ANTICONVULSANTS IN LITHIUM-REFRACTORY BIPOLAR PATIENTS

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Using the anticonvulsant carbamazepine (CBZ) we have documented in double-blind trials acute response in approximately two-thirds of acutely manic patients and one-third of acutely depressed patients. In many instances response has been confirmed in a drug-placebo-drug (B-A-B) design. Lithium augmentation of inadequate response is also observed in both mania and depression despite greater decrements in T3 and T4 compared with either agent alone. Long-term prophylaxis of both manic and depressive episodes has also been documented with CBZ although a subgroup of patients shows loss of efficacy over time (tolerance) and this may be reversible with a period of time off medications. Patients who are inadequately responsive to CBZ may respond to valproate and vice- versa. Many of the predictors of poor response to lithium may be associated with good response to CBZ or valproate, and these agents appear to be important clinical options for lithium-refractory bipolar patients. Positive effects of the anticonvulsant calcium channel blocker nimodipine have been observed and summarized in Z01 MH 02635. We have preliminarily identified clinical and biological markers of differential response among the mood stabilizers. These include rapid cycling as a predictor of poor response to both lithium and CBZ but a good response to their combination. Temporal lobe hypermetabolism is associated with good response to CBZ, while frontal lobe hypometabolism appears to be a predictor of nimodipine response. A blind, randomized, parallel design protocol to study two new anticonvulsants with novel mechanisms of action -- GABApentin and lamotrigine -- have been approved. The endogenous anticonvulsant neuropeptide TRH has been administered into the CSF during a routine lumbar puncture in 8 patients. Improvement in mood, anxiety, and suicidal preoccupation was observed compared with the sham procedure. Repeated transcranial magnetic stimulation (rTMS) of the brain is being explored in randomized patients as an antidepressant and potential substitute for some patients who would otherwise require electroconvulsive therapy (ECT).