Epigenetic dysregulation in schizophrenia: molecular and clinical aspects of histone deacetylase inhibitors

Alkomiet Hasan, Amanda Mitchell, Anja Schneider, Tobias Halene, Schahram Akbarian

Notwithstanding the considerable advances in the treatment options for schizophrenia, the cognitive symptoms in particular are not receptive to antipsychotic treatment and considered one of the main predictors for poor social and functional outcome of the disease. Recent findings in preclinical model systems indicate that epigenetic modulation might emerge as a promising target for the treatment of cognitive disorders. The aim of this review is to introduce some of the principles of chromatin biology to the reader and to discuss a possible role in the neurobiology and pathophysiology of schizophrenia. We will discuss potential epigenetic targets for drug therapy, including histone deacetylase inhibitors (HDACi). In a second part, conceptual and practical challenges associated with clinical trials of chromatin-modifying drugs in psychiatric patient populations are discussed, including safety profiles, the potential for adverse effects and general issues revolving around pharmacokinetics and pharmacodynamics. Additional investigations are required in order to fully evaluate the potential of HDACi and similar "epigenetic therapies" as novel treatment options for schizophrenia and other psychotic disease.