Schizophrenia is a multifactorial neuropsychiatric disorder arising from a combination of neurochemical imbalances, genetic and epigenetic influences, environmental exposures, and other non-genetic factors. The field of pharmacoepigenetics examines how epigenetic variations influence an individual’s response to medications. This review aimed to provide a descriptive synthesis of current insights into the epigenetic regulation of pharmacogenes encoding metabolizing enzymes involved in the processing of second-generation antipsychotics (SGAs) for schizophrenia and to explore the clinical consequences of these mechanisms. Key pharmacogenes, including CYP2D6, CYP1A2, CYP2C9, CYP2C19, and CYP3A4, were summarized alongside their enzymatic roles in metabolizing SGAs such as clozapine, olanzapine, risperidone, paliperidone, and quetiapine. The review primarily focused on epigenetic processes—DNA methylation, histone methylation, and acetylation—affecting these pharmacogenes, as well as epigenetic modifications triggered by enzyme-inducing drugs and SGAs themselves. Although the literature on epigenetic regulation of pharmacogenes is still limited, current evidence points to DNA methylation and histone trimethylation and acetylation as predominant mechanisms, with certain enzyme-inducing medications potentially promoting additional epigenetic alterations. These findings carry important implications for optimizing the clinical management and pharmacological treatment of patients with schizophrenia.
