Susceptibility genes for the side effect of antipsychotics on body weight and obesity.

Antipsychotic-induced body weight gain is becoming a major health concern since the increasing use of this medication in different mental disorders with a high prevalence in different populations. The percentage of patients gaining weight following antipsychotic medication can reach up to 80% according to the antipsychotic used, with around 30% developing obesity. The origins of this adverse effect of antipsychotics are probably multifactorial with the environment (food and exercise habits, medication) and the genetics coming into play. We have compiled the available genetic results on the antipsychotic-induced body weight gain and obesity. Candidate genes analysis showed that six genes have been associated with this adverse effect of antipsychotics. Among these, the associations with the serotonin receptor 2C and the leptin genes have been observed in more then one study. Thirteen other genes, mainly antipsychotic known receptors, have shown negative results. To find informative gene variations, we have also compared the effects of some polymorphisms of the serotonin receptor 2C and 2A in mental disorders, for antipsychotic therapeutic effect, for antipsychotic neuronal side effects, and for obesity. We have found results for six polymorphisms in each of the two genes. When association was observed for more then one phenotype, the same genotype or allele was generally involved identifying those sensitive to environmental pressures and to genetic background. Animal transgenic models of knockout or overexpressed genes of antipsychotic receptors have been evaluated for changes in obesity-related phenotypes. Seventeen out of the twenty-three antipsychotic receptors with transgenic models showed some effects on obesity-related phenotypes. Ten of these receptors have not been tested yet for antipsychotic-induced body weight gain, while the others have been tested only once with negative results, or is already associated to the effect such as the serotonin receptor 2C. Finally, pharmacogenomic approaches have allowed to detect more then 300 possible candidate genes for antipsychotic-induced body weight gain.