Comprehensive DNA methylation analysis of brain and peripheral tissues following chronic risperidone treatment in...

Antipsychotic drugs are increasingly recognized to exert therapeutic effects not only through neurotransmitter modulation but also, in part, through epigenetic mechanisms. Risperidone is an atypical antipsychotic drug widely used to treat schizophrenia, yet its in vivo epigenomic effects remain poorly understood. We investigated genome-wide DNA methylation changes induced by chronic risperidone administration in the common marmoset, a non-human primate with high translational relevance. Adult males were treated orally with risperidone for 28 days. DNA methylation was analyzed in four brain regions (frontal cortex, hippocampus, cerebellum, and caudate nucleus) and two peripheral tissues (blood and liver) using a HumanMethylation450K BeadChip adapted to the marmoset genome. Risperidone induced region- and tissue-specific methylation alterations. The brain showed predominant hypermethylation, and the hippocampus had the largest number of differentially methylated probes. Rank-rank hypergeometric overlap analysis revealed partial hypermethylation-hypermethylation concordance between the hippocampus or caudate and peripheral tissues, indicating partially coordinated changes. We also found that risperidone-treated neuroblastoma cells showed methylation patterns closely resembling those of the hippocampus, suggesting that the epigenetic changes are partly conserved in the cell models. These findings offer a framework for understanding the molecular basis of antipsychotic actions and for identifying potential epigenetic markers relevant to clinical effects.