Section of Clinical Neuropharmacology, Department of Psychological Medicine, Institute of Psychiatry, Denmark Hill, London SE5 8AF, UK

Correspondence to: M J A, spjumja@iop.kcl.ac.uk

SIR - Smeraldi and collaborators¹ 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 (5-HTTLPR) 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.² We have previously reported association between polymorphisms in serotonin receptors and response to clozapine, a drug that displays high levels of affinity for them.^3,4,5 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,¹ 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)⁶ 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 (5-HTTLPR) were genotyped following the methods previously described.^7,8 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 patients who did not appropriately respond to clozapine. Analysis of the 5-HTTLPR results showed that homozygotes for the short allele (480 bp/480 bp) were more frequent among treatment non-responders than heterozygotes (520 bp/480 bp) and homozygotes for the long variant (520 bp/520 bp), although this difference was not statistically significant (² = 2.99, P = 0.08; odds ratio = 1.70, 95% CI = 0.89-3.24). Haplotype combinations of both polymorphisms did not improve the association with clozapine response.

Our results on the 5-HTTLPR polymorphism, although not significant, followed the same trend reported by Smeraldi and collaborators:¹ individuals homozygous for the short allele (480 bp) were more likely to be found among non-responders than in responders. This trend could be a chance finding or reflect a minor contribution of the 5-HTTLPR polymorphism in determining clozapine response. Lack of statistically significant association in our study could be due to the variety of neurotransmitter receptors targeted by clozapine. Although mutations in the 5-HTT may contribute to clozapine treatment outcome, they may not be the only factor influencing response. By contrast, fluvoxamine is more directly related to 5-HTT, therefore genetic alterations in the transporter should play a bigger role in determining response, translated into stronger association between 5-HTT polymorphisms and fluvoxamine response. Still, the more simplistic explanation for our negative results is that 5-HTT variants do not play a major role in determining clozapine response, which does not contradict the previous finding of association with response to antidepressants acting on the serotonergic system.

1 Smeraldi E et al. Mol Psychiatry 1998; 3: 508-511, MEDLINE

2 Lesch KP. Mol Psychiatry 1998; 3: 278-281, MEDLINE

3 Arranz MJ et al. Lancet 1995; 346: 281-282, MEDLINE

4 Arranz MJ et al. Schiz Res 1998; 32: 93-99,

5 Sodhi MS et al. Neuroreport 1995; 7: 169-172, MEDLINE

6 Endicott J et al. Arch Gen Psychiatry 1976; 33: 766-771, MEDLINE

7 Collier DA et al. Neuroreport 1996; 7: 1675-1679, MEDLINE

8 Collier DA et al. Mol Psychiatry 1996; 1: 453-460, MEDLINE

Table 1 Genotype frequencies of the 5-HTT VNTR (intron 2) and the 5-HTTLPR polymorphisms in a sample of clozapine-treated patients