Risperidone is an atypical antipsychotic agent with efficacy for both positive and negative symptoms of schizophrenia. However, what makes an antipsychotic 'atypical' remains unclear. We recently found that the T102C polymorphism in the 5-HT2A receptor gene could affect risperidone's efficacy for negative symptoms. The present study investigated the effect of the Ser311Cys polymorphism in the dopamine D2 receptor (DRD2) gene on risperidone treatment response. A total of 123 Han Chinese patients with acutely exacerbated schizophrenia were given risperidone for up to 42 days. Clinical manifestations were measured bi-weekly with Positive and Negative Syndrome Scale (PANSS) and Nurses' Observation Scale for Inpatients Evaluation (NOSIE, for assessment of social function). For adjusting the within-subject dependence over repeated assessments, multiple linear regression with generalized estimating equation methods was utilized to analyse the effects of Ser311Cys polymorphism and other covariates on clinical performance. Compared with patients who had the Ser311Ser genotype, patients with the Ser311Cys genotype had lower scores on PANSS Positive, Negative, General Psychopathology and Cognitive subscales and NOSIE, after adjustment for 5-HT2A T102C polymorphisms and other confounders. The 5-HT2A T102C polymorphism had marginal influences on PANSS Total and Negative subscale scores. Male gender, fewer previous hospitalizations, and higher risperidone dose predicted better treatment response after control for other variables. The preliminary results suggest that variations in the DRD2 gene influence risperidone treatment response for positive, negative, and cognitive symptoms, general psychopathology, and social functioning. Several clinical factors may also contribute to inter-individual differences in risperidone treatment response.

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Risperidone is an atypical antipsychotic agent with efficacy for both positive and negative symptoms of schizophrenia. Risperidone is a potent dopamine D3 antagonist and agonism at D3 sites induces behavioral suppression in rodents. We thus hypothesized that D3 antagonism may contribute to response to risperidone in negative symptoms. This study aimed to explore the influence of the Ser9Gly polymorphism of the dopamine D3 receptor (DRD3) gene on response to risperidone after controlling for nongenetic factors. One hundred twenty-three Han Chinese patients with acutely exacerbated schizophrenia were given risperidone monotherapy for up to 42 days. Clinical manifestations were measured biweekly with Positive and Negative Syndrome Scale and Nurses' Observation Scale for Inpatients Evaluation (for assessment of social functioning). For adjusting the within-subject dependence over repeated assessments, multiple linear regression with generalized estimating equation methods was used to analyze the effects of Ser9Gly polymorphism and other covariates on clinical performance. Compared with patients with the Gly9Gly genotype, those with either Ser9Ser or Ser9Gly had better performance on negative symptoms after control for other prognostic factors (P = 0.0002 and 0.0092, respectively). Patients with the Ser9Ser genotype had better social functioning than those with Gly9Gly (P = 0.0029). The Ser9Gly polymorphism, however, did not significantly affect positive symptoms. Male gender, fewer previous hospitalizations, and higher risperidone dose also predicted better treatment response. These data suggest that the DRD3 Ser9Gly polymorphism or, alternatively, another genetic variation that is in linkage disequilibrium, may influence response to risperidone in negative symptoms and social functioning.