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Lithium Carbonate–Is it Successful?
Lithium Carbonate -
Is It Successful?
GILBERT C. MILNER, III, M.D., WILLIAM C. RUFFIN, NANCY H. MCGINNIS, M.A. INTRODUCTION • Lithium carbonate as a specific psychopharmacologic agent in the treatment of manic-depressive illness has been known for over 20 years but was not approved by the F.D.A. until 1970. The general historical course followed by a drug initially offering clinical promise can be divided into four stages: 1) enthusiastic response immediately after discovery; 2) verifying reports by other investigators; 3) application of the drug outside the originally discovered area of effectiveness with reported favorable results; and 4) increasing criticism, resulting in more critical investigations to delineate the limits of efficacy of the drug. It appears that lithium is presently in this fourth stage. REVIEW OF LITERATURE The original use of lithium for treatment of mania was discovered in 1949 by Cade l in Australia. While investigating the toxic effects of uric acid and urea, he noted the concomitant sedative properties of lithium. He then treated ten cases of manic excitement in bipolar manic depressive illness (cyclic affective states with at least one episode of mania), reporting dramatic improvement in all. This study, however, was criticized for lack of double-blind and placebo controls. Doubleblind placebo-controlled studies were then reported by Schou 2 in Denmark. Of 38 patients demonstrating manic behavior, 14 derived some benefit, 6 no benefit, and 18 questionable benefit over a two-year treatment period. ImDr. Milner is a Resident, Dr. Ruffin is Professor of Psychiatry and Miss McGinnis is Research Assistant, Department of Psychiatry, University of Florida, College of Medicine, Gainesville, Florida 32601. September-October 1971
JR., M.D., and
provement was most frequent in patients witn a history of bipolar manic depressive illness. Those deriving no benefit were "atypical manic reactions" or possibly schizoaffective states. However, manic symptoms recurred when lithium was withdrawn. Fieve and Wharton'l in a single-blind study of 25 patients, with manic excitements previously resistant to phenothiazines, found lithium effective in 44% and possibly effective in another 24%. Bunney' in an extensive, detailed double-blind placebo-controlled study, found that daily doses of lithium not only reduced the mania but returned patients to their normal states. Also, again, manic symptoms rapidly returned with lithium withdrawal. A world literature review in 1967 by Schou 5 reported 1800 cases of mania treated with lithium, of which approximately 80% responded with excellent to modest improvement. When lithium was extended from the treatment of mania to other conditions, specifically cyclic depressive episodes,l.6 little or no amelioration was reported. In a recent study comparing patients with unipolar depressive symptomatology (cyclic depressions with no manic episodes) to bipolar (having at least one previous episode of mania alternating with depressions), 10 of 14 in the bipolar group showed definite improvement, but none of the five in the unipolar group showed improvement. Lithium's effectiveness as a prophylactic agent in preventing recurrent mood disorders was next investigated. Hartigan,~ on the basis of informal observations, first proposed the possible prophylactic effects of lithium in prolonging the period between manic or depressive episodes. His observations were supported by a 6th-year study of Baastrup and Schou,n which found that lithium treatment: 1) effectively lowered the average length of time in psychotic states per year; 2) shortened the 321
PSYCHOSOMATICS
duration of relapses; and 3) significantly lengthened the period between relapses. Again, it was noted that bipolar manic depressive states responded more favorably than the recurrent depressions, with the atypical depressions showing paranoid symptomatology responding least favorably. Blackwell and Shepherd 1<' criticized this study on the basis of insufficiently rigorous criteria for the selection of patients, the definition of prophylaxis, faulty evaluation, and over-enthusiastic observer bias in interpreting the results. Baastrup and Schou in combination with Angst and Weiss,l1 followed with a study of 244 patients on maintenance lithium therapy. In those cases of recurrent depression the time between episodes was lengthened 76% and in bipolar manic depressive states it was lengthened 61 %. However, only in the bipolar manic depressive illnesses were the episodes of depression significantly shortened. A doubleblind placebo-controlled study of patients on lithium maintenance for at least one year (50 diagnosed as cyclic manic depressives; 34 as recurrent endogenous depressions) was conducted". In both groups who were continued on lithium