Histone deacetylases (HDACs) as therapeutic target for depressive disorders

Major depressive disorder (MDD) represents approximately 40% of the disability caused by mental illnesses globally. The poorly understood pathophysiology and limited efficiency of pharmacological treatment (based primarily on the principles of the monoaminergic hypothesis) make depression a serious medical, public and socio-economical problem. An increasing number of studies suggest that epigenetic modifications (alterations in gene expression that are not due to changes in DNA sequence) in certain brain regions and neural circuits represent a key mechanism through which environmental factors interact with individual's genetic constitution to affect risk of mental disorders. Accordingly, chromatin-based epigenetic regulation seems to be a promising direction for the development of new, more effective antidepressant drugs. Recently, several inhibitors of histone deacetylases (HDAC) have been extensively studied in the context of antidepressant action. So far, none of them has been used to treat depression in humans due to the low selectivity for specific HDAC isoforms, and consequently, a risk of serious adverse events. In this review, we focus on the HDAC inhibitors (HDACi) with the greatest antidepressant efficacy and their activity in the preclinical studies. Moreover, we discuss their potential therapeutic usefulness in depression and the main limitations.