ABCB1 and DRD3 polymorphism as a response predicting biomarker and tool for pharmacogenetically guided clozapine dosing in Asian Indian treatment resistant schizophrenia patients

Abstract

Purpose: To investigate association of two single nucleotide polymorphisms (SNPs) ABCB1(rs1045462) and DRD3(rs6280) with clozapine response and the dose in treatment resistant schizophrenia (TRS) patients.

Methods: 200 TRS patients were enrolled in the study during their follow up visit post clozapine initiation. SNP assessment was performed for DRD3 (rs6280) and ABCB1(rs1045462) by sequencing. Blood sample for genotyping was collected with disease and treatment related variables recording on case record form. Patients were classified as responders or nonresponders based upon Andreasen criteria and Positive and Negative Syndrome Scale (PANSS).

Results: Mean clozapine dose, the genotype frequency distribution of ABCB1, DRD3 SNPs were significantly different in clozapine responder and non-responder study population (p < 0.05). CT genotype of ABCB1 and AG genotype of DRD3 were observed to be more prevalent in the responder group. TT genotype of ABCB1 and AG genotype of DRD3 were prevalent in the nonresponder group. Clozapine dosing equations for responder and nonresponder TRS populations were developed through logistic regression analysis. 27% variability in clozapine dose was explained by possible combinations of ABCB1 and DRD3 SNP analysis.

Conclusion: Differential ABCB1(rs1045462) and DRD3(rs6280) genotype frequencies among the clozapine responders and non-responders explained clear feasibility of response predictor potential along with clozapine dose variability association. Pharmacogenetically guided clozapine dosing is possible if more SNPs are considered together with ABCB1(rs1045462) and DRD3(rs6280) in TRS patients.

Keywords: Clozapine; Pharmacogenetics; Treatment resistant schizophrenia.