Psychiatric Annals

POSSIBLE SYNERGISTIC ACTION BETWEEN CARBAMAZEPINE AND LITHIUM CARBONATE

Abstract

Recent findings indicate that acutely manic patients who are unresponsive or react adversely to lithium alone may respond well to the combined use of lithium and carbamazepine. Their favorable response to lithium and carbamazepine coprescribed suggests a synergistic action between the two drugs.

Three patients who responded well to the combination of these drugs are described by Lipinski, et al.1 A 21-year-old man diagnosed as having a bipolar disorder was treated with lithium carbonate. During a five-year period, the patient experienced two periods of depression and three prolonged manic episodes, with only two months of euthymia during the entire five years. Lithium at levels of 1 .0 to 1 .5 mEq/liter proved ineffective during these manic episodes. When treated with lithium, 100 to 125 mg/day of molindone and up to 800 mg/day of chlorpromazine, Irritability, aggressiveness, hyperactivity, sleeplessness and pressured speech persisted. After 18 days of such treatment, carbamazepine was administered. Within four days, the patient was markedly improved; neuroleptics were discontinued shortly thereafter. With the discontinuation of lithium, however, manic symptoms redeveloped rapidly. Lithium therapy was resumed and within one week, the patient became euthymic and was discharged two weeks later maintained on carbamazepine and lithium. Three months after discharge, the symptoms continued to be in complete remission.

Another patient, a 21 -year-old woman who was treated for a severe manic disorder, had a poor-tofair response to lithium and neuroleptics alone or in combination and responded poorly to 12 unilateral ECT treatments. Treatment with lithium, neuroleptics and lithium plus various neuroleptics failed to reduce manic symptoms. Lithium alone was administered and sometime after carbamazepine was added. Within two days, improvement was noticeable. Carbamazepine was then discontinued to determine whether improvement was due to the drug or spontaneous remission. Manic symptoms reappeared within two days and rapidly worsened; accordingly carbamazepine was resumed. The patient's manic symptoms declined steadily while she was taking carbamazepine. Five months later she was without manic or depressive symptoms.

The third patient, a 27-year-old man, had a seven-year history of chronic psychotic symptoms and manic depressive illness. Treatment with lithium carbonate in combination with various neuroleptics proved only slightly effective. Lithium and fluphenazine hydrochloride 20 mg/day also produced little improvement. Lithium was discontinued, but fluphenazine continued in the same dosage range. Shortly after carbamazepine was added. Manic symptoms improved somewhat, then became worse despite a carbamazepine level of 8.6 ng/ml. Lithium treatment was resumed in conjuction with carbamazepine and fluphenazine and improvement was noted within three days. Within two weeks the patient was clearly better than at any time prior to this treatment.

In a follow-up case of the American report, Puszet reported the successful use of carbamazepine and lithium in the treatment of a patient suffering from bipolar affective disorder.2

The patient, a 35-year-old woman diagnosed as having severe bipolar affective disorder, required almost continuous hospitalization over a ten-year period. During this time, her mood was unstable with short intervals of euthymia lasting from hours to a maximum of one week. She remained unstable despite past treatment with ECT1 neuroleptics (chlorpromazine, thioridazine up to 1 g/day), antidepressants 1 50 mg/day, and lithium carbonate.

During one year of treatment with lithium carbonate 2*g/day and carbamazepine 800 mg/day and chlorpromazine 100 mg/day the patient was hospitalized for only one day. She states that she now has some control over her life and is not prone to rapid mood swings.

In addition to the cases reported by Lipinski and Puszet, Moss and James report another favorable, although brief, response to the combination of these two drugs in a patient who had not responded adequately to either drug alone.3…

Recent findings indicate that acutely manic patients who are unresponsive or react adversely to lithium alone may respond well to the combined use of lithium and carbamazepine. Their favorable response to lithium and carbamazepine coprescribed suggests a synergistic action between the two drugs.

Three patients who responded well to the combination of these drugs are described by Lipinski, et al.1 A 21-year-old man diagnosed as having a bipolar disorder was treated with lithium carbonate. During a five-year period, the patient experienced two periods of depression and three prolonged manic episodes, with only two months of euthymia during the entire five years. Lithium at levels of 1 .0 to 1 .5 mEq/liter proved ineffective during these manic episodes. When treated with lithium, 100 to 125 mg/day of molindone and up to 800 mg/day of chlorpromazine, Irritability, aggressiveness, hyperactivity, sleeplessness and pressured speech persisted. After 18 days of such treatment, carbamazepine was administered. Within four days, the patient was markedly improved; neuroleptics were discontinued shortly thereafter. With the discontinuation of lithium, however, manic symptoms redeveloped rapidly. Lithium therapy was resumed and within one week, the patient became euthymic and was discharged two weeks later maintained on carbamazepine and lithium. Three months after discharge, the symptoms continued to be in complete remission.

Another patient, a 21 -year-old woman who was treated for a severe manic disorder, had a poor-tofair response to lithium and neuroleptics alone or in combination and responded poorly to 12 unilateral ECT treatments. Treatment with lithium, neuroleptics and lithium plus various neuroleptics failed to reduce manic symptoms. Lithium alone was administered and sometime after carbamazepine was added. Within two days, improvement was noticeable. Carbamazepine was then discontinued to determine whether improvement was due to the drug or spontaneous remission. Manic symptoms reappeared within two days and rapidly worsened; accordingly carbamazepine was resumed. The patient's manic symptoms declined steadily while she was taking carbamazepine. Five months later she was without manic or depressive symptoms.

