The mechanisms underlying weight gain resulting from antipsychotic drugs are not fully understood, although antagonism of the 5-HT2C receptor is likely to contribute. Animal studies indicate that the drugs most likely to cause weight gain, clozapine and olanzapine, have direct effects on the NPY-containing neurons of the hypothalamus; these neurons mediate the effects of the circulating anorexigenic hormone leptin on the control of food intake. The substantial differences between individuals in the extent of antipsychotic-induced weight gain suggest that genetic factors may be important. We have been studying pharmacogenetic correlates and find that a common 5-HT2C receptor promoter region polymorphisms demonstrates strong associations with weight gain in two first episode psychotic samples. In both series, we have found further association of antipsychotic drug-induced weight gain with a common and functional polymorphism of the gene for leptin. Along with initial BMI, these two pharmacogenetic factors account for almost 30% of the variance in drug-induced weight gain. Interestingly, the 5-HT2C polymorphism appears to determine levels of circulating leptin, providing a potential mechanism underlying the genetic association of the 5-HT2C receptor with weight gain. We have undertaken functional studies of haplotypes of the 5-HT2C promoter region and find the allele associated with protection from weight gain results in reduced promoter activity. These findings demonstrate the value of pharmacogenetics in determining liability to a major side effect of antipsychotic treatment, and indicate both the molecular and physiological mechanisms underlying this side effect.