Allelic variation in the promoter region of the dopamine D2 receptor gene influences the antipsychotic response to clozapine

Allelic variation in the genes coding for the neurotransmitter receptors may influence the interindividual variation in antipsychotic drug response. The dopamine D₂ receptor gene (DRD2) represents the most logical candidate gene for antipsychotic drug response as all of the known antipsychotic drugs bind to the D₂ receptor. Recently, Arinami and colleagues discovered a polymorphism, -141C Ins/Del, in the promoter region of DRD2 that appeared to produce significant effects on D₂ receptor gene expression. We have investigated whether -141C Ins/Del is associated with clinical response to the atypical antipsychotic drug clozapine in 72 schizophrenic or schizoaffective patients. Brief Psychiatric Rating Scale (BPRS) ratings were obtained after patients were treated for 10 weeks with clozapine (mean dose = 407 ±113 mg/d) by raters blind to treatment status and compared to base-line ratings. Patients were genotyped for -141C Ins/Del by PCR amplification of DNA and digestion with BstN1. Analyses of allele and genotype frequencies revealed that both were significantly associated with response to clozapine (P = 0.02). Del- patients had a five-fold greater reduction in psychotic symptoms in comparison to the Del+ patients. Moreover, of the 21 patients with the Del allele, only 2 (9%) met criteria for clozapine response. These preliminary data suggest that a D₂ receptor gene polymorphism with reported functional effects is associated with the antipsychotic response to clozapine. Replication studies and functional data in humans will be needed to further elucidate the role of this variant in antipsychotic drug efficacy.