Valproic acid: how it works. Or not

Bipolar disorder (BPD) affects approximately 1% of the population worldwide (Weissman MM, Bland RC, Canino GJ, et al. Cross-national epidemiology of major depression and bipolar disorder. J Am Med Assoc 1996;276:293-99, [1]) and is a debilitating illness associated with high morbidity and mortality (10% lifetime risk of suicide). Valproic acid (VPA) is a widely used alternative to lithium salts for the treatment of BPD. and has been in clinical use for epilepsy for years, but its mechanism of action has not been defined in any setting. A large number of indirect targets as well as a more limited number of direct in vitro targets for VPA have been described, but strong evidence that these targets play a role in the therapeutic response is lacking. VPA was recently shown to inhibit histone deacetylases (HDACs), key regulators of chromatin structure and transcription. In this review we summarize the history and pharmacology of VPA and address the potential role of HDACs in the response to VPA. Review of these studies suggests that inhibition of HDACs is a highly plausible mechanism for VPA-mediated cellular differentiation and teratogenesis, but cannot account for the anticonvulsant and mood regulating actions of VPA that more likely involve different or additional targets. (C) 2004 Association for Research in Nervous and Mental Disease. Published by Elsevier B.V. All rights reserved.