Influence of genetic variants (SNP) and plasma concentration on late adverse reactions in patients with mental disorders treated with clozapine

Author(s)

João Kleber Novais Pereira

• Document type: Doctoral Thesis
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas
• Defense date: 2024-08-09

Examining board members

Patricia Moriel; Paulo Caleb Júnior de Lima Santos; Patricia Melo Aguiar; Marília Berlofa Visacri; Marcela Forgerini

• Advisor: Patricia Moriel

Abstract

Clozapine is considered the gold standard antipsychotic for the treatment of treatment-resistant schizophrenia and is also used in other severe mental disorders, such as bipolar affective disorder and, in some cases, autism spectrum disorder. Clozapine has been associated with a general improvement in symptoms, a reduction in hospitalization rates, and overall mortality, as well as beneficial effects on other aspects affecting patients with severe mental disorders. Despite its demonstrated efficacy in a significant proportion of patients, clozapine remains underutilized, potentially due to its complex profile of adverse drug reactions (ADRs). The general objective of this study was to investigate the relationship between the presence of ADRs and genetic variants related to the metabolism and transport of clozapine, as well as the plasma concentration of clozapine and its metabolite in patients with severe mental disorders undergoing chronic clozapine treatment. This analytical, observational/longitudinal cohort study was conducted at the Psychiatry Outpatient Clinic of the Hospital de Clínicas da Unicamp (HC/UNICAMP). Patients who had been taking clozapine for at least one year and had a diagnosis of severe mental disorder were included. Blood samples were collected, and genomic DNA was extracted for genotyping. The allelic variants of the ABCB1 (rs1045642, rs1128503, and rs2032582), CYP1A2 (rs792551, rs2470890, and rs2069514), CYP3A4 (rs2740574), LEP (rs7799039), LEPR (rs1137101), and MC4R (rs489693 and rs11782313) genes were genotyped using TaqMan® probes in a Polymerase Chain Reaction (qPCR) assay. The plasma concentrations of clozapine and its metabolite norclozapine were measured using the HPLC method, considered the gold standard for assessing adherence to drug treatment. ADRs related to lipid metabolism, carbohydrate metabolism, inflammatory markers, and weight gain were evaluated using the CTCAE (Common Terminology Criteria for Adverse Events) criteria. The study received approval from the Research Ethics Committee (83192918.9.0000.5404). The study included 46 patients with a mean age of 32.5 ± 10.2 years, predominantly men (69.6%), self-identified as white (73.9%), single (82.6%), and unemployed (54.4%). Hypertriglyceridemia was present in 45.7% of patients, with 23.9% exhibiting grade 1, 15.2% grade 2, 4.4% grade 3, and 2.2% grade 4 hypertriglyceridemia. During treatment, 74.0% of patients experienced weight gain, with 17.4% classified as grade 1 (5 < 10% increase compared to baseline), 19.6% as grade 2 (10 < 20% increase compared to baseline), and 37.0% as grade 3 (> 20% increase compared to baseline). The average clozapine concentration was 638.2 ng/mL. The frequencies of the genetic variants studied were consistent with those reported in the literature for Brazilian and global populations. For the ABCB1 gene (rs1045642), individuals with AG or GG genotypes were 13.7 times more likely to exhibit reduced HDL levels compared to those with the AA genotype (95% CI 1.95; 97.17, p = 0.008). Similarly, individuals with the CA or AA genotype in the MC4R gene (rs489693) were 6.6 times more likely to have an elevated ESR compared to those with the CC genotype (95% CI 1.14; 38.83, p = 0.035). These findings align with existing literature, which indicates that antipsychotics, particularly clozapine and olanzapine, are associated with weight gain, warranting further investigation. Additionally, the data suggest that the genetic variant in the ABCB1 gene (rs1045642) may influence a decrease in HDL levels, and the variant in the MC4R gene (rs489693) may influence the increase in inflammation (AU)

• FAPESP's process: 19/19460-8 - Clozapine toxicity in treatment of patients with schizophrenia: possible relation to genetic polymorphisms
• Grantee: João Kleber Novais Pereira
• Support Opportunities: Scholarships in Brazil - Doctorate