Genetic predictors of efficacy and safety of clozapine therapy (review)
Background: Clozapine remains an indispensable antipsychotic for patients with treatment-resistant schizophrenia, but its use can induce adverse drug reactions. Genetic characteristics of patients explain interindividual variability in clozapine concentration in the blood. Predictive pharmacogenetic testing, which determines the carriage of single-nucleotide variants of genes encoding key enzymes of metabolism and transport, can help predict the efficacy and safety of clozapine for a specific patient. The aim of the study:To determine allelic variants of genes encoding key enzymes of metabolism and key transporters of clozapine, based on an analysis of modern literature. Materials and methods: A search for full-text articles was conducted in the bibliographic databases PubMed, eLIBRARY.RU, Google Scholar. Results: The AA genotype of CYP1A2*1F (rs762551) encodes a form of the CYP1A2 isoenzyme with higher activity in the presence of an inducer, such as smoking. The rs2472297 variant is associated with higher activity of the CYP1A2 isoenzyme, to a greater extent also in the presence of an inducer. The CYP1A2*1C (rs2069514) variant is associated with reduced activity of the CYP1A2 isoenzyme and an increased risk of developing adverse drug reactions when taking clozapine, and the CYP3A4*22 (rs35599367) variant is associated with reduced expression of this isoenzyme. The results of association studies of the CYP2C19*2/*2 genotype are contradictory. No association was found between CYP2D6 gene polymorphisms and the rate of clozapine metabolism. UGT2B:GA and UGT1A4*3 isoenzyme variants did not affect the efficacy of clozapine, but were associated with variability in the rate of clozapine glucuronidation, which may affect its toxicity. A significant association was found between the minor C allele of rs28379954 of the NFIB gene and reduced blood clozapine concentrations, so patients with the rs1045642 CC genotype require higher doses of this antipsychotic to achieve the same plasma concentrations as patients with the CT or TT genotypes. Patients carrying nonfunctional variants of rs2032582 in the ABCB1 gene had lower clozapine clearance, and rs212090 in the ABCC1 gene was associated with increased serum clozapine levels. Nonfunctional variants of rs2231142 in the ABCG2 gene appear to have the greatest impact on clozapine exposure in the brain by significantly slowing its efflux. Conclusion: Genetic predictors of changes in clozapine metabolism and efflux may be useful for developing personalized therapeutic strategies in the treatment of psychiatric disorders using clozapine
Nasyrova RF, Kidyaeva AV, Zakharova NV, et al. Genetic predictors of efficacy and
safety of clozapine therapy (review). Research Results in Biomedicine. 2026;12(3):462-480. Russian.
DOI: 10.18413/2658-6533-2026-12-3-0-7
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