Association of a Schizophrenia Risk Variant at the DRD2 Locus With Antipsychotic Treatment Response in First-Episode Psychosis

Abstract

Findings from the Psychiatric Genomics Consortium genome-wide association study (GWAS) showed that variation at the DRD2 locus is associated with schizophrenia risk. However, the functional significance of rs2514218, the top DRD2 single nucleotide polymorphism in the GWAS, is unknown. Dopamine D2 receptor binding is a common mechanism of action for all antipsychotic drugs, and DRD2 variants were related to antipsychotic response in previous studies. The present study examined whether rs2514218 genotype could predict antipsychotic response, including efficacy and adverse events, in a cohort of patients with first episode of psychosis treated with either risperidone or aripiprazole for 12 weeks. Subjects were genotyped using the Illumina Infinium HumanOmniExpressExome array platform. After standard quality control, data from 100 subjects (49 randomly assigned to treatment with aripiprazole and 51 assigned to risperidone) was available for analysis. Subjects were assessed for psychotic symptomatology and medication-related adverse events weekly for 4 weeks, then biweekly for 8 weeks. Linear mixed model analysis revealed that the homozygotes for the risk (C) allele at rs2514218 had significantly greater reduction in positive symptoms during 12 weeks of treatment compared to the T allele carriers. In the aripiprazole group, C/C homozygotes also reported more akathisia than the T allele carriers, while in the risperidone group, male T allele carriers demonstrated greater prolactin elevations compared to male C/C homozygotes. These findings suggest that the schizophrenia risk variant at the DRD2 locus (or another variant in close proximity) is associated with observable differences in response to treatments which reduce striatal dopamine signaling.

Keywords: DRD2; antipsychotic; pharmacogenetics.