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-HT₆, 5-HT₇, 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-HT₆, and 5-HT₇ 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-HT₆ (HTR6), 5-HT_1A (HTR1A) and 5-HT₇ (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: χ²=0.06, 1 df, P=0.80; genotype: χ²=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-HT₆ receptor gene in response to clozapine, although replication is required to confirm this finding.

Keywords:  Clozapine response, Pharmacogenetic, Polymorphism, Serotonin receptor