Tegretol and Mania
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Post et al. review carbamazepine (CBZ), valproic acid (VPA) and the newer anticonvulsants in the treatment of bipolar affective disorder. They have gathered information from a large number of trials in bipolar disorder and have included those trials in which the methods included some kind of controlled design. As part of the introduction, they note that lithium (Li) is thought of as the standard therapy, but that the largest controlled trial of Li in acute mania indicates only 50% of patients demonstrated 50% improvement after three weeks of therapy in the acute setting. Poor response to Li was associated with rapid cycling, negative family history, increasing number of episodes prior to initiation of Li therapy, and comorbid substance abuse.
CBZ in acute mania: there were 19 controlled studies included in the paper, comprising 203 patients. 123 of the 203 patients with acute mania showed a marked to excellent response to CBZ. (61% response rate in acute mania).
CBZ in acute depression: there were fewer studies; the authors included one of their own pilot studies and said that only 17 of 57 acutely depressed patients (30%) had a moderate to marked effect with CBZ monotherapy. In uncontrolled studies, there was a reported 73% treatment effect.
CBZ in prophylaxis: there were 14 “partly controlled” / controlled studies included in the analysis of prophylaxis. In these studies, 63% of patients given CBZ showed a moderate to excellent prophylactic response, which compared to 63% response to Li. In a trial comparing Li to CBZ in which patients were crossed over to the other treatment group after a year of therapy, 31% of the patients on Li and 37% of the patients on CBZ dropped out because of inadequate response to the medication.
Additional observations about CBZ:
- No real target blood reference range identified across subjects; there does seem to be some relevance of blood levels for individual patients
- Theory that activity in the mesial temporal structures (preliminary PET data) may predict response to CBZ
- Rapid cycling seems to be a poor prognostic factor for CBZ as well as for Li therapy
- Patients with negative family history may respond better to CBZ
- Mechanism of action: 1996 demonstration of CBZ blocking the Ca influx through NMDA receptors
- Cytochrome P450 3A4 inducer; decreases its own levels as well as those of OCP’s
- Potential adverse effect of agranulocytosis
Small et al. performed a longitudinal, prospective study of newly hospitalized patients with bipolar disorder, mixed or manic episodes. Patients were excluded if they had a history of other axis I disorders, significant medical problems, substance abuse or physical illness, or other contraindications to Li or CBZ. Dropout rate was high; by eight weeks, 2/3 of patients were excluded because of lack of efficacy or refusal to continue. Patients who were evaluated were assessed based on the GAS, MRS, BPRS, CGI, and SDMS-M subscale. Both Li and CBZ were found to be “modestly effective” in the short-term treatment of acute mania. In this study, 52 subjects were initially included. In the CBZ group, one had decreased granulocyte count and had to be dropped from the study. Rate of recurrent mania and depression were similar; rate of noncompliance was slightly higher in the lithium group. Overall, dropout rate was similar but dropouts occurred earlier in the CBZ group than in the Li group.
Dilsaver et al. performed an evaluation of CBZ vs. chlorpromazine in the treatment of 36 inpatients with bipolar disorder (depressed). They found that CBZ treatment was about as effective as chlorpromazine in improving mood, sleep, headache, and mood fluctuations (there were some trends on physician global improvement scale favoring CBZ, but these were not significant). In this study, one patient had blurry vision and another had rash and fever as reasons for withdrawal from the CBZ group.
Bottom Line: According to the data reviewed in these articles, CBZ appears to be about equally effective as Li in the treatment of acute mania and in prophylaxis of bipolar disorder. Depending on the patient and the potential tolerability of CBZ, it could be a viable option for the treatment of acute mania as well as for prophylaxis in bipolar disorder. Importantly, the authors of these articles take care to point out that response to one agent does NOT predict response to another, and it may be necessary to switch or add medications for adequate treatment of patients with bipolar disorder.
Dilsaver SC; Swann SC; Chen y et al. Treatment of bipolar depression with carbamazepine: Results of an open study. Biological Psychiatry(1996) 40: 935-937.
Small JC; Klapper MH; Milstein V et al. Carbamazepine compared with lithium in the treatment of mania. Archives of General Psychiatry (1991) 48: 915-921.
Presented by Jane Gagliardi, MD, on 10/30/00
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