of 18 and 40 years. Typically, the depressions occur periodinally, but some individuals may have only one attack in a lifetime. Oncasionally, there are alternating periods of depression and elation. Each episode of depression may last from three months to two years, but suicide is always a risk. In the more severe depressions of this type, hospitalization is definitely indicated. Because of appetite and weight loss there may be dehydration and nutritional deficiencies, hence it is advisable to supplement the diet with vitamins and provide a high calorie intake and adequate fluids. Hypnotics are needed for the sleep disturbances. In our experience, chloral hydrate has been more useful than the barbiturates and is usually given in doses of 0.5 to 1 gram. Amobarbital sodium (Sodium Amy tal) in doses of 200 to 300 mg. (2 to 5 grains) has also been used. In mild depressions, hospitalization is usually not indicated, although some supervision in the home may be necessary to guard against suicide. For these mild cases, onc may u"e amobarbital sodium and racemic amphetamine sulfate (Benzedrine), given together. 13 These drugs have a synergistic antidepressive action, and therefore are more effective when used together than singly. They should be given on rising in the morning and at noon. Ordinarily, amobarbital sodium in doses of 60 to 100 mg. is given with 5 to 10 mg. of racemic amphetamine sulfatc. If somnolence or drowsiness tends to occur with this regimen, the amobarbital sodium is decreased and the amphetamine may be increased. If excitement and restlessness occur, the opposite change in dosage is made. In the late afternoon (for instance, at 4 P.M.), the dose of amobarbital sodium may be given alone in order to produce a certain amount of sedation if needed. Those depressions of moderate and severe degree which require hospitalization usually do not respond to the above management. A number of new experimental drugs, such as Ritalin and Meretran, are being evaluated at the present time, but their efficacy has not yet been proved. Most moderate and scvcr<~ dppressions require electroconvulsive therapy. M anic Episodes
In the manic episodes of manic-depressive illness the subject feels elated, becomes overactive, overenthusiastic, jovial, grandiose and un-
1390
J. S. Gottlieb, G. Tourney, P. G. S. Beckett, P. Lowinger
realistic in his thinking. He becomes so engrossed in his own t.houghts and activities that he frequently refuses to eat. and as a result nutritional disturbances, such as dehydration and electrolyte imbalance, are common. Close dietary supervision, as outlined under depreiolsion, is necessary. Sedation is oftpll needed to reducp the overactivity and to aid in the avoidance of exhaustioll which can })(' a very real problem. The nse of intravenouiol amobarbital sodium may be necessary to combat the patient's resistance and uncooperation. It is given as for the acutely disturbed sehizophrenic patient. Hmvevcr, this type of sedation can be used only for a short period of time to handle the immediate excitement. Chlorpromazine has reeently been suggested for the treatment of mania. 14 On occasion it redueeiol the overaetivity quite readily. Ordinarily, such patients are giv(,l1 up to 500 mg. a day in doses of 100 mg. orally every four to iolix hours. If the patients arc noncooperative, one can give 100 mg. by deep intramuscular injection. The parenteral administration is often needed early in the course of the disease but can be supplemented by oral medieat.ion later. Chlorpromazine, hmvever, has definite limitations in th(' management of mania, not only because of its toxic side effects but becam,e its effects arp often temporary. A more rapid recovery may be obtained by the use of electroconvulsive t.herapy. Involutional Psychosis
Involutional psychosis occurs after the age of 4.5 years, and is characterized by depression, somatic concern and paranoid thoughts. Again, thoughts of self-blame and self-abnegation, suicidal tendencies, agitation and restlessness, severe insomnia, appetite loss and weight loss arc prominent symptomiol. The illness accounts for a large number of suicides in this age group. The physical state of the patient with involutional psychosis may be severely depleted, hence treatmpnt for dehydration and undernourishment must be carried out. As with manic-depressive illness, various hypnotics may be needed to produce sleep and reduce agitation; again chloral hydrate is the preferred drug. Estrogenic hormones in the female and testosterone in the male have been of little or no value in the treatment of involutional psychosiiol, although these drugiol may relieve some of the symptoms of the menopausal syndrome. Amphetamine and amobarbital sodium when used as described above may be helpful, but in moderate and severe depressions these drugs are really of little value. As with the manic-depressive illneRs, electroconvuliolive therapy is indieated. Conclusions
Before pro('eeding further it should llf' pointed out that the use of drugs for the funetional psychoses have symptomatic value only and must be considered aiol one aspect of a total therapeutic approach.
