Epigenetic Alterations in Hepatic Histone H3K4me2 Associated with Metabolic Side Effects of Olanzapine and Clozapine

Olanzapine and clozapine, two of the most efficacious second-generation antipsychotic drugs (SGAs), are known to cause serious metabolic side effects. Despite their clinical utility, the epigenetic basis of these metabolic side-effects remains poorly understood. This exploratory study investigated whether histone methylation is associated with metabolic disorders following chronic SGA treatment. Rats were treated with olanzapine or clozapine for 9 weeks and then sacrificed 2 h after the final treatment. After evaluating the metabolic parameters, Chromatin immunoprecipitation (ChIP)-deep sequencing was conducted on liver tissue pooled from twelve samples per group to quantify histone H3K4me2 methylation and transcriptional changes. Gene ontology term enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were used to explore shared functional pathways of genes with differential histone methylation. Key findings revealed that both olanzapine and clozapine induced widespread changes in hepatic histone methylation, particularly hypermethylation at H3K4me2 across genes involved in lipid and glucose metabolism, insulin signalling, and adipogenesis. Olanzapine- and clozapine-treated rats displayed increased H3K4me2 levels at numerous gene loci and at distinct genomic regions. These findings suggest the importance of monitoring metabolic parameters in psychiatric patients and potential novel strategies to mitigate SGA-induced metabolic side effects.