Dopamine D₂ receptor gene polymorphisms predict well the response to dopamine antagonists at therapeutic dosages in patients with schizophrenia

Abstract  Previous reports have shown that both A1 allele carriers of TaqI A and Del allele non-carriers of −141C Ins/Del for dopamine D₂ receptor (DRD₂) gene polymorphisms have a better antipsychotic drug response. The present study aimed to examine the validity of a combination of these two DRD₂ polymorphisms as predictors for response to DRD₂ antagonists. The subjects consisted of 49 acutely exacerbated inpatients with schizophrenia treated with bromperidol (30 cases, 6–18 mg/day) or nemonapride (19 cases, 18 mg/day) for 3 weeks. Brief Psychiatric Rating Scale and Udvalg for Kliniske Undersøgelser side-effects rating scale were used for clinical assessments. DRD₂ genotypes were determined using a polymerase chain reaction method. In the overall 49 subjects, combined DRD₂ polymorphisms weakly predicted the response to DRD₂ antagonists (Fisher exact test, P = 0.049), that is, good response in A1(+) or Del(–) subjects and poor response in A1(–) plus Del(+) subjects. In the former subjects, non-responders with A1(+) or Del(–) showed higher scores of psychic, extrapyramidal and total side-effects. At therapeutic doses (6–8 mg/day haloperidol equivalent dose) in 30 subjects, the predictability of response was greatly increased (Fisher exact test, P < 0.0045) with higher positive and negative predictive values (78.3% and 85.7%, respectively). These findings suggest that combined DRD₂ polymorphisms can be used as a pretreatment marker for response to DRD₂ antagonists at therapeutic doses, and that A1(+) or Del(–) subjects are highly sensitive to DRD₂ antagonists, expressed as either treatment responders or non-responders vulnerable to extrapyramidal symptoms.