−759C/genetic variation of 5HT 2C receptor and clozapine-induced weight gain

Abstract

We attempted to replicate in clozapine-treated patients the finding of an association between the 5HT2c −759 C/T promoter polymorphism and antipsychotic-induced weight gain reported by G P Reynolds and colleagues.1Reynolds GP Zhang ZJ Zhang XB Association of antipsychotic drug-induced weight gain with a 5-HT2C receptor gene polymorphism.Lancet. 2002; 359: 2086-2087Summary Full Text Full Text PDF PubMed Scopus (373) Google Scholar Weight gain limits the use of atypical antipsychotics.2Allison DB Mentore JL Heo M et al.Antipsychotic-induced weight gain: a comprehensive research synthesis.Am J Psychiatry. 1999; 156: 1686-1696PubMed Google Scholar This side-effect is serious and may result in non-adherence to medication, psychological distress, medical morbidity, and mortality, yet it is commonly underestimated. Agonists at the 5HT2 family of receptors cause hypophagia and can cause weight loss in animals and human beings. In rats, 5HT2C antagonists cause an increase in feeding. Clozapine is a potent 5HT2C antagonist. Autoradiographic studies have shown that 5HT2C receptors are localised in high density in the ventromedial and dorsomedial nuclei within the hypothalamic satiety control centres. 5HT2C knockout mice are overweight and exhibit increased feeding as opposed to metabolic changes.3Tecott LH Sun LM Akana SF et al.Eating disorder and epilepsy in mice lacking 5-HT2C serotonin receptors.Nature. 1995; 374: 542-546Crossref PubMed Scopus (1125) Google Scholar Clozapine may disrupt serotonergic pathways, resulting in weight gain in predisposed people. We investigated the −759C/T polymorphism of the 5HT2C receptor gene, among other central and peripheral candidate gene polymorphisms, in relation to clozapineinduced weight gain in a review of the current obesity and weight-regulation research.4Basile VS Masellis M MacIntyre RS Meltzer HY Lieberman JA Kennedy JL Genetic dissection of atypical antipsychotic-induced weight gain: novel preliminary data on the pharmacogenetic puzzle.J Clin Psychiatry. 2001; 62: 45-66PubMed Google Scholar We prospectively assessed 80 patients (58 white, 22 black) with diagnosed schizophrenia for clozapine-induced weight gain by comparison of weight at baseline and after 6 weeks of treatment. We did genotyping by the same method as Reynolds and colleagues. To replicate their methods, we classified patients as weight gainers (>7% weight increase) and non-weight gainers (⩽7% weight increase). We used χ2Allison DB Mentore JL Heo M et al.Antipsychotic-induced weight gain: a comprehensive research synthesis.Am J Psychiatry. 1999; 156: 1686-1696PubMed Google Scholar case-control analysis to compare the two groups for presence or absence of the variant allele (−759T) of the −759C/T polymorphism. Additionally, we used parametric ANCOVA analysis to compare the mean change in weight between the different genotypic panels (table). Correction was done for possible confounding from baseline weight, sex, age, ethnic origin, and response or nonresponse.4Basile VS Masellis M MacIntyre RS Meltzer HY Lieberman JA Kennedy JL Genetic dissection of atypical antipsychotic-induced weight gain: novel preliminary data on the pharmacogenetic puzzle.J Clin Psychiatry. 2001; 62: 45-66PubMed Google ScholarTableMean (SD) change in weight after clozapline treatmentWeightBaseline (kg)pChange at 6 weeks (kg)pAll patientsAbsence of T (CC or C, n=52)74·1 (12·7)0·953·2 (4·6)0·21Presence of T (TT or CT, n=21)74·4 (15·8)4·7 (4·1)MenAbsence of T (CC or C, n=36)78·4 (10·5)0·743·6 (4·9)0·047Presence of T (TT or CT, n=9)77·1 (10·1)7·2 (3·9)WomenAbsence of T (CC or C, n=16)64·5 (12·1)0·202·4 (3·7)0·33Presence of T (TT or CT, n=12)72·3 (19·2)2·8 (3·3) Open table in a new tab The two genotypic panels did not differ significantly for mean weight gain after 6 weeks of clozapine (table). Similarly, there was no association with weight classification (p=0·41). We noted confounding effects for sex and ethnic origin. Hemizygous T allele men gained significantly more weight than hemizygous C allele men. Black men generally gained more weight than white men (5·95 vs 2·71 kg), but genetic associations were similar in stratified analysis. Also, genotype frequencies did not differ between white and black patients, which suggests that population stratification biases did not confound the results. Genotype frequencies did not deviate from those expected under Hardy-Weinberg equilibrium. Our inability to replicate Reynolds and colleagues’ finding may be attributed to sample differences in ethnic origin of the samples, or in antipsychotic treatment—chlorpromazine or risperidone elicit less weight gain than does clozapine, and may have different mechanisms of weight gain. Our data show a nonsignificant trend in the opposite direction to that of the Reynolds study, especially for men with the T allele. This polymorphism might be in linkage disequilibrium with another variant more directly involved in 5HT2C gene function and might be cosegregated differently in different ethnic groups.