Antipsychotic Polypharmacy and Epigenetic Age Acceleration in Schizophrenia

Schizophrenia spectrum disorders (SSD) are debilitating psychiatric illnesses that require extensive pharmacologic, cognitive, and functional management. SSD patients are often prescribed different medications, most commonly antipsychotics, which bear numerous side effects. Recently, accumulating evidence has shown epigenetic aging changes in SSD. However, the effects of antipsychotic medications on this phenomenon remain unexplored.We investigated whether antipsychotic medications are associated with epigenetic age acceleration (EAA) in 153 SSD patients. EAA was estimated using six different epigenetic clocks, based on the methylation patterns of peripheral blood cells.The analysis revealed some evidence of aging deceleration based on the Hannum DNAm Age in individuals on antipsychotic polypharmacy, relative to their monopharmacy counterparts (mean difference=-0.59 years, p=0.0109), which was only nearing significance after adjusting for multiple comparisons (padjusted=0.0654). In sex-specific analysis, only females displayed significantly decelerated epigenetic aging in the polypharmacy group in three of the six clocks. Furthermore, we observed no dose-dependent effects of antipsychotics on EAA in all clocks using three dose standardization methods (daily defined dose, chlorpromazine equivalents, and percent of maximum allowed dose).The findings suggest that antipsychotic treatment may modulate biological aging in SSD; however, this effect is not dose-dependent. Moreover, there appears to be an interplay between sex, polypharmacy, and epigenetic aging. These findings contribute to our understanding of the biological effects of antipsychotic treatment, and future research in this area is key for weighing the benefits and the risks of pharmacological management of SSD.