Drug Therapy of the Psychoses
1391
As has been mentioned, electroconvulsive therapy is the most specific treatment for the patients with depressive psychoses. The new tranquilizing drugs are of importance because of the symptomatic improvement which allmvs the applicatiOll of the very important socialization and psychotherapeutic technique:,;. TIlE ORGANIC PSYCHOSES
In these conditions the psychosis is related to organic brain disease. The characteristic symptomatology involves thinking, feeling and behavior, often reflects the premorbid personality patterns, and may be of any degree of severity. The organic psychoses may be acute or chronic. Ordinarily the acute organic psychoses are not associated with structural brain disease and are reversible, while the chronic organic psychoses are part of an irreversible organic process. Both the acute and chronic psychoses may be due to or a:,;sociated with infectious processes, intoxication, trauma, circulatory disturbances, disturbances of metabolism, nutrition, neoplasm, or to uncertain causes. Characterizing the organic psychoses are a number of symptoms often referred to as the organic: syndrome. Typically there is a memory disturbance, with recent memory and retention being involved more severely. With this is associated anxiety, confusion and disorientation. Impairment of the critical faculties and judgment occurs. The emotions bec:ome quite labile; there is easy laughter and crying. Attention difficulties are common. Finally one may observe delusions and hallucinations. Physical and neurological symptoms such as tremor, speech difficulties, poor coordination, and ataxia are often present. Acute Deliria and Toxic Reactions
Acute deliria probably account for the greatest number of psychotic reactions seen in medic:al prac:tice. Such deliria oc:cur in association with aieoholism, drug intoxicatioll, infectious diseases, cardiovascular disease, injuries, and postoperative ('omplications.
Delirium Tremens The most common alc:oholic psychosis is delirium tremens. Although this may vary considerably in severity of symptoms, it should be recognized as a serious illness that needs energetic treatment. Incipient delirium tremens, characterized by anxiety and tremors, may occur in a chronic alcoholic who has continued to drink heavily, but is also precipitated by the sudden withdrawal from alcohol. The condition may progress to an overt psychosis with such symptoms as marked psyc:homotor excitement, overactivity and vivid visual halluninations. Hospitalization then becomes nec:essary. Various drugs play an important role in the treatmmlt of delirium tremens. Such treatment ineludes the use of the "Bellevue Cocktail"
1392
J. S. Gottlieb, G. Tourney, P. G. S. Beckett, P. Lowinger
given intravenously as frequently as three to four times a day. This is a mixture of 50 cc. of 50 per cent glucose, 20 units of regular insulin, thiamine 50 mg., nicotinic acid 100 mg., and ascorbic acid 100 mg. The oral administration of paraldehyde in doses of 8 to 16 cc. every four to six hours reduces excitement, anxiety and concern over hallucinations. Other management should inelude liberal amounts of oral fluids ineluding water, fruit juices and milk in amounts of 3000 to 4000 cc. per day, 2 grams of sodium chloride three times a day, high calorie, high vitamin diet, and oral as well as parenteral vitamins of the B complex group. In the more severe cases of delirium tremens, parenteral fluids may be required. An occasional complication of delirium tremens is an infeetious process which may increase the degree of delirium and should be treated appropriately. Other associated illnesses include cardiac decompensation, head injury, and grand mal convulsions. To forestall or treat the convulsions, Dilantin 0.1 gram may be given three times a day. More recently, newer drugs such as chlorpromazine 15 and reserpine 16 have been advocated for the control of excitement and overactivity of these patients. However, because chlorpromazine potentiates the effect of alcohol and also has led to repeated eases of jaundice, we have felt that this drug is not indicated.
