Pharmacogenetics of сlozapine: toward personalized therapy in treatment resistant schizophrenia

Background. Clozapine is recognized as the most effective medication for treatment-resistant schizophrenia (TRS). However, the use of clozapine in clinical practice remains limited due to challenges related to its efficacy and safety. Pharmacogenetics may help enhance both the effectiveness and safety of its use. Aims — to analyze the role of polymorphic variants in genes associated with pharmacogenetic factors in the development of adverse reactions and the efficacy of clozapine therapy. Methods. We conducted a prospective pharmacogenetic study of the efficacy and safety of clozapine in patients with TRS (F20 according to ICD-10). The observation period was 28 ± 3 days. The primary endpoint was the change in the severity of psychopathological symptoms, assessed using the PANSS, CGI-S, and CGI-I scales. Treatment safety was evaluated using the UKU Side Effect Rating Scale. Genotyping was performed using the real-time PCR method. Results. The study included 61 patient receiving treatment in a psychiatric inpatient facility. According to our data, clozapine efficacy was associated with CYP2C9 rs1799853, DRD4 rs1800955, and ABCB1 rs1128503. The final clozapine dose was influenced by ABCB1 rs1045642, rs2032582, and rs1128503. Associations with safety were identified for CYP2D6 rs3892097 and rs1065852; CYP2D6 rs3892097; CYP2C19 rs4244285; CYP2C9 rs1057910; CYP3A4 rs2740574; CYP2C19 rs12248560; ABCB1 rs1045642, rs2032582, and rs1128503; HTR2A rs6313; DRD2 rs1800497 and DRD4 rs1800955. Conclusions. Our study revealed considerable interindividual variability in clozapine treatment outcomes among patients with TRS. Polymorphisms CYP2C9 and DRD4 were associated with improvements in negative symptoms, while ABCB1 variants showed the strongest impact, influencing both final clozapine dose and tolerability. Additional associations with CYP2D6, CYP2C19, CYP3A4, HTR2A, and DRD2 were observed for adverse drug reactions such as sedation, weight gain, memory impairment, and depression. These findings highlight the importance of pharmacogenetic profiling in optimizing clozapine therapy, though replication in larger and ethnically diverse cohorts remains necessary.