DRD4 48 bp VNTR but not 5-HT 2C Cys23Ser receptor polymorphism is related to antipsychotic-induced weight gain

Weight gain is a major side effect of antipsychotic treatment. The antidopaminergic and antiserotonergic effect of antipsychotics may contribute to antipsychotic-induced weight gain. We, therefore conducted a prospective clinical study, to investigate whether the D4 receptor (DRD4) 48 bp (base pair) variable number of tandem repeat (VNTR) polymorphism and the 5-hydroxytryptamine 2C receptor (HT(2C)) cysteine for serine substitution at position 23 (Cys23Ser) polymorphism may influence weight gain during antipsychotic treatment in a naturalistic setting of 102 Caucasian psychiatric in-patients. Patients suffering from psychotic disorders and treated according to local clinical practice were classified as either homozygous for the shorter alleles of the DRD4 48 bp VNTR polymorphism (<7-fold repeat, group 1) or heterozygous/homozygous for the long allele (7-fold repeat or higher, group 2). HT(2C) Cys23Ser polymorphism male patients were grouped hemizygous G (Cys) or C (Ser), while female patients were GG, GC or CC and both sexes were evaluated separately. Concerning the DRD4 48 bp VNTR polymorphism the increase in body mass index was significantly less in group 1 (0.38 kg m(-2); s.d.=1.04) than in group 2 (0.89 kg m(-2); s.d.=1.23; P=0.003). The difference between the genotype groups remained significant in male patients but not in female patients. In contrast, no influence on antipsychotic-induced increase in body weight was observed for the HT(2C) Cys23Ser polymorphism. These results support the hypothesis that the DRD4 48 bp VNTR polymorphism influences antipsychotic-induced weight gain. Male patients may be more affected than female patients. Due to the limitations of the study (heterogeneity of treatment, pretreatment and concomitant therapy) further studies are required before diagnostic genotyping of the DRD4 48 bp VNTR polymorphism may be useful for individualizing therapy.