Relationship between serum valproate and lithium levels and efficacy and tolerability in bipolar maintenance therapy

Background. In spite of widespread recognition of the importance of maintenance treatment for bipolar disorder, there are relatively few available well-designed clinical trials that have provided rigorous evidence for the efficacy of specific agents. One approach used effectively in analyses of lithium studies has been the stratification of efficacy and tolerability results based on serum drug concentrations. Therefore, we conducted a similar analysis of the efficacy of divalproex or lithium, based on serum concentrations in the maintenance treatment of bipolar I disorder in a recent 12-month placebo-controlled trial. Methods. This was a post-hoc analysis of results obtained in a 12-month, double-blind, placebo-controlled trial of divalproex and lithium involving 372 patients (intent-to-treat). The patient set was stratified into four therapeutic drug concentration ranges (Non-therapeutic, Low Therapeutic, Medium Therapeutic, and High Therapeutic) for both divalproex and lithium. Efficacy measures were Kaplan-Meier survival analyses of time to discontinuation for any reason, time to discontinuation for a protocol-defined manic episode, and time to discontinuation for a manic or depressive episode. Results. Significant differences between divalproex at the Medium Therapeutic range (75-99.9 µg/ml) and placebo were demonstrated in Kaplan-Meier survival results for discontinuation for any reason (median survival time: divalproex, 8 months; placebo, 4 months; P<0.05) and for discontinuation for a manic or depressive episode (median survival time: divalproex, 8 months; placebo, 3 months, P=0.003). At 12 months, the proportion of divalproex-treated patients (Medium Therapeutic range) who did not discontinue for a protocol-defined manic episode (85%) was higher than the proportion of lithium (Medium Therapeutic range; 70%) or placebo-treated (83%) patients. Conclusions. Divalproex at the Medium Therapeutic range provided significantly better bipolar maintenance treatment response than placebo in survival analyses, suggesting a possible serum concentration target range for clinicians in providing optimal treatment response. The value of this analytic approach, used for the first time here for divalproex, is discussed, along with a call for further research into optimal therapeutic drug levels.