there were no recurrences of symptoms; however, in those switched to a placebo, 55 % of patients with bipolar manic depressive illness and 53% with recurrent depressions relapsed. Other studies, particularly in the United States, have not yielded such affirmative results. Fieve, Platman, and Plutchik 13 reported that lithium did not alter the frequency of attacks but acted as a mild antidepressant for each depressive attack and as a strong antimanic agent for each recurrent manic episode. The prophylactic effect of maintenance lithium is still questionable; however, there is some evidence that phophylaxis occurs in a greater percentage of cases of bipolar manic depressive illness than in recurrent depressions. Lithium has also been used to treat other emotional and behavioral disorders involving hyperexcitability, in particular the schizoaffective states. Sclagenhauf, Tupin, and White" found lithium exerted excellent sedative effects in intense psychomotor agitation in schizoaffective states. but it did not alter 322
the underlying thought disorder. Zall' 5 applied this effect as a diagnostic tool; that is, lithium was used to reduce intense agitation in order to more clearly delineate the basic thought disturbances. Still, most investigators consider the phenothiazines to be superior to lithium in the treatment of schizoaffective states. This brief summary of the literature suggests that lithium exerts a demonstrable antimanic effect, returning patients to their normal mood states. It apparently exerts a mild sedative effect in other conditions with hyperexcitability as a prominent symptom, particularly the schizoaffective state, but in no way alters the thought disorders. Its effect on a single episode of depression in the bipolar manic depressive states and in unipolar recurrent depressive states is still not completely understood. However, recent investigations indicate that it has a significantly greater antidepressant effect in the bipolar states, as opposed to the unipolar. Also, recent studies indicate that lithium exerts a definite prophylactic effect on the recurrent mood disorders, both in lengthening the cycle betweeq exacerbations and shortening the episode. METHOD OF ACTION
Studies by Winokur, Clayton, and Reich '6 indicate that the bipolar manic depressive state should be separated from the unipolar cyclic depression, because the bipolar condition may be an inherited linkage dominant illness. This conclusion was based on a careful study of 426 cases of affective disorder with emphasis on inheritance patterns and a familial study of depressive illness. If this is so, it points to possible reasons that lithium is more effective in the bipolar disorders for then lithium would be applied to an inherited biochemical abnormality. Although specific mechanisms of the action of lithium have not been found, there are several known central nervous system effects. Lithium has biochemical properties similar to those of sodium and gains easy access to the cell interior, but is not readily removed and lowers excitability of the neuron. Lithium apparently accelerates the destruction of norepinephrine presynaptically before release. It also increases the uptake Volume XII
LITHIUM CARBONATE-MILNER. ET AL.
of norepinephrine by the synaptosomes and serotonin by the platelets. It is possible that these effects can contribute to decreasing the mood swings in the bipolar manic depressive iIlnesses. 17 OUR DATA AND CASE HISTORIES
At Shands Teaching Hospital, University of Florida, and Veterans Administration Hospital, GainesviIle, Florida, the treatment of manic depressive iIlness with ECT and/or phenothiazines was not felt to be satisfactory. A review of the literature showed the promise that lithium offered in the treatment of the manic phase, as a prophylactic agent, and the possibility of its use in the schizoaffective states. In March 1970 the Human Experimentation Committee approved the clinical utilization of lithium carbonate in the treatment of cyclic affective states and schizoaffective reactions. A review of the clinical records of 13 patients treated with lithium since March 1970 seems to substantiate the increased efficacy of lithium in bipolar manic depressive illness. Eight patients had clearly defined histories of bipolar manic depressive psychoses with at least one episode of mania, cyclic depressions and a family history of affective disorder. The patients were all begun on lithium during an acute episode of mania, and serum levels of lithium were maintained between 1.0 and 1.2 mgs. percent (the therapeutic range being between 0.8 mg. percent and 1.6 mgs. percent). Seven of the patients responded in two weeks with return to their normal mood states. One patient did not respond to lithium, and it is interesting to note that his serum lithium level did not rise above 0.6 mg. percent, despite 2100 mgs. of lithium daily. All of the seven oatients who responded to lithium during the acute manic period have been maintained on approximately 900 mgs. of lithium daily for a four-to-six-month period, and none have had a recurrence of mania or depression. Five patients were diagnosed as schizophrenic reactions, schizoaffective type with moderate to severe excitement, and were given lithium with serum levels maintained between 1.0 and 1.2 mgs. percent. In all cases there was little alteration of the excited state. Four September-October 1971
