DNA Methylation Changes Associated with Antipsychotic Serum Concentrations in Patients with Psychosis.

Background Antipsychotic drugs (AP) are commonly prescribed for the treatment of psychotic symptoms in schizophrenia (SCZ), bipolar disorder (BP), and major depressive disorder (MDD). However, despite over 70 years of clinical use, the pharmacological mechanisms underlying AP drug action remain incompletely understood. DNA methylation (DNAm) provides a means to investigate epigenetic changes associated with AP exposure and to explore biological pathways potentially involved in AP pharmacology. This study aims to identify DNAm changes associated with treatment using olanzapine, quetiapine, and risperidone which may suggest shared or drug-specific epigenetic signatures. Methods We analysed genome-wide DNAm levels in the blood of 263 psychiatric patients who were treated with AP monotherapies (n = 136, olanzapine n = 89, quetiapine n = 26, risperidone n = 21) or were medication-free (n = 127). We assessed the correlation between DNAm levels and AP serum concentrations of each drug individually and of those shared between the three drugs. To identify drug-specific effects, we compared DNAm profiles between drugs and DNAm levels of medication-free patients. Results We identified 60 CpGs and seven differentially methylated regions (DMRs) consistently associated with all three AP treatments (experiment wide significant threshold p  < 6.1 x 10 ^− 8 ), involving genes linked to postsynaptic density regulation in glutamatergic neurons ( SHANK2 ), signal transduction ( GNB1 ), synaptic plasticity ( GAS7 ), and neuronal signalling ( FBXW4 and ZNF471 ). No significant DNAm effects were associated with any specific AP monotherapy. None of the identified effects were among DNAm differences reported in a large EWAS between cases with SCZ and controls. These findings contribute to the characterization of the association between AP treatment and DNAm and provide insights into AP molecular mechanisms of action.