Valproate

OBJECTIVES: This article summarizes the role of valproate as a treatment for bipolar disorder and related conditions. METHODS: Published studies and reviews were systematically reviewed. Results from randomized, parallel group, double-blind, placebo-controlled studies that included an active comparator are emphasized. RESULTS: Valproate is an effective treatment for manic patients. Valproate was superior to placebo in one 1-year randomized, parallel group study in rate of recurrence requiring discontinuation, rate of depression requiring discontinuation, total early termination and time to 25% of patients relapsing with mania, and in controlling mild depressive symptoms. On some measures, including time to development of a manic episode, valproate did not differ from placebo. Assessments of maintenance efficacy of valproate and other putative prophylactic treatments for bipolar disorder are problematic, because of the need to analyze multiple indices of efficacy, and practical and ethical issues that limit generalizability of results of placebo-controlled studies. Valproate has some advantages over lithium in treatment of mania for persons with more severe illnesses. Valproate benefits a broader spectrum of bipolar conditions than lithium. Valproate appears at best modestly effective for bipolar depression. Used in combination with several other treatments, additive benefits result, that are greater than with any of the treatments as monotherapy. Side effects are generally mild and manageable, particularly with divalproex. Weight gain and pharmacokinetic interaction with lamotrigine are perhaps the most consistent problems in use. Valproate contributes to neural tube defects if taken during the first trimester of pregnancy, and this risk must be conveyed to women. CONCLUSIONS: Valproate is an effective and useful treatment for bipolar disorder. Studies clarifying its spectrum of efficacy, its safety and efficacy in combination regimens, and its mechanisms of action are warranted.