subsequently responded to haloperidol and one to a course of ECT. No cases of unipolar cyclic depressions were treated with lithium for comparison to the bipolar cases. In these 15 cases only two patients had significant side effects; one patient developed severe tremors when his serum lithium level rose to 1.6 mgs. percent and another patient developed diarrhea and episodes of hypotension with a serum lithium of 1.4 mgs. percent. CASE NUMBER ONE
Louise R., a 52-year-old Caucasian housewife from rural Florida, was admitted to the Psychiatric Inpatient Unit with hypomanic symptomatology. A diagnosis of manic depressive illness. circular type (bipolar), was made. The patient had a 12-year history of episodes of hypomania and depression at six-months-to-one-year intervals and a maternal history of cyclic affective disorder. Depressive states in 1958. 1967. and November 1969 required hospitalization, and the patient generally responded to imipramine and milieu therapy after one week to one month of hospitalization. After these depressions. the patient would gradually enter into the hypomanic phase of her illness with pressure of speech, restlessness and periods of intense euphoria. During these periods the patient was usually treated with Mellaril which reduced the restlessness but did not alter her flight of ideas. Following admission the patient completed a urinalysis. CBC. BUN, T, uptake and EKG. a standard battery to avoid complications of lithium therapy. All were within normal limits. and a daily course of 1800 mgs. of lithium was begun. In 48 hours her serum lithium was 1.2 mgs. percent, and she was subsequently maintained on 900 mgs. of lithium daily with a serum lithium stability at 1.0 mg. percent. After two weeks of treatment at 900 mgs. daily, the patient's restlessness and hyperexcitability had noticeably decreased. The patient commented that she felt she could "control her ideas and impulses at this time" and was discharged two weeks later. Three weeks after discharge, however, the patient experienced a severe depression and was readmitted and given a course of six ECTs while lithium was continued. The depression rapidly abated and the patient was discharged again on 900 mgs. of lithium daily. From that time to the present, a ninemonth period, the patient has maintained her normal mood state. The next case is presented as typical of the schizo-affective group. CASE NUMBER TWO
Charles M., a 24-year-old Caucasian male junior college student, was admitted to the Psy-
323
PSYCHOSOMATICS chiatr:c Inpatient Unit with a diagnosis of schizophrenic reaction, schizoaffective type, manifested by hyperexcitability, hyperactivity, impulsive behavior, with grandiosity and occasional belligerence, auditory hallucinations, paranoid delusions, loosening of associations and blocking. The patient was first hospitalized in November 1968 with similar symptoms and treated for three months with Thorazine and individual, group, and milieu therapy. He was discharged as much improved and entered junior college. Subsequently, he discontinued the Thorazine, developed increasing grandiose expectations and became increasingly hyperactive until the time of his admission. He was started on 800 mgs. of "Thorazine with no appreciable alteration of his symptoms. Baseline studies for lithium as previously mentioned were completed and found normal, and the patient was begun on 1800 mgs. of lithium carbonate daily. His serum lithium rose to 1.4 mgs. percent in three days. At this time the patient developed diarrhea and episodes of hypotension. The lithium was decreased to 900 mgs. daily with abatement of the side effects. The patient's symptoms, however, did not improve over a 31h -week period, and lithium was discontinued. Thorazine was reinstituted at 1200 mgs. daily with gradual improvement of his ward behavior. He was discharged three weeks later much improved. Five weeks after discharge, however, the patient became hyperactive again and was started on haloperidol with rapid improvement. The last case is presented to illustrate the changing sleep patterns following lithium. CASE NUMBER THREE