Barbiturate Delirium Various barbiturates may produce a wide variety of psychiatric syndromes. The coma of acute barbiturate poisoning is well recognized. Barbituratps may also produce many of the same symptoms as alcohol, and frequently the clinical picture elosely resemhles delirium tremens. Many patients have been consuming large quantities of hoth alcohol and barbiturates for prolonged periods, so that the exact etiology of the subsequent reaction may not be entirely dear. The treatment of delirious reactions related to barbiturates elosely resembles the treatment of alcoholic: delirium tremens. Fluid administration and sedation are the most important measures. Also, on(~ mU8t realize that ehlorpromazine potentiates barbituraks as well as alc:ohol, hence this drug should be used eautiously, if at allY The withdrawal of barbiturates from patients long habituated to them should be done gradually, so that anxiety, convulsions and psychotic symptoms may be minimized. This withdrawal is often necessary in the deliriou8 patient, consequently the patient should be placed on a gradually decreasing maintenance dose of the barbiturate, given at regular intervals. If the previous dose is unknown, the standard D.S.P. dosage of any of the barbiturates may be used three to four times daily. Proportionate reduction of this dose over a five to 15 day period usually proves suitable. For the sedation of an excited barbiturate patient, who may be suffering from marked tremors and hallucinations, paraldehyde is preferable in
Drug Therapy of the Psychoses
1893
oral doses of 8 to 16 cc. given every four to six hours for symptomatic relief.
Bromide Intoxication Bromides, commonly used in patent medicines, may lead to the development of psychosis if taken over a long period of time. The bromide replaces the chloride of the blood, and psychosis is usually associated with a blood bromide level of 150 mg. per 100 cc. In the bromide psychosis there is confusion, disorientation, hallucinations, paranoid thoughts, and often an acneform rash. In the treatment of such reactions, one should immediately stop the ingestion of the drug and give 6 to 8 grams of sodium chloride in enteric-coated capsules in divided doses, and 4000 to 5000 cc. of fluids a day as long as there is no evidence of cardiac or renal disease. Such psychotic reactions usually clear in two to six weeks.
Deliria Associated with Systemic Disease Toxic psychoses are commonly seen during an infectious illness, following injury or surgery, and in cardiovascular renal disease. These reactions may have many and various precipitating factors. In some cases psychological stress seems to be an important factor, which includes fears and misconceptions concerning surgery, guilt over circumstances of the injury, difficulties in the emotional acceptance of illness, and similar types of experiences. It is interesting to note that psychotic reactions not uncommonly occur following surgical procedures on the genitalia and the eyes, these organ systems having considerable emotional significance for each individual. In other circumstances, more purely physical factors may be significant. Such factors include fluid and electrolyte imbalance, toxic reactions to various drugs, toxic factors associated with infectious diseases, uremia, anoxia, other metabolic disturbances, and cerebral arteriosclerosis. Most often there is a combination of various stresses, some obvious and others not so obvious, which lead to a disturbed patient on a general hospital ward. Symptoms which these patients show may be many and varied. There is often confusion and disorientation, especially at night, with the patient behaving as if he were not in a hospital at all. He may have hallucinations of friends or relatives in his room or in the hall. Often he becomes overactive and wants to leave his room and the hospital. The patient may be quiet, retarded, depressed, or even logical and rational most of the time, but highly suspicious that he is being poisoned and persecuted. The management of such a problem will depend primarily on a thorough investigation of all the factors involved. It will be necessary to know as much as possible about the extent of physical disease and whether it is systemic or intracranial. Heart failure, myxedema, Cushing's syndrome and lupus erythematosus are examples of diseases that may present
