Linear relationship of valproate serum concentration to response and optimal serum levels for acute mania.

OBJECTIVE: Several studies have shown that achieving adequate serum valproate levels is critical to rapid stabilization of acute mania, but estimates of the target therapeutic level have been imprecise. A post hoc analysis of pooled intent-to-treat data from three randomized, placebo-controlled studies of divalproex treatment for acute mania was performed to test a hypothesized linear relationship between serum concentration and response and to determine optimal blood levels for treatment of acute mania. METHOD: Subjects (N=374) were stratified into seven groups (six valproate serum level ranges and placebo), and effect size was determined for each. Linearity of dose response was tested with both parametric and nonparametric techniques. ANOVA was used to compare the response at each serum level range with that of placebo as well as the lowest valproate level (≤55.0 μg/ml). The mean serum valproate level was then determined for all subjects with an effect size greater than or equal to the maximal effect de...