William N., a 52-year-old Caucasian male, was admitted to the Psychiatric Inpatient Unit with a diagnosis of manic depressive illness, circular hypomanic stage, manifested by increasing irritability, insomnia, impulsive grandiose financial investments, hyperactivity, and rapidity of speech. The patient had a two-year history of alternating periods of depression and hypomanic symptoms at six-to-eight month intervals. Prior to the present admission these had not received psychiatric attention. Baseline studies as previously outlined were completed and found to be within normal limits. Also prior to being placed on lithium, a sleep stUdy consisting of EEG and monitoring of eye movements was completed. This showed that the patient spent no time in the fourth stage of sleep although total length of sleep was normal. He was then placed on 900 mgs. daily of lithium carbonate and the serum lithium stabilized at 1.0 mg. percent after one week. At this time his symptoms had decreased and the patient felt he was in his normal mood state. A subsequent sleep study showed that the patient now spent forty minutes in the fourth stage of sleep. 324
Studies of lithium carbonate suggest that it is specifically indicated in the treatment of manic symptoms of manic-depressive illness, characterized by increased psychomotor activity, intensely elevated feelings, poor social judgments, "flight of ideas," and reduced need for sleep. Its effects are negligible on conditions involving schizophrenic or paranoid thinking and on depressive states not alternating with periods of mania. It does, however, exert a mild to moderate antidepressant effect in the depressions of the bipolar manic-depressive illness. Further, there is evidence that it is effective in preventing recurrences of mania and depression. Eight cases have been presented that confirm its effectiveness as an agent for the treatment of mania and hypomanic symptoms and as a prophylactic agent. However, five patients with schizoaffective reactions did not respond and required other treatment modalities. Careful, constant monitoring of serum levels is required to prevent side effects and toxic reactions19 • It has also been illustrated that lithium helps to restore the fourth stage of sleep characteristically decreased in manic depressive illness. REFERENOES
1. Cade, J. F. J.: Lithium salts in the treatment of psychotic excitement, Med. J. Aust., 36: 349-352, 1949. 2. Schou, M., Juel-Nielson, N., Stromgren, E., and Voldsby, H.: The treatment of manic psychoses by the administration of lithium salts, J. Neurol. Psychiat., 7 :250-260, 1954. 3. Wharton, R. N. and Fieve, R. R.: The use of lithium in the affective psychoses, Amer. J. Psychiat., 123 :706-712, 1966. 4. Bunney, W. E., Jr., GoodWin, F. K., Davis, J.M., and Fawcett, J.A.: A behavioral-bio· chemical study of lithium treatment, Amer. J. Psychiat., 125 :499-512, 1968. 5. Schou, M.: Lithium in psychiatric therapy and prophylaxis, J. Psychiat. Res., 6:67-95, 1968. 6. Hansen, C. J., Retboll, K., and Schou, M.: Unpublished data reported in Schou, M.: Lithium in psychiatric therapy: Stock-taking after 10 years, Psychopharm., 1 :65-78, 1959. 7. Goodwin, F. K., Murphy, D. L., and Bunney, W. E., Jr.: Lithium in depression and mania: a double-blind behavioral and biochemical study, Arch. Gen. Psychiat., 21 :486-496, 1969. 8. Hartigan, S. P.: The use of lithium salts in affective disorders, Brit. J. Psychiat., 5 :396408,1964. Volume XII
LITHIUM CARBONATE-MILNER, ET AL. 9. Baastrup, P. C. and Schou, M.: Lithium as a prophylactic agent. Its effects against recurrent depressions and manic-depressive psychosis, Arch. Gen. Psychiat., 16:162-172, 1967. 10. Blackwell, B. and Shepherd, M.: Prophylactic lithium: another therapeutic myth? An examination of evidence to date, Lancet, 1 :968971, 1968. 11. Angst, J., Weiss, P., Grof, P., Baastrup, P. C., and Schou. M. : Prophylaxis in recurrent affective disorders, Brit. J. Psychiat., 116: 535-604. 1970. 12. Controlled lithium tt!sts demonstrate manlcdepressive prophylactic effect. Medical TribUlIc aml Medical News, 11(50) :1, September 28, 1970. 13. Fieve. R. R., Platman, S. R., and Plutchik,
14.
15.
16.
17. 18.
R. R.: The use of lithium in affective disorders: II Prophylaxis of depression in chronic recurrent affective disorders, Amer. J. Psychiat., 125:84-90, 1968. Schlagenhauf, S. K., Tupin, P. P., and White, R. B.: Three years' experience with lithium carbonate, Dis. Nerv. Syst., November 1969. Zall, H., Therman, P. O. G., and Myers, J. M.: Lithium carbonate: A clinical study, Amer. J. Psychiat., 125 :'549-555, 1968. Winokur, S., Clayton, P. J., and Reich, T.: Mallic Depressive IllneslJ, C. V. Mosby Co., 1969. Kopin, I. J.: How does lithium work? New Eng. J. Med., 280:560-561, 1969. Fieve, R.R.: The lithium breakthrough, M edtcal World News-Psychiatry, 1970, p. 69-70.
Regional Meeting The Regional Meeting of the Academy of Psychosomatic Medicine will be held at the Menninger Clinic in Topeka, Kansas, November 10-12, 1971. For further information contact Dr. Walter Bruschi at the Menninger V.A. HospitaJ.
