Pharmacogenetics of antipsychotic-induced weight gain

Rationale: Antipsychotic medications have been associated with considerable weight gain. The degree of inter-individual variability and known genetic contributions to obesity suggest a combination of genetic and environmental factors. In the absence of established mechanisms and valid predictors for this relevant adverse effect, pharmiacogenetic studies may provide the basis for the development of individualized treatment and preventive interventions. Objective: The aim of the present review is to analyze the theoretical and empirical knowledge base for the selection of the most promising target genes that may contribute to antipsychotic-induced weight gain. Methods: Examination of the preclinical and clinical literature that can inform the rational choice of target genes that may play a role in the development of adverse changes in body composition associated with antipsychotic treatment. Results: Theoretically, candidate gene selection can be guided by knowledge about molecular pathways associated with obesity, receptors modulated by antipsychotic drugs, and enzymes implicated in their metabolism and bioavailability. While most available data relate to the general mechanisms of obesity and few studies have directly examined the genetic contributions to antipsychotic-induced weight gain, several genes warrant further investigation. These include the 5-HT2C, pro-opiomelanocortin, leptin, ghrelin, tumor necrosis factor alpha, adiponectin, dopamine D-2 receptor, histamine-H-1 receptor, and alpha(1), beta(2) and beta(3) adrenergic receptor genes. Conclusions: Pharmacogenetic studies can provide powerful tools for the pre-treatment identification of individuals at high risk for antipsychotic-induced weight gain, to uncover biological mechanisms that may even generalize to non-drug-induced weight gain, and to isolate novel targets for treatments of weight gain and obesity. To enhance power, future studies should pay close attention to population selection and avoidance/control of confounds, particularly past treatment exposure.