1394
J. S. Gottlieb, G. Tourney, P. G. S. Becketl, P. Lowinger
predominantly psychotic symptoms before the physical manifestations are readily apparent. Another point for early consideration in the management of these cases is a careful check on the medication that the patient has been receiving. It may sometimes happen that there has been a continuation of large doses of narcotics, barbiturates or other drugs which, especially in elderly people, may not be necessary. These drugs complicate any underlying confused or delirious state and should be reduced in amount or discontinued in so far as possible. A convenient hypnotic which may be substituted is chloral hydrate, 0.5 to 1 gram, given orally at night and repeated if necessary. Regular treatment of the underlying physical disease must be continued and special attention paid to fluid and electrolyte balance. The possibility of intracranial complications and complicating infectious processes should be considered. A light left on in the room at night may help considerably in orienting the confused patient. Once the current status of the patient has been thoroughly evaluated, the restlessness, anxiety and bewilderment so frequently present can be treated effectively by such new drugs as reserpine or chlorpromazine. Chlorpromazine may be given by deep intramuscular injection in doses beginning with 25 or 50 mg. three or four times a day, later supplemented by oral medication, 50 mg. four to six times a day. Dosage may be increased to a total of 400 to 500 mg. per day if necessary. Reserpine has also been helpful in managing these reactions and is given intravenously or intramwlcularly in doses of 2.5 to 5 mg. and repeated once or twice during the first day. Oral medication can be given to replace the parenteral medication ill doses of 2 to 6 mg. per day in three to four divided doses. With thiH approach to the acute toxic reactions, one usually sees marked improvement in a matter of several days, and recovery not infrequently within a period of a week. These eases are often treated effectively in a general hospital in which there is good nursing care, which may at first need be on a 24 hour basis for the disturbed patient to avoid the possibility of self-injury or even suicide.
Traumatic Delirium An acute delirious reaction to head trauma may appear as the patient emerges from stupor or coma. The underlying cause may be concussion, contusion, laceration, hemorrhage or increaHed intracranial pressure. However, in most cases the actual cerebral damage is mild and no focal lesion is elicitable. It is far more common in children than adults. In any such ease, thorough neurological and neurosurgical investigation is necessary. There is often confusion, di~;orientation, marked irritability and very vivid and terrifying. hallucinations. This reaction often requires hospitalization in a psychiatric setting. Chlorpromazine and reserpine, used in dosages described for the toxic deliria, may be of aid in the man-
Drug Therapy of the Psychoses
1395
agement of this illness, which will usually clear within one to three weeks if no serious organic disease is present. Other Alcoholic Psychoses
Delirium tremens, the most common alcoholic psychosis, was discussed previously. Chronic psychotic reactions associated with alcoholism include chronic hallucinosis, paranoid alcoholic psychosis and simple deterioration. With these conditions there is little or no response to drug therapy and care is largely institutional in nature. Two less common alcoholic reactiolls are Korsakoff's psychosis and Wernicke's encephalopathy. Treatment consists of improving the nutritional state with the utilization of multiple vitamins as des(:ribed under "Delirium Tremens." Vitamin Deficiencies
Cerebral symptoms oceur with vitamin deficiencies, particularly those of the vitamin B complex group which play a very integral role in cerebral metabolism. Wernicke's encephalopathy may be associated with such deficiency states. Psychoses with pellagra arc characterized by dementia and delirium. These, too, are often associated with alcoholism. These cases respond very well to ni(:otinic acid. 18 However, deficiencies involving the other B groups are usually present, and so B complex medication should be given. One hundred milligrams of nicotinic acid amide every two hours, given parenterally or orally, may be valuable. Subsequently the dosage may be reduced to 100 mg. given orally four times a day, Psychosis Associated with Metanic Poisons