September-October 1971
325
Is It Successful?
GILBERT C. MILNER, III, M.D., WILLIAM C. RUFFIN, NANCY H. MCGINNIS, M.A. INTRODUCTION • Lithium carbonate as a specific psychopharmacologic agent in the treatment of manic-depressive illness has been known for over 20 years but was not approved by the F.D.A. until 1970. The general historical course followed by a drug initially offering clinical promise can be divided into four stages: 1) enthusiastic response immediately after discovery; 2) verifying reports by other investigators; 3) application of the drug outside the originally discovered area of effectiveness with reported favorable results; and 4) increasing criticism, resulting in more critical investigations to delineate the limits of efficacy of the drug. It appears that lithium is presently in this fourth stage. REVIEW OF LITERATURE The original use of lithium for treatment of mania was discovered in 1949 by Cade l in Australia. While investigating the toxic effects of uric acid and urea, he noted the concomitant sedative properties of lithium. He then treated ten cases of manic excitement in bipolar manic depressive illness (cyclic affective states with at least one episode of mania), reporting dramatic improvement in all. This study, however, was criticized for lack of double-blind and placebo controls. Doubleblind placebo-controlled studies were then reported by Schou 2 in Denmark. Of 38 patients demonstrating manic behavior, 14 derived some benefit, 6 no benefit, and 18 questionable benefit over a two-year treatment period. ImDr. Milner is a Resident, Dr. Ruffin is Professor of Psychiatry and Miss McGinnis is Research Assistant, Department of Psychiatry, University of Florida, College of Medicine, Gainesville, Florida 32601. September-October 1971
JR., M.D., and
provement was most frequent in patients witn a history of bipolar manic depressive illness. Those deriving no benefit were "atypical manic reactions" or possibly schizoaffective states. However, manic symptoms recurred when lithium was withdrawn. Fieve and Wharton'l in a single-blind study of 25 patients, with manic excitements previously resistant to phenothiazines, found lithium effective in 44% and possibly effective in another 24%. Bunney' in an extensive, detailed double-blind placebo-controlled study, found that daily doses of lithium not only reduced the mania but returned patients to their normal states. Also, again, manic symptoms rapidly returned with lithium withdrawal. A world literature review in 1967 by Schou 5 reported 1800 cases of mania treated with lithium, of which approximately 80% responded with excellent to modest improvement. When lithium was extended from the treatment of mania to other conditions, specifically cyclic depressive episodes,l.6 little or no amelioration was reported. In a recent study comparing patients with unipolar depressive symptomatology (cyclic depressions with no manic episodes) to bipolar (having at least one previous episode of mania alternating with depressions), 10 of 14 in the bipolar group showed definite improvement, but none of the five in the unipolar group showed improvement. Lithium's effectiveness as a prophylactic agent in preventing recurrent mood disorders was next investigated. Hartigan,~ on the basis of informal observations, first proposed the possible prophylactic effects of lithium in prolonging the period between manic or depressive episodes. His observations were supported by a 6th-year study of Baastrup and Schou,n which found that lithium treatment: 1) effectively lowered the average length of time in psychotic states per year; 2) shortened the 321
PSYCHOSOMATICS
duration of relapses; and 3) significantly lengthened the period between relapses. Again, it was noted that bipolar manic depressive states responded more favorably than the recurrent depressions, with the atypical depressions showing paranoid symptomatology responding least favorably. Blackwell and Shepherd 1<' criticized this study on the basis of insufficiently rigorous criteria for the selection of patients, the definition of prophylaxis, faulty evaluation, and over-enthusiastic observer bias in interpreting the results. Baastrup and Schou in combination with Angst and Weiss,l1 followed with a study of 244 patients on maintenance lithium therapy. In those cases of recurrent depression the time between episodes was lengthened 76% and in bipolar manic depressive states it was lengthened 61 %. However, only in the bipolar manic depressive illnesses were the episodes of depression significantly shortened. A doubleblind placebo-controlled study of patients on lithium maintenance for at least one year (50 diagnosed as cyclic manic depressives; 34 as recurrent endogenous depressions) was conducted". In both groups who were continued on lithium there were no recurrences of symptoms; however, in those switched to a placebo, 55 % of patients with bipolar manic depressive illness and 53% with recurrent depressions relapsed. Other studies, particularly in the United States, have not yielded such affirmative results. Fieve, Platman, and Plutchik 13 reported that lithium did not alter the frequency of attacks but acted as a mild antidepressant for each depressive attack and as a strong antimanic agent for each recurrent manic episode. The prophylactic effect of maintenance lithium is still questionable; however, there is some evidence that phophylaxis occurs in a greater percentage of cases of bipolar manic depressive illness than in recurrent depressions. Lithium has also been used to treat other emotional and behavioral disorders involving hyperexcitability, in particular the schizoaffective states. Sclagenhauf, Tupin, and White" found lithium exerted excellent sedative effects in intense psychomotor agitation in schizoaffective states. but it did not alter 322
the underlying thought disorder. Zall' 5 applied this effect as a diagnostic tool; that is, lithium was used to reduce intense agitation in order to more clearly delineate the basic thought disturbances. Still, most investigators consider the phenothiazines to be superior to lithium in the treatment of schizoaffective states. This brief summary of the literature suggests that lithium exerts a demonstrable antimanic effect, returning patients to their normal mood states. It apparently exerts a mild sedative effect in other conditions with hyperexcitability as a prominent symptom, particularly the schizoaffective state, but in no way alters the thought disorders. Its effect on a single episode of depression in the bipolar manic depressive states and in unipolar recurrent depressive states is still not completely understood. However, recent investigations indicate that it has a significantly greater antidepressant effect in the bipolar states, as opposed to the unipolar. Also, recent studies indicate that lithium exerts a definite prophylactic effect on the recurrent mood disorders, both in lengthening the cycle betweeq exacerbations and shortening the episode. METHOD OF ACTION
Studies by Winokur, Clayton, and Reich '6 indicate that the bipolar manic depressive state should be separated from the unipolar cyclic depression, because the bipolar condition may be an inherited linkage dominant illness. This conclusion was based on a careful study of 426 cases of affective disorder with emphasis on inheritance patterns and a familial study of depressive illness. If this is so, it points to possible reasons that lithium is more effective in the bipolar disorders for then lithium would be applied to an inherited biochemical abnormality. Although specific mechanisms of the action of lithium have not been found, there are several known central nervous system effects. Lithium has biochemical properties similar to those of sodium and gains easy access to the cell interior, but is not readily removed and lowers excitability of the neuron. Lithium apparently accelerates the destruction of norepinephrine presynaptically before release. It also increases the uptake Volume XII
LITHIUM CARBONATE-MILNER. ET AL.
of norepinephrine by the synaptosomes and serotonin by the platelets. It is possible that these effects can contribute to decreasing the mood swings in the bipolar manic depressive iIlnesses. 17 OUR DATA AND CASE HISTORIES
At Shands Teaching Hospital, University of Florida, and Veterans Administration Hospital, GainesviIle, Florida, the treatment of manic depressive iIlness with ECT and/or phenothiazines was not felt to be satisfactory. A review of the literature showed the promise that lithium offered in the treatment of the manic phase, as a prophylactic agent, and the possibility of its use in the schizoaffective states. In March 1970 the Human Experimentation Committee approved the clinical utilization of lithium carbonate in the treatment of cyclic affective states and schizoaffective reactions. A review of the clinical records of 13 patients treated with lithium since March 1970 seems to substantiate the increased efficacy of lithium in bipolar manic depressive illness. Eight patients had clearly defined histories of bipolar manic depressive psychoses with at least one episode of mania, cyclic depressions and a family history of affective disorder. The patients were all begun on lithium during an acute episode of mania, and serum levels of lithium were maintained between 1.0 and 1.2 mgs. percent (the therapeutic range being between 0.8 mg. percent and 1.6 mgs. percent). Seven of the patients responded in two weeks with return to their normal mood states. One patient did not respond to lithium, and it is interesting to note that his serum lithium level did not rise above 0.6 mg. percent, despite 2100 mgs. of lithium daily. All of the seven oatients who responded to lithium during the acute manic period have been maintained on approximately 900 mgs. of lithium daily for a four-to-six-month period, and none have had a recurrence of mania or depression. Five patients were diagnosed as schizophrenic reactions, schizoaffective type with moderate to severe excitement, and were given lithium with serum levels maintained between 1.0 and 1.2 mgs. percent. In all cases there was little alteration of the excited state. Four September-October 1971
