A Cochrane review included 6 RCTs with a total of 876 subjects. Five trials enrolled only outpatients; one study recruited only children and adolescents. The trials lasted 6 to 24 months. Two studies (n=312) compared valproate with placebo, 4 studies (n=618) valproate with lithium, one study (n=23) valproate with olanzapine and one study (n=220) valproate with the combination of valproate plus lithium. Valproate was more effective than placebo in preventing study withdrawal due to any mood episode (RR 0.68, 95% CI 0.49 to 0.93; NNTB 8; 2 RCTs, n=312), and no difference in efficacy was found between valproate and lithium (RR 1.02, 95% CI 0.87 to 1.20; 4 trials, n=618). Valproate was associated with fewer participants dropping out of treatment for any cause when compared with placebo or lithium (RR 0.82, 95% CI 0.71 to 0.95; 2 trials, n=312 and RR 0.87, 95% CI 0.77 to 0.98; 4 trials, n=618, respectively). However, combination therapy with lithium plus valproate was more likely to prevent relapse than was monotherapy with valproate (RR 0.78, 95% CI 0.63 to 0.96; 1 trial, n=220). Significant differences in adverse event frequencies were found, and lithium was associated with more frequent diarrhoea, polyuria, increased thirst and enuresis, whereas valproate was associated with increased sedation and infection.
A Cochrane review included 10 studies with a total of 1 091 subjets. Valproate was more efficacious than placebo (RRR 38%; RR 0.62; 95% CI 0.51 to 0.77) in the treatment of mania. There was no significant difference between valproate and lithium (RRI 5%; RR 1.05; 95% C.I. 0.74-1.50) or between valproate and carbamazepine (RRR 34%; RR 0.66; 95% C.I. 0.38 to 1.16). Valproate was less effective than olanzapine (failure to achieve clinical response; RRI 25%; RR 1.25, 95% C.I. 1.01 to 1.54; average of 2.8 point less change on the Mania Rating Scale (95% CI 0.83 to 4.79). There were no significant differences in acceptability as measured by total number of subjects withdrawing from the study. There were significant differences in the side effect profiles of valproate and olanzapine, with more sedation and weight gain on olanzapine.