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 D(2) receptor (DRD(2)) gene polymorphisms have a better antipsychotic drug response. The present study aimed to examine the validity of a combination of these two DRD(2) polymorphisms as predictors for response to DRD(2) 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. DRD(2) genotypes were determined using a polymerase chain reaction method. In the overall 49 subjects, combined DRD(2) polymorphisms weakly predicted the response to DRD(2) 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 DRD(2) polymorphisms can be used as a pretreatment marker for response to DRD(2) antagonists at therapeutic doses, and that A1(+) or Del(-) subjects are highly sensitive to DRD(2) antagonists, expressed as either treatment responders or non-responders vulnerable to extrapyramidal symptoms.