Lack of association between the T→C 267 serotonin 5-HT6 receptor gene (HTR6) polymorphism and prediction of response to clozapine in schizophrenia

Abstract The affinity of clozapine for 5-HT 2A , 5-HT 2C , 5-HT 6 , 5-HT 7 , and 5-HT 1A receptors has been suggested to contribute to various aspects of its complex clinical actions. This study examined the hypothesis that genetic variation in 5-HT 1A , 5-HT 6 , and 5-HT 7 receptor genes is involved in the variability observed in response to clozapine. We employed a pharmacogenetic approach in a group ( n =185) of schizophrenia patients that have been clinically well characterized for clozapine response. Polymorphisms in the 5-HT 6 (HTR6), 5-HT 1A (HTR1A) and 5-HT 7 (HTR7) receptor genes were genotyped. No evidence for either an allelic or genotypic association of the T→C 267 HTR6 polymorphism with response to clozapine was found in our sample (allele: χ 2 =0.06, 1 df, P =0.80; genotype: χ 2 =1.21, 2 df, P =0.55). The pro16leu HTR1A polymorphism was not observed in our sample; all individuals genotyped were pro/pro 16 homozygotes. With respect to the pro279leu HTR7 polymorphism, one Caucasian male responder to clozapine was observed to be heterozygous (pro/leu 279 genotype). This individual was clinically similar to the other clozapine responders. Overall, our findings do not support a role for the T→C 267 polymorphism of the 5-HT 6 receptor gene in response to clozapine, although replication is required to confirm this finding.