A translational perspective on histone acetylation modulators in psychiatric disorders

A large volume of research now provides evidence correlating aberrant histone deacetylase (HDAC) activities and hypoacetylation of histones to disruptions in synaptic plasticity, neuronal survival/regeneration, memory formation and consolidation. Hence, maintaining the acetyl-histone homeostasis as a component of neuronal mechanisms by targeting HDACs has emerged as an exciting intervention strategy for several neuropsychiatric disorders. Though extensive preclinical animal studies have elevated the translational potential of HDAC inhibitors (HDACis) in psychiatric disorders, so far, the translational gain remains low. This is perhaps attributed to the anticipated specificity issues and off-target effects which might negate the risk-reward advantage over the approved antipsychotics in use. So, to harness the therapeutic potential of HDACis in psychiatric disorders, a combination therapeutic strategy involving co-administration of an approved HDAC inhibitor (HDACi) along with a marketed antipsychotic drug has emerged in parallel. This takes advantage of the ability of HDACi, like SAHA, to reverse the potentially detrimental hypoacetylated state of chromatin and facilitate to augment the efficacy of atypical antipsychotics like clozapine. Apart from these efforts, as an alternative therapeutic strategy, highly tolerable oral metabolic acetate supplements with an ability to reverse the hypoacetylation states of histone were initiated in animal models. Exogenous acetate carrier enriches the cellular acetyl-CoA pool restoring acetyl-histone homeostasis, reminiscent of HDACi effect, without the associated toxicity. Though the path towards therapeutic intervention in psychiatric disorders using histone acetylation modulators is riddled with challenges, the growing number of tool compounds along with innovative research strategies, however, bodes well for the future.