subsequently responded to haloperidol and one to a course of ECT. No cases of unipolar cyclic depressions were treated with lithium for comparison to the bipolar cases. In these 15 cases only two patients had significant side effects; one patient developed severe tremors when his serum lithium level rose to 1.6 mgs. percent and another patient developed diarrhea and episodes of hypotension with a serum lithium of 1.4 mgs. percent. CASE NUMBER ONE
Louise R., a 52-year-old Caucasian housewife from rural Florida, was admitted to the Psychiatric Inpatient Unit with hypomanic symptomatology. A diagnosis of manic depressive illness. circular type (bipolar), was made. The patient had a 12-year history of episodes of hypomania and depression at six-months-to-one-year intervals and a maternal history of cyclic affective disorder. Depressive states in 1958. 1967. and November 1969 required hospitalization, and the patient generally responded to imipramine and milieu therapy after one week to one month of hospitalization. After these depressions. the patient would gradually enter into the hypomanic phase of her illness with pressure of speech, restlessness and periods of intense euphoria. During these periods the patient was usually treated with Mellaril which reduced the restlessness but did not alter her flight of ideas. Following admission the patient completed a urinalysis. CBC. BUN, T, uptake and EKG. a standard battery to avoid complications of lithium therapy. All were within normal limits. and a daily course of 1800 mgs. of lithium was begun. In 48 hours her serum lithium was 1.2 mgs. percent, and she was subsequently maintained on 900 mgs. of lithium daily with a serum lithium stability at 1.0 mg. percent. After two weeks of treatment at 900 mgs. daily, the patient's restlessness and hyperexcitability had noticeably decreased. The patient commented that she felt she could "control her ideas and impulses at this time" and was discharged two weeks later. Three weeks after discharge, however, the patient experienced a severe depression and was readmitted and given a course of six ECTs while lithium was continued. The depression rapidly abated and the patient was discharged again on 900 mgs. of lithium daily. From that time to the present, a ninemonth period, the patient has maintained her normal mood state. The next case is presented as typical of the schizo-affective group. CASE NUMBER TWO
Charles M., a 24-year-old Caucasian male junior college student, was admitted to the Psy-
323
PSYCHOSOMATICS chiatr:c Inpatient Unit with a diagnosis of schizophrenic reaction, schizoaffective type, manifested by hyperexcitability, hyperactivity, impulsive behavior, with grandiosity and occasional belligerence, auditory hallucinations, paranoid delusions, loosening of associations and blocking. The patient was first hospitalized in November 1968 with similar symptoms and treated for three months with Thorazine and individual, group, and milieu therapy. He was discharged as much improved and entered junior college. Subsequently, he discontinued the Thorazine, developed increasing grandiose expectations and became increasingly hyperactive until the time of his admission. He was started on 800 mgs. of "Thorazine with no appreciable alteration of his symptoms. Baseline studies for lithium as previously mentioned were completed and found normal, and the patient was begun on 1800 mgs. of lithium carbonate daily. His serum lithium rose to 1.4 mgs. percent in three days. At this time the patient developed diarrhea and episodes of hypotension. The lithium was decreased to 900 mgs. daily with abatement of the side effects. The patient's symptoms, however, did not improve over a 31h -week period, and lithium was discontinued. Thorazine was reinstituted at 1200 mgs. daily with gradual improvement of his ward behavior. He was discharged three weeks later much improved. Five weeks after discharge, however, the patient became hyperactive again and was started on haloperidol with rapid improvement. The last case is presented to illustrate the changing sleep patterns following lithium. CASE NUMBER THREE
