The effectiveness of divalproate in all forms of mania and the broader bipolar spectrum: many questions, few answers

Divalproate (VPA) was the first drug, other than lithium, reported to be efficacious for the treatment of bipolar disorder. Since then, the effectiveness of VPA, alone, in combination, and as maintenance therapy, has been investigated in a number of studies. As a monotherapy, clinical studies revealed that VPA was superior to lithium with regard to being effective in a broader patient population: patients with depressive symptoms concurrent with their mania, patients previously poorly responsive to lithium, patients with more lifetime episodes, and on specific symptoms of elation/grandiosity and reduced need for sleep. In addition, while VPA had superior efficacy versus carbamazepine (CBZ), an anti-manic agent, and equivalent efficacy to the anti-psychotic agent olanzapine (OLZ) in manic patients with psychotic manic features, patients showed much better tolerability to VPA than CBZ, anti-psychotics, and, in particular, lithium. Recently, combination therapy (mood stabilizers plus anti-psychotic agents) has shown some advantages compared with monotherapy. Manic symptoms have been observed to improve to a greater extent when the mood stabilizer was co-administered with an anti-psychotic rather than either agent used alone. While only a few maintenance studies have been conducted to date, two randomized studies have indicated consistent trends toward greater efficacy of VPA than lithium, and significant superiority over placebo on most, although not all, measures. In general, VPA provides a well-tolerated treatment that is efficacious for a broad spectrum of manic states and improves outcomes during maintenance treatment.