Valproate for the treatment of acute bipolar depression: Systematic review and meta-analysis

Background: Our aim was to analyse existing data on the efficacy and tolerability of valproate for the treatment of acute bipolar depression. Methods: Randomized controlled trials comparing valproate with placebo were identified using searches of electronic databases in October 2008. Outcomes investigated were depression, anxiety, hypomania, attrition, and adverse events. Trial quality was assessed, and data were summarized using meta-analyses. Results: Four randomized, controlled, doubleblind trials of 142 participants were included. Trial quality was good, although individual study sample sizes were small. Study duration was six weeks (2 studies) and eight weeks (2 studies). Meta-analysis showed a significant difference in favour of valproate for reduction in depressive symptoms, both on depression symptom scales (standardized mean difference (SMD) - 0.35 (95% confidence interval, - 0.69, - 0.02)), and participants with at least 50% improvement in symptoms - relative risk (RR) 2.00 (1.13, 3.53). Effects on anxiety symptoms were small, SMD - 0.32 (- 0.72, 0.08) and inconclusive (p = 0.12). No evidence of a difference in mania symptoms, withdrawal for any reason, lack of effectiveness or adverse events was detected. Nausea occurred more frequently with valproate compared with placebo though the difference was not significant, RR 2.01 (0.98, 4.11). Other adverse events occurring more frequently with valproate (somnolence, fatigue/muscle weakness, headache, diarrhoea and dry mouth) did not differ significantly between treatment groups. Limitations: Sample sizes were small warranting a larger study to confirm or disprove these findings. Conclusions: Valproate is effective for the reduction of depressive symptoms of acute bipolar depression, and was well tolerated.