William N., a 52-year-old Caucasian male, was admitted to the Psychiatric Inpatient Unit with a diagnosis of manic depressive illness, circular hypomanic stage, manifested by increasing irritability, insomnia, impulsive grandiose financial investments, hyperactivity, and rapidity of speech. The patient had a two-year history of alternating periods of depression and hypomanic symptoms at six-to-eight month intervals. Prior to the present admission these had not received psychiatric attention. Baseline studies as previously outlined were completed and found to be within normal limits. Also prior to being placed on lithium, a sleep stUdy consisting of EEG and monitoring of eye movements was completed. This showed that the patient spent no time in the fourth stage of sleep although total length of sleep was normal. He was then placed on 900 mgs. daily of lithium carbonate and the serum lithium stabilized at 1.0 mg. percent after one week. At this time his symptoms had decreased and the patient felt he was in his normal mood state. A subsequent sleep study showed that the patient now spent forty minutes in the fourth stage of sleep. 324
Studies of lithium carbonate suggest that it is specifically indicated in the treatment of manic symptoms of manic-depressive illness, characterized by increased psychomotor activity, intensely elevated feelings, poor social judgments, "flight of ideas," and reduced need for sleep. Its effects are negligible on conditions involving schizophrenic or paranoid thinking and on depressive states not alternating with periods of mania. It does, however, exert a mild to moderate antidepressant effect in the depressions of the bipolar manic-depressive illness. Further, there is evidence that it is effective in preventing recurrences of mania and depression. Eight cases have been presented that confirm its effectiveness as an agent for the treatment of mania and hypomanic symptoms and as a prophylactic agent. However, five patients with schizoaffective reactions did not respond and required other treatment modalities. Careful, constant monitoring of serum levels is required to prevent side effects and toxic reactions19 • It has also been illustrated that lithium helps to restore the fourth stage of sleep characteristically decreased in manic depressive illness. REFERENOES
1. Cade, J. F. J.: Lithium salts in the treatment of psychotic excitement, Med. J. Aust., 36: 349-352, 1949. 2. Schou, M., Juel-Nielson, N., Stromgren, E., and Voldsby, H.: The treatment of manic psychoses by the administration of lithium salts, J. Neurol. Psychiat., 7 :250-260, 1954. 3. Wharton, R. N. and Fieve, R. R.: The use of lithium in the affective psychoses, Amer. J. Psychiat., 123 :706-712, 1966. 4. Bunney, W. E., Jr., GoodWin, F. K., Davis, J.M., and Fawcett, J.A.: A behavioral-bio· chemical study of lithium treatment, Amer. J. Psychiat., 125 :499-512, 1968. 5. Schou, M.: Lithium in psychiatric therapy and prophylaxis, J. Psychiat. Res., 6:67-95, 1968. 6. Hansen, C. J., Retboll, K., and Schou, M.: Unpublished data reported in Schou, M.: Lithium in psychiatric therapy: Stock-taking after 10 years, Psychopharm., 1 :65-78, 1959. 7. Goodwin, F. K., Murphy, D. L., and Bunney, W. E., Jr.: Lithium in depression and mania: a double-blind behavioral and biochemical study, Arch. Gen. Psychiat., 21 :486-496, 1969. 8. Hartigan, S. P.: The use of lithium salts in affective disorders, Brit. J. Psychiat., 5 :396408,1964. Volume XII
LITHIUM CARBONATE-MILNER, ET AL. 9. Baastrup, P. C. and Schou, M.: Lithium as a prophylactic agent. Its effects against recurrent depressions and manic-depressive psychosis, Arch. Gen. Psychiat., 16:162-172, 1967. 10. Blackwell, B. and Shepherd, M.: Prophylactic lithium: another therapeutic myth? An examination of evidence to date, Lancet, 1 :968971, 1968. 11. Angst, J., Weiss, P., Grof, P., Baastrup, P. C., and Schou. M. : Prophylaxis in recurrent affective disorders, Brit. J. Psychiat., 116: 535-604. 1970. 12. Controlled lithium tt!sts demonstrate manlcdepressive prophylactic effect. Medical TribUlIc aml Medical News, 11(50) :1, September 28, 1970. 13. Fieve. R. R., Platman, S. R., and Plutchik,
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R. R.: The use of lithium in affective disorders: II Prophylaxis of depression in chronic recurrent affective disorders, Amer. J. Psychiat., 125:84-90, 1968. Schlagenhauf, S. K., Tupin, P. P., and White, R. B.: Three years' experience with lithium carbonate, Dis. Nerv. Syst., November 1969. Zall, H., Therman, P. O. G., and Myers, J. M.: Lithium carbonate: A clinical study, Amer. J. Psychiat., 125 :'549-555, 1968. Winokur, S., Clayton, P. J., and Reich, T.: Mallic Depressive IllneslJ, C. V. Mosby Co., 1969. Kopin, I. J.: How does lithium work? New Eng. J. Med., 280:560-561, 1969. Fieve, R.R.: The lithium breakthrough, M edtcal World News-Psychiatry, 1970, p. 69-70.
Regional Meeting The Regional Meeting of the Academy of Psychosomatic Medicine will be held at the Menninger Clinic in Topeka, Kansas, November 10-12, 1971. For further information contact Dr. Walter Bruschi at the Menninger V.A. HospitaJ.
September-October 1971
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