Valproate in bipolar disorder: 2000 onwards

Objective: To describe the evidence for the efficacy and tolerability of valproate in treatment of bipolar disorders, as well as factors associated with favorable or unfavorable outcomes. Method: Studies published from 2000 onwards were reviewed, as well as published abstracts. For clinical trials, randomized, prospective studies were emphasized. Results: Several mechanisms of action of valproate on central nervous system neurons that may be relevant to its actions in bipolar disorders have been recently reported. These include inhibition of glycogen synthase kinase and activation of extracellular signal-regulated kinase. Several of the actions overlap those observed from lithium. Valproate is effective in treatment of mania, and somewhat more effective in certain patient subgroups than other treatments, e.g. mixed mania, and mania with prominent irritability. Valproate is comparable with olanzapine in maintenance treatment, and somewhat better tolerated. Higher serum levels, particularly above 110 mu g/ml, are associated with more reports of weight gain, sedation, and reductions in platelet count. Valproate may be associated with an increased rate of polycystic ovarian syndrome, with increased weight contributing to the risk. Valproate reduces total cholesterol levels, particularly among patients with baseline elevations of cholesterol. Several studies indicate that valproate can be beneficially combined with antipsychotic drugs and other treatments for bipolar disorder. Conclusion: Valproate continues to be studied in further clarification of its mechanisms, efficacy, risks, and spectrum of benefits in bipolar disorder. It is a major treatment for bipolar disorder, both in monotherapy and combination therapy regimens.