Abstract: The 2012 update search identified 19 further relevant studies, most of which were from China. Thus the review currently includes 26 studies with a total of 2184 participants. All trials examined the effectiveness of valproate as an adjunct to antipsychotics. With the exception of two studies, the studies were small, the participants and personnel were not blinded (neither was outcome assessment), and most were short-term and incompletely reported. For this update we prespecified seven main outcomes of interest: clinical response (clinically significant response, aggression/agitation), leaving the study early (acceptability of treatment, overall tolerability), adverse events (sedation, weight gain) and quality of life. Adding valproate to antipsychotic treatment resulted in more clinically significant response than adding placebo to antipsychotic drugs (14 RCTs, n = 1049, RR 1.31, 95% CI 1.16 to 1.47, I2 = 12%, low-quality evidence). However, this effect was removed after excluding open RCTs in a sensitivity analysis. In terms of acceptability of treatment (measured by the number of participants leaving the study early due to any reason) valproate was just as acceptable as placebo (11 RCTs, n = 951, RR 0.76, 95% CI 0.47 to 1.24, I2 = 55%). Also overall tolerability (measured by the number of participants leaving the study early for adverse events) between valproate and placebo was similar (6 RCTs, n = 974, RR 1.33, 95% CI 0.90 to 1.97, I2 = 0). Participants in the valproate group were found to be less aggressive than the control group based on the Modified Overt Aggression Scale (3 RCTs, n = 186, MD -2.55, 95% CI -3.92 to -1.19, I2 = 82%, very low-quality evidence). Participants receiving valproate more frequently experienced sedation (8 RCTs, n = 770, RR 1.38, 95% CI 1.07 to 1.79, I2 = 0, low-quality evidence) but were no more likely to gain weight than those receiving placebo (4 RCTs, n = 427, RR 1.17, 95% CI 0.76 to 1.82, I2 = 0, low-quality evidence). No study reported on the important outcome of quality of life. There is limited evidence, based on a number of trials, that the augmentation of antipsychotics with valproate may be effective for overall clinical response, and also for specific symptoms, especially in terms of excitement and aggression. However, this evidence was entirely based on open RCTs. Moreover, valproate was associated with a number of adverse events among which sedation and dizziness appeared significantly more frequently than in the control groups. Further randomised studies which are blinded are necessary before any clear recommendation can be made. Ideally these would focus on people with schizophrenia and aggression, on those with treatment-resistant forms of the illness and on those with schizoaffective disorders.

Plain-language summary: The review includes 26 studies, found through electronic searching of relevant databases, with a total of 2184 participants. All trials examined the effectiveness of valproate as an add on to antipsychotics. With the exception of two studies, the studies were small, and most of them were short-term and poorly reported. Data from the included trials showed that participants receiving valproate plus an antipsychotic had better clinical response, compared to those taking an antipsychotic with a placebo. However, this advantage was lost when lower-quality trials were taken out of the analysis. Valproate was also indicated to be effective in controlling excitement and aggression. Acceptability and overall tolerability of the combined treatment was similar between treatment groups and did not cause more weight gain, however, adding valproate did cause greater sedation and dizziness. No trial reported effect on quality of life. Evidence is limited and firm conclusions cannot be made. For the main outcomes of interest, the review authors judged the quality of evidence to be low or very low quality, due to methodological issues in the reviewed studies. Most of them were small, short-term and did not blind the participants or personnel. Large, double-blind and long-term randomised trials should be undertaken to properly determine the clinical effects of adding valproate to antipsychotic treatment for people with schizophrenia. This summary was written by Ben Gray, Senior Peer Researcher, McPin Foundation. mcpin.org/