Pharmacogenetics of treatment in first-episode schizophrenia: D3 and 5-HT2C receptor polymorphisms separately associate with positive and negative symptom response.

We have been studying the pharmacogenetic correlates of side effects and early response to antipsychotic treatment in a series of Chinese Han first-episode drug-naive patients with schizophrenia. Here, we report the association of three functional polymorphisms of receptor genes on initial symptom severity and outcome in these patients. We studied the dopamine D3 receptor ser9gly, the dopamine D2 receptor Taq IA and the 5-HT2C receptor promoter -759C/T polymorphisms in 117 patients who had symptoms assessed by Positive and Negative Syndrome Scale (PANSS) on admission and following 10-week antipsychotic treatment, primarily with risperidone or chlorpromazine. The D2 polymorphism was found not to be significantly associated with baseline levels or changes in total PANSS in these patients. The D3 genotype is associated with the change in total PANSS (p<0.01), an effect reflecting positive and general (each p<0.01) but not negative symptom improvement. However, symptom improvement at 10 weeks strongly correlates with total PANSS score on admission, in which the greater improvement is seen with the more severe initial symptom score. The D3 genotype is also related to severity on admission, i.e. to total baseline PANSS (p<0.05), including baseline PANSS score as a covariate, the association of the genotype to change over 10 weeks remains significant for total PANSS (p<0.05) and for positive and general, but not negative, symptom scores. The 5-HT2C promoter polymorphism was also associated with improvement in PANSS (p<0.05), but reflecting effects on negative and general, but not positive, symptom scores. This polymorphism was not associated with PANSS score on admission, although after controlling for the effect of this parameter on 10-week outcome, a stronger association with change in total PANSS (p<0.01) was apparent, again reflecting improvements in negative and general symptoms but not changes in positive symptoms.