Pharmacogenomics of clozapine in schizophrenia patients and associations with efficacy and adverse drug reactions
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Abstract
Clozapine, an atypical antipsychotic drug, is approved for use in treatment-resistant schizophrenia or accompanied by persistent suicidal or self-injurious behavior. Multiple factors could play a role affecting the clinical response of clozapine in schizophrenic patients, including genetic variations. Our objectives were to evaluate the associations between host genetic factors and clinical response, as well as adverse drug reactions, in schizophrenia patients receiving clozapine. Methods: Consenting adults receiving clozapine for at least 1 month had a blood sample collected 12 hours after their last dose of clozapine. Clinical data and laboratory data were collected from patient chart. Genotyping candidate genes (CYP1A2, ABCB1, HTR2A; T102C, and DRD2; Taq IA) was performed TaqMan® real-time PCR. Plasma clozapine and its active metabolite (N-Desmethyl clozapine) concentrations were determined using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Clinical responses were evaluated by CGI-S and Thai HoNOS scores. Results: The clinical symptoms of the majority of patients (88%, n=37/42) were normal to mildly ill in severity (CGI-S = 1-3); 5 patients were in the categories of normal or stable illness by CGI-S and Thai HoNOS (CGI-S = 1 and Thai HoNOS = 0). The average + standard deviation (min-max) dose of clozapine was 75.63±68 (6.25-400.00) mg/day. Dose-normalized clozapine concentrations were statistically significant lower in smokers than non-smokers (1.11+0.87 and 2.12+1.60 ng/mL/mg of dose per day, respectively). Moreover, dose-normalized clozapine concentrations were statistically significant higher in fluoxetine users than non-users (2.69±1.68 and 1.48±1.24 ng/mL/mg of dose per day, respectively). A genetic polymorphism of ABCB1 (rs1045642) was statistically significant associated with the ratio of clozapine to N-Desmethyl clozapine, as well as neutrophil profiles (% neutrophile of less than 50). The non-genetic factors, fluphenazine used and a genetic polymorphism of DRD2 Taq IA were statistically significant associated with the clinical response evaluated by CGI-S. Conclusion: We found associations between genetic polymorphisms of DRD2 (Taq IA) and ABCB1 gene (rs1045642) with clinical efficacy and potential adverse drug reaction of clozapine. These associations are likely complicated by multiple genes and their interactions and may also be related to clozapine dose or plasma concentrations. These preliminary findings support exploring other potential candidate genes that could provide a better understanding of the pharmacogenomics of clozapine and help optimize treatment for schizophrenia patients.
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