Mechanisms of action of the mood stabilizer valproate: a focus on GSK-3 inhibition

Abstract

Valproate is the most widely prescribed antiepileptic drug worldwide, and it is also used in the treatment of bipolar affective disorder, migraine headache and cancer. However, the therapeutic mechanism of action of valproate in these illness states is not understood. This article reviews the pharmacological effects of valproate that may explain its therapeutic efficacy. It focuses on the hypothesis that inhibition of glycogen synthase kinase-3 by valproate is a crucial therapeutic mechanism of this drug in the treatment of bipolar affective disorder. Other cellular pathways and signaling molecules that are targets of valproate (such as inositol de novo biosynthesis, histone deacetylase, protein kinase C, γ-aminobutyric acid, the extracellular signal-regulated kinase pathway and others) are also discussed.