A Cochrane review [Abstract] 1 included 26 studies with a total of 2184 subjects. All trials examined the effectiveness of valproate as an adjunct to antipsychotics.Adding valproate to antipsychotic treatment resulted in more clinically significant response than adding placebo to antipsychotic drugs (RR 1.31, 95% CI 1.16 to 1.47; 14 RCTs, n = 1049). However, this effect was removed after excluding open RCTs. In terms of acceptability of treatment (number of patients leaving the study early due to any reason) valproate was just as acceptable as placebo (RR 0.76, 95% CI 0.47 to 1.24; 11 RCTs, n = 951). Also overall tolerability (number of patients leaving the study early for adverse events) between valproate and placebo was similar (RR 1.33, 95% CI 0.90 to 1.97; 6 RCTs, n = 974).Patients in the valproate group were found to be less aggressive than the control group based on the Modified Overt Aggression Scale (MD -2.55, 95% CI -3.92 to -1.19; 3 RCTs, n = 186). Patients receiving valproate more frequently experienced sedation (RR 1.38, 95% CI 1.07 to 1.79, 8 RCTs, n = 770) but were no more likely to gain weight than those receiving placebo (RR 1.17, 95% CI 0.76 to 1.82; 4 RCTs, n = 427). No study reported on the quality of life.
Comment: The quality of evidence is downgraded by study quality (lack of blinding) and indirectness (short follow-up time, most of the studies are from China). The effects of valproate on important subgroups such as those with schizophrenia and aggressive behaviour or those with schizoaffective disorder are unknown.
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