VALPROATE VERSUS LITHIUM IN BIPOLAR RAPID CYCLING

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Although lithium remains the treatment of choice for bipolar disorder, only 6O-80% of classic bipolar patients have a satisfactory clinical response. When the response rate of lithium is considered across the wide spectrum of bipolar disorders, it probably approaches 50%. A large subgroup of lithium-resistant manic patients are rapid cyclers, which is defined by Dunner and Fieve as 4 or more depressions and hypomanias or manias in a 12 month period. About 13-20% of bipolar patients become rapid cyclers and most are females. As many as 72-82% of rapid cyclers exhibit poor responses to lithium. Thus, a substantial percentage of poor response to lithium is accounted for on the basis of rapid cycling. Although controlled trials have demonstrated the efficacy of carbamazepine in the treatment of rapid-cycling bipolar disorder, the response to carbamazepine frequently deteriorates over time. Furthermore, its ability to autoinduce and heteroinduce drug metabolism complicates its routine use. These findings suggest substantial numbers of rapid cyclers become resistant to both carbamazepine and lithium and that additional mood stabilizers are needed. The acute and prophylactic efficacy of valproate in the management of the rapid-cycling bipolar disorder was recently reported by us. These open but prospective trials, as well as other positive reports of its efficacy in rapid cycling, indicate a need for controlled trials. We propose a modified random assignment, single center, 18 month, double- blind, parallel group comparison of valproate and lithium for the prophylactic outpatient management of hypomania/mania in 60 patients with rapid-cycling bipolar disorder. The primary objective of this study is to test the hypothesis that valproate monotherapy is more effective than lithium monotherapy in the prophylactic management of hypomania and mania. The primary efficacy variable for the study will be time to first hypomanic or manic relapse during maintenance monotherapy defined by Research Diagnostic Criteria. Secondary efficacy variables will be studied to further test the primary hypothesis: quality of life, total days hypomanic, total numbers hypomanic episodes, and severity of hypomanic episodes. Mean and worst score depression ratings during hypomanic and manic episodes will reflect the mixed quality of each individual episode. Data regarding antidepressant efficacy will be gathered including time to first depressive relapse, total days depressed, total number of depressed episodes, and mean and worst scores of depression severity. This study should provide novel data describing the safety and efficacy of valproate compared to lithium in a patient population with high public health significance.