Objective: Atypical antipychotics are linked to a higher incidence of metabolic side effects, including weight gain, dyslipidemia, and diabetes. In this study, we examined the prevalence and potential genetic predictors of metabolic side effects in 60 adult patients on clozapine. Method: Genetic variants of relevance to clozapine metabolism, clearance, and response were assessed through targeted genotyping of cytochrome P450 enzymes CYP1A2 and CYP2C19, the efflux transporter ABCB1, the serotonin receptor (HTR2C), leptin (LEP), and leptin receptor (LEPR). Clozapine levels and other potential confounders, including concurrent medications, were also included in the analysis. Results: More than half of the patients were obese (51%), had metabolic syndrome (52.5%), and 30.5% were overweight. There was a high prevalence of antipsychotic polypharmacy (61.9%). With multivariable linear regression analysis, LEP -2548G>A, LEPR c.668A>G, and HTR2C c.551-3008 C>G were identified as genetic predictors of body mass index (BMI) after considering effects of clozapine dose, blood level, and concurrent medications (adjusted R 2 ¼ 0.305). Metabolic syndrome was found to be significantly associated with clozapine level and CYP2C19*2 and LEPR c.668 G alleles. Clozapine levels in patients with metabolic syndrome were significantly higher compared to those without metabolic syndrome (1886 + 895 vs. 1283 + 985 ng/mL, P < 0.01) and were associated with the CYP2C19*2 genotype. No association was found between the genetic variants studied and lipid or glucose levels. Conclusion: This study confirms a high prevalence of metabolic side effects with clozapine and suggests higher clozapine level and pharmacogenetic markers in CYP2C19, LEP, LEPR, and HTR2C receptors as important predictors of BMI and metabolic syndrome.
Abré géObjectif : Lea antipsychotiques atypiques sont liés à une incidence accrue d'effets secondaires métaboliques, dont la prise de poids, la dyslipidémie et le diabète. Dans cette étude, nous avons examiné la prévalence et les prédicteurs génétiques potentiels des effets secondaires métaboliques chez 60 patients adultes traités par clozapine. Mé thode : Les variantes génétiques se rapportant au métabolisme, à la clairance et à la réponse de la clozapine ont été évaluées par le génotypage ciblé des enzymes CYP1A2, CYP2C19 du cytochrome P450, du transporteur d'efflux ABCB1, du