A psychotic picture may follow the ingestion of heavy metals. A few examples will be discussed with emphasis on the use of drugs and their treatment. BAL (British anti-lewisite) is useful in promoting the excretion of certain metallic poisons. This is particularly true of arsenic, mercury, thallium and cadmium. A 5 per cent solution in peanut oil and benzyl benzoate, given by the intramuscular route in amounts of 2 cc. every four hours, should be given during the first day. During eaeh of the second, third and fourth days, two doses of 2 cc. each are given, and for the fifth and sixth days, only one dose of 2 cc. is administered each day.19 The encephalopathy, delirium or convulsions of lead poisoning, especially as they occur in children or after poisoning by tetraethyllead vapor, respond less well to BAL. This reaction may need a sedative program similar to that discussed under toxic psychosis and such symptomatic measures as may be necessary to eontrol convulsions and excitability. In the initial stages, a high calcium diet, including 2 quarts of milk daily and 5 gram;; of calcium lactate three times a day, promotes fixation of lead in the bones. 19 Whpll the toxic symptoms have disappeared, a low calcium diet and careful use of ammonium chloride, 1 gram
1396
J. S. Gottlieb, G. Tourney, P. G. S. Beckett, P. Lowinger
eight to ten times a day for as long as three weeks, will help to promote lead excretion. Ammonium chloride should not be given in the presence of symptoms of encephalopathy. * Chronic Psychotic Reactions Associated with Central Nervous SysteDl Disease
Another common problem in practice is presented by a patient with a chronic central nervous system disease associated with psychosis, severe behavioral disturbances, mental deficiency or dementia. Here, again, the new tranquilizing drugs are useful. In hyperactive retarded children, 25 to 100 mg. or more of chlorpromazine intramuscularly per day is effective. 2o In seriously disturbed adult psychotic epileptic patients, reserpine in initial dose of 2.5 to 5 mg. intramuscularly plus 3 mg. orally with gradual tapering off of the intramuscular dose, and continuance of the oral dose, has given good results. 21 However, with both reserpine and chlorpromazine seizures may increase, hence anticonvulsant medication should always; be used. In Huntington's chorea reserpine, used as described above, has been of considerable value in controlling motor behavior. Convulsive Disorders
Other patients in whom psychotic behavior accompanies psychomotor or temporal lobe epilepsy and in whom a surgical treatable lesion has been excluded, are more difficult to control. When surgical therapy is not indicated, a specific antieonvulsant should be given. Epilepsy may lead to an acute confusional state and psychosis in some cases following grand mal convulsions, as well as states of chronic epileptic deterioration. Severe epileptic episodes of confusion and continuously uncontrolled behavior often require hospitalization of the patient and immediate sedation. A useful drug is amobarbital sodium given in doses of 0.5 to 1 gram intravenously and followed by sodium phenobarbital 0.1:3 to 0.25 gram intramuscularly every four to six hours. Paresis
General paresis, a disease of the central nervous system associated with syphilis, ordinarily results in psychotic behavior. Other forms of neurosyphilis do not usually lead to a definite psychotic pattern of behavior. Typical organic symptoms, such as gradual intellectual deterioration as well as depression, manic behavior, delusions and hallucinations, and paranoid behavior, may occur in the paretic. With the introduction of penicillin in the treatment of paresis, fever therapies and the use of heavy metals have largely been replaced. The usual treatment of paresis consists of penicillin, 300,000 units, twice a day to total at least 12 million units. * Calcium versenate (Ca EDT A) is also being used suecessfully in the treatment of children with lead encephalopathy.--Ej.
