Lack of association between the T→C 267 serotonin 5-MT6 receptor gene (HTR6) polymorphism and prediction of response to clozapine in schizophrenia

The affinity of clozapine for 5-HT2A, 5-HT2C, 5-HT6, 5-HT7, and 5-HT1A receptors has been suggested to contribute to various aspects of its complex clinical actions. This study examined the hypothesis that genetic variation in 5-HT1A, 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-MT1A (HTR6) 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: chi (2)=0.06, 1 df, P=0.80; genotype: chi (2)=1.21. 2 df, P=0.55), The pro161eu 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. (C) 2001 Elsevier Science B.V. All rights reserved.