The 5-HT2C receptor and antipsychoticinduced weight gain - mechanisms and genetics.
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.
Reynolds
Gavin P
GP
Division of Psychiatry and Neuroscience, Queen's University Belfast, Belfast, UK. g.reynolds@qub.ac.uk
Hill
Matthew J
MJ
Kirk
Shona L
SL
D000818:Animals; D014150:Antipsychotic Agents / Q000009:adverse effects* / Q000494:pharmacology; D015992:Body Mass Index; D006239:Haplotypes; D006801:Humans; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics; D044405:Receptor, Serotonin, 5-HT2C / Q000235:genetics*; D015430:Weight Gain / Q000187:drug effects*
D014150:Antipsychotic Agents; D044405:Receptor, Serotonin, 5-HT2C