Drug Therapy of the Psychoses
1397
Psychoses Associated with Arteriosclerosis and Senility
With increased life expectancy, it is not surprising that a larger number of psychotic reactions of an organic nature related to senility and arterioscleroti(~ changes are seen by the medical practitioner. It is difficult to differentiate between pure senile and arteriosclerotic reactions, and these may often occur concomitantly. Since the symptomatic pictures and the treatment methods are similar, they are described together. Both of these illnesses occur late in life, and are characterized by a gradual impairment of brain tissue function. The symptoms develop insidiously and often consist of a gradual breakdown in high cultural and ethical standards, impairment in skills, disturbances of memory and judgment, and often delusions and hallucinations. Eventually the individual becomes quite deteriorated in his intellectual function, personal care and behavior. Acute cerebral syndromes developing later in life are confused with chronic brain reactions in this age group, and may lead to unnecessary custodial care. The aging person with beginning senile and arteriosclerotic changes is more susceptible to mild injuries, infections, small doses of alcohol, drugs, and other stressful stimuli. Such toxic reactions can be managed by reducing drug or alcohol intake, treating injuries and infections and the initiation of measures to improve the nutritional state of the patient. The specific methods described for treatment of the acute toxic psychoses are applicable here. Drug doses should be made proportionately lower for the elderly individual. Milder cases of senile and arteriosclerotic brain syndromes may be cared for in the home where the patient has a routine and familiar environment. However, problems frequently occur, such as nocturnal restlessness and delirium. It is best to avoid much sedation, particularly the use of the barbiturates. Small doses of chloral hydrate, 0.5 to 1 gram, may be helpful when sedation is needed. When delusions, hallucinations or agitation become prominent, small oral doses of reserpine, 1 to 3 mg. per day, or chlorpromazine, 100 to 300 mg. a day, may be used. 22 Many of these patients are depressed and may require hospitalization and electroconvulsive therapy. Amphetamine and amobarbital sodium, used in doses of 5 mg. and 60 mg. respectively, with adjustment of dose as described in the discussion of depressiolls, may be useful. An important aspect of treatment is to maintain the nutritional state since many arterioseierotic and senile patients become quite capricious about their appetites and refuse to eat many foods. Supplementary vitamins arc usually helpful. ~icotinic acid is used as a vasodilator to augment cerebral circulation. It is given in large oral doses, usually 50 to 100 mg., one to three times a day. An initial flushing reaction and dizziness may occur, which is usually transitory. The use of pentylenetetrazol (Metrazol) orally, as a measure to overcome fatigue and mental confusion and stimulate the patient, has been of some help.23 It is given in 100 to 200 mg. doses, three times a day. Although I-glutamic acid has
1398
J. S. Gottlieb, G. Tourney, P. G. S. Beckett, P. Lowinger
also been advocated in the treatment of the aging patient, there is no evidence that it passes the blood brain barri('!' or has any effect Oil a(~tual cerebral metabolism. It must be re(:ognized that the psy(:hoses associated with arteriosclerosis and senility have a uniformly poor prognosis and frequently custodial or nursing home care is eventually indicated. Drug therapy is purely a symptomatic and temporary measure. SUMMARY ANn CONCLUSIONS
The aim of this contribution has been to present briefly the corwcpt of psychosis, classify the various psychoses, and describe their drug therapies. It has been pointed out that the psychoses usually require hospitalization, and that drug therapies are purely a symptomatic rather than a specific etiologie approach to their management. Other measures beside the use of drugs are required, including other somati(~ therapies, special nursing care, socialization and psy(:hotherapy. Treatment in each of the psychoses is dependent upon the diagnosis, which may require an extensive history, observation, and elillical and laboratory studies. 1'\ ot infrequently, ('ven after a diagnosis is made, considerable individualization of treatment depending OIl the severity of symptoms, premorbid personality and available facilities is indicated. The role of the new tranquilizing drugs, chlorpromazine and reserpine, in the treatment of the psychoses has been discussed. Their toxic symptoms, with which anyone using them must be familiar, have) been outlined. These drugs and similar products need further study to delineateearefully their proper use in the trpatmellt of emotional and mental disturbances. REFERENCES 1. Tourney, G., Tsi>erg, E. M. and Gottlieh, .1. H.: Use of Reserpine in an Aeutf.) Psychiatrie Treatment Setting. A.M.A. Arch. Neurol. & Psy(:hiat.. '14: 32.~, 1955. 2. Cohen, I. M. and Areher, J. D.: Liver Function and Hcpatie Complications in Patients Receiving Chlorpromazill() ..I.A.M.A. 15.9: un, 195f). 3. Council on I'h:mmwy and Chemistry: Blood DYRcrasias AS30ei,c\{'d with Chlorpromazine Thempv. J.A.M.A. WO: 287, 1\)55. 4. Elliott, R. N., Hchrut, A. H. and Marra. J ..1.: Fatal Acu'e As~ptie Nerosis of the Liver Associated with Chlorpromw ine. Am. J. Psychiat. 112: 940, 1956. 5. Kline, H. S.: Use of Rauwolfia Herpentina Benth. in NeJropsyehiatrie Conditions. Anll. Nc:w York Aead. Se. 5U: 107, 1954. 6. N oce, R. H., Willi:tms, D. B. and Rapaport, VI.: Reserpine (Herpasil) in lV:anagement of Mentally III and Ment~.lly Eet.:mj(,(1. J.A.lV'.A. 1517: 821, 1!l54. 7. Kline, N. H. and Htanley, A. M.: Use of R()sc:rpine in a Keuropsychiatrie Hospital. AIIIl. New York Aead. Se. 61: 8fi, Il1.55. 8. Lowinger, 1'.: Rauwolfia Serpentina ill Control of Anxiety. SubrniUc:d for publication. n. Winkelman, N. W . .Jr.: Chlorproma7,ine in Treatment of Neuropsychiatric Disorders. J.A.M.A. 155: 18, 1\).54. 10. Bird, E. G., Goss, J. D. Jr. and Denbpr, H. C.: Chlorpromazine in Tr(' ,tl'~():\L of Mental Illness: Study of 750 Pati()nts. Am ..1. Psychiat. 111: U"", El;);).
