The serotonin transporter and clozapine response

SIR – Smeraldi and collaborators reported that genetic variants of the serotonin transporter (5-HTT) gene are associated with levels of response to the antidepressant fluvoxamine. Individuals homozygous for a short allele (480 bp) of a polymorphism in the promoter region (5HTTLPR) of the gene showed poorer response to the antidepressant fluvoxamine than subjects heterozygous or homozygous for the long allele (520 bp). Variation in the 5-HT uptake may also affect antipsychotic action mediated through the serotonergic system. We have previously reported association between polymorphisms in serotonin receptors and response to clozapine, a drug that displays high levels of affinity for them. However, those associations could not fully explain the heterogeneous response to clozapine treatment observed and contribution from other genes has been hypothesised. We have tested the contribution of the 5-HTT genetic variants in determining clozapine response by genotyping two polymorphisms (the biallelic polymorphism in the promoter region of the gene, 5-HTTLPR, studied by Smeraldi and collaborators, and a VNTR in intron 2 of the gene) in a sample of subjects undergoing clozapine treatment. Two hundred and sixty-eight schizophrenic patients were included in this study. The patients were white Caucasians of British origin and were collected in the London, Cambridge and Burnley areas. All patients had a DSM-IIIR or DSM-IV diagnosis of schizophrenia and had shown no improvement after treatment with at least two neuroleptics before undergoing treatment with clozapine. Treatment response was assessed at least 3 months after optimisation of therapeutic doses. Response was evaluated using the Global Assessment Scale (GAS) and an improvement of 20 points was considered as the threshold for appropriate response. According to this criteria the sample included 180 subjects who improved satisfactorily and 88 patients who showed poor response to clozapine treatment. Informed consent was obtained from all the subjects included in the study. The 5-HTT VNTR in intron 2 and the biallelic polymorphism in the linked polymorphic region (5HTTLPR) were genotyped following the methods previously described. The genotyping results are summarised in Table 1. Chi-square tests were calculated for all comparisons using the SPSS (version 8.0) and EpiInfo (version 6) statistical packages. Haplotype analyses were performed using the EH programme (version 1.11). This sample had an 80% power to detect association with an odds ratio of 2.2. No differences were observed in allele or genotype frequencies of the 5-HTT VNTR polymorphism in intron 2 when comparing patients who showed marked improvement with Table 1 Genotype frequencies of the 5-HTT VNTR (intron 2) and the 5-HTTLPR polymorphisms in a sample of clozapinetreated patients