Association study of 12 polymorphisms spanning the dopamine D₂ receptor gene and clozapine treatment response in two treatment refractory/intolerant populations

Rationale: Dopamine D₂ receptor blockade is the major basis for the antipsychotic action of typical antipsychotic drugs (AP) and a necessary but not sufficient basis for the antipsychotic action of atypical APs such as clozapine and other multireceptor antagonists which rely, in part, upon 5-HT_2A antagonism. Genetic factors affecting the density and/or function of D₂ receptors may therefore affect AP response. Objectives: This exploratory study investigates the effect of 12 single nucleotide polymorphisms (SNPs) spanning the entire dopamine D₂ gene on clozapine response in two distinct schizophrenic populations (Caucasian and African-American) refractory or intolerant to conventional APs. Methods: This study included 183 Caucasian and 49 African-American DSM-III-R or DSM-IV schizophrenics. Genotyping was determined by 5′-exonuclease fluorescence assays. Within each population genotype, allele, allele +/-, and haplotype frequencies were compared between responders and non-responders by X ² tests. Linkage disequilibrium analysis was also performed. Results: In the Caucasian sample, no significant associations were found for individual SNP tests; however, two haplotypes were identified as having significant protective effects on treatment outcome. In the African-American sample, individual SNP tests identified the Taq1A, Taq1B, and rs1125394 markers as being predictive of clozapine response. Haplotype analyses identified four protective haplotypes containing these SNPs. In addition, no association between the -141C Ins/Del site and clozapine response was found in either population. Conclusions: Interindividual variability in clozapine response among treatment refractory/intolerant patients is still not fully understood and likely involves multiple factors. This exploratory analysis suggests that the D₂ receptor gene may be one such factor.