Drug Therapy
(~l
the Psychoses
1399
11. Killl'oss-Wright. Y.: Chlorpromazine ill Treatment of Mental Disorders. Am ..J. Psychiat. 111: 007, 1\J55. 12. Ayd, F. J . .1r.: Large Doses of Chlorpromazine in Treatment of Psychiatric Patients. Dis. J\Terv. System 16: 146, lOSS. 13. Gottlieb, .1. S.: Use of Sodium Amy tal and Benzedrine Sulfate in Symptomatic TreatnlPllt of Depressions. Dis. Nerv. System 10: 50, 1949. 14. Lehmann, H. K and Hanrahan, G. E.: Chlorpromazine: New Inhibitory Agent for Psy<,homotor Excitement and Manic States. A.M.A. Arch. Neurol. & Psychiat. 71: 227, 1\J54. 15. Sehultz, .1. D., Rea, E. L., Fazekas, .J. F. and Shea, J. C.: Chlorpromazine in ManagmllPnt of Acute Alcoholic States. Quart. J. Stud. Alcohol 16: 245, 1055. \(i. Avol, M. and Yogel, P. J.: Treatment of Delirium Tremens with Reserpine (Serpasil) ..I.A.M.A. 159: 1516, l055. 17. Broob, W., Deutsch, L. and DickeR, R.: Use of Chlorpromazine Hydrochloride in Treatment of Barbiturate Addiction with Acute Withdrawal Syndrome Am ..1. l's.vchi~t. 111: 6!)6, 1\J.~5. 18. Spies, T. D., Aring, C. D., Gelperin, J. and Bean, W. E.: Mental Symptoms of Pellagra and Their Relief with Nicotinic Acid. Am. J. M. Se. 196: 461, 1\J38. ID. Wilson, S. A.K. :tlld Eruee, A. N.: Neurology. 2d Ed. Baltimore, Williams & Wilkills Co., lOSS. 20. Bail', I!. V. and Herold, W.: Eflicaey of Chlorpromazine in Hyperactive Mentally Retarded Children. A.M.A. Arch. Neurol. & Psychiat. 7-4: 363, 1\155. 21. Bat'sa, .1. A. and Kline, N. S.: R<,sm-pinc in Treatment of Psychotics with Convulsivp Disorders. A.M.A. Ardl. Neurol. & I's.v<,hiat. 7-4: 31, 1(J.~fi. :l2. Kurland, A. A.: Chlorpromazine in Managempnt of Institutionalized Aged l'sydliatric Patient with Chronic Brain Syndrome. Dis. N erv. System 16: 360, UJ55. 23. Scidel, H., !-lilvcr, A. A. and Nagel, H.: Effects of Metrazol and Nicotinamide on Psychic and Mental Disorders in Geriatric Patient; Preliminary Report.. J. Am. Geriat. Soc. 1: 280, 1\)53. !)fil E. LafayeU,e Street lJdroit 7, Michig:tn