Pharmacogenetic Factors of Clozapine-Induced Metabolic Syndrome

(1) Introduction: Despite modern therapies, approximately 20-30% of patients with schizophrenia remain resistant to psychopharmacotherapy. Clozapine is the only antipsychotic with proven efficacy for treatment resistance in schizophrenia (TRS). The most common adverse drug reaction (ADR) during clozapine administration are metabolic disturbances, particularly metabolic syndrome (MS). Because MS leads to a twofold increase in mortality from cardiovascular disease and a 1.5-fold increase in mortality from all causes, and clozapine is often the only treatment option for TRS, it is critical to monitor and management metabolic abnormalities. The high interindividual differences in the development of clozapine-induced MS suggest that genetic factors may play an important role. (2) Purpose: The aim of this study was to identify relevant single nucleotide polymorphisms (SNPs) of candidate genes for clozapine-induced MS, because based on these data, a genetic risk panel can be constructed to assess the likelihood of developing clozapine-induced MS in patients with schizophrenia. (3) Materials and Methods: We searched for full-text publications in PubMed, Web of Science, Springer, Google Scholar, and electronic libraries in English and Russian, available from inception to 30 October 2023. Keywords were the following: metabolic disturbances, clozapine, metabolic syndrome, schizophrenia, genes, adverse drug reactions, antipsychotics, pharmacogenetics, genetic biomarker, single nucleotide variant, polymorphism, association, variation, and metabolic syndrome genes. (4) Results: we included 6 naturalistic cross-sectional open-label trials, included patients with schizophrenia, schizoaffective, schizophreniform disorder or psychotic disorder, who were treated with first and second generations antipsychotics, among which there was also clozapine and 1 meta-analysis which reviewed association between HTR2C gene polymorphisms and anti-psychotic-induced MS in schizophrenia patients. According to the results of our scoping review the carriage of SNPs in the studied candidate genes associated with clozapine-induced MS are the following: 1) CYP1A2 gene: genotype AA of rs762551 (NG_008431.2:g.32035C>A); 2) CYP2C19 gene: CYP2C19*2 polymorphism; 3) HTR2C gene: genotype CC of rs518147 (NM_000868.2:c.-697G>C), minor allele C of rs1414334 (NG_012082.3:g.324497C>G), genotype CC of rs518147 (NM_000868.2:c.-697G>C), genotype GG of rs12836771 (NG_012082.3:g.71829A>G); 4) LEP gene: genotypes AG and GG of rs7799039 (NG_044977.1:g.475G>A); 5) LEPR gene: genotypes AG and GG of rs1137101 (NG_015831.2:g.177266A>G). (4) Conclusions: Uncovering the genetic biomarkers of clozapine-induced MS may provide a key to developing a strategy for the personalized prevention and treatment of this ADRs of clozapine in patients with schizophrenia spectrum disorders in real clinical practice.