The third patient, a 27-year-old man, had a seven-year history of chronic psychotic symptoms and manic depressive illness. Treatment with lithium carbonate in combination with various neuroleptics proved only slightly effective. Lithium and fluphenazine hydrochloride 20 mg/day also produced little improvement. Lithium was discontinued, but fluphenazine continued in the same dosage range. Shortly after carbamazepine was added. Manic symptoms improved somewhat, then became worse despite a carbamazepine level of 8.6 ng/ml. Lithium treatment was resumed in conjuction with carbamazepine and fluphenazine and improvement was noted within three days. Within two weeks the patient was clearly better than at any time prior to this treatment.

In a follow-up case of the American report, Puszet reported the successful use of carbamazepine and lithium in the treatment of a patient suffering from bipolar affective disorder.2

The patient, a 35-year-old woman diagnosed as having severe bipolar affective disorder, required almost continuous hospitalization over a ten-year period. During this time, her mood was unstable with short intervals of euthymia lasting from hours to a maximum of one week. She remained unstable despite past treatment with ECT1 neuroleptics (chlorpromazine, thioridazine up to 1 g/day), antidepressants 1 50 mg/day, and lithium carbonate.

During one year of treatment with lithium carbonate 2*g/day and carbamazepine 800 mg/day and chlorpromazine 100 mg/day the patient was hospitalized for only one day. She states that she now has some control over her life and is not prone to rapid mood swings.

In addition to the cases reported by Lipinski and Puszet, Moss and James report another favorable, although brief, response to the combination of these two drugs in a patient who had not responded adequately to either drug alone.3

A 35-year-old man with a ten-year psychiatric history had been diagnosed as having major affective disorder, manic type. Previous therapy included electroconvulsive therapy and maintenance therapy with lithium carbonate alone. Prior to admission into an adult psychiatric program the patient was maintained on lithium carbonate (1,500 mg/day) and haloperidol (10 mg/day). The day before admission, the patient stopped taking haloperidol. On the third day after admission, while receiving only lithium (1,500 mg/day), the patient exhibited signs of serious discompensation, with mania, loose associations, delusions, and poor cooperation. His Clinical Assessment Inventory (CAI) score decreased from an average of 90 on days 1 and 2 to a low of 72 on day 5, when haloperidol was required to maintain behavioral control. On day 7, the patient received carbamazepine 200 mg/day which was increased over three days to 600 mg/day. The patient's condition improved quickly with this combined regimen of lithium and carbamazepine. One week later, lithium was reduced to 300 mg/day between days 14 and 21 , during which time the patient's condition rapidly deteriorated. Small doses of haloperidol were required to maintain behavioral control. On day 25 lithium therapy was resumed at 1 ,500 mg/day; the patient showed an immediate and favorable response. On day 31 the dosage of carbamazepine was increased to 800 mg/day and the patient was released one week later, receiving lithium carbonate (1,500 mg/day) and carbamazepine (800 mg/day). Within one week of discharge, the patient's condition began to deteriorate, with recurrence of agitation, insomnia, and inappropriate social behaviors, requiring the patient to be readmitted to the hospital. Therapy with haloperidol and lithium was resumed, and the patient's condition improved to the level maintained before the trial of carbamazepine, with CAI scores improving from 71 on admission to 91 on discharge.

Moss and James note, "The initial results of using a combination of lithium carbonate and carbamazepine to treat a manic patient with a previous inadequate response to lithium carbonate and haloperidol were consistent with those reported previously." And, "Initially, the results were cieariy superior to those obtained with lithium carbonate and haloperidol."

Post and Uhde propose several reasons for the lack of a continued favorable response to carbamazepine with lithium carbonate in Moss and James' patient.4 Increases in carbamazepine dosage were postponed because slight suppression of bone marrow activity was indicated, The 800 mg/day dosage they used was slightly below the average dosage given in the other cases, and less than this patient may have been able to tolerate without alterations in bone marrow function. A second possible reason for this brief response to CBZ, Post says, is enzyme induction. "With administration of carbamazepine for several weeks, there is substantial evidence of induction of hepatic enzymes that metabolize carbamazepine, resulting in concomitant lowering of serum levels, particularly after the second and third weeks of treatment." The initial response to CBZ may have been connected to the natural progression of the illness.

The favorable results reported by Lipinski, Puszet, and Moss and James suggest that the combination of lithium carbonate and carbamazepine might be considered for patients who have not responded adequately to either drug alone.

REFERENCES

1. Lipinski JF, Pope HG: Possible synergistic action between carbamazepine and lithium carbonate in the treatment of three acutely manic patients. Am J Psychiatry 1982; 139:7.

2. Puszet PJ: Case Report: The combined use for one year of carbamazepine and lithium carbonate in manic depressive psychosis. Pharmabulletin 1982, ? 65.

3. Moss GR, James CR: Carbamazepine and lithium carbonate synergism in mania. Arch Gen Psychiatry 1983; 40:588.

4. Post RM, Uhde TW: Carbamazepine and lithium carbonate synergism in mania. Arch Gen Psychiatry 1984;41:210.

10.3928/0048-5713-19840701-13

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