Food and Drug Administration issued a warning associating AAPs with a connection to increased risk for diabetes and hyperglycemia. Clozapine is an atypical antipsychotic often used for its demonstrated superiority in the treatment of refractory schizophrenia. However, clozapine exhibited a higher long-term incidence rate of MetS as compared with other AAPs, using the National Cholesterol Education Program’s Adult Treatment Panel III criteria. Accordingly, investigating the mechanisms that contribute to the high occurrence of clozapine-induced MetS may help facilitate the identification and clinical management of this significantly adverse effect. Obesity, a status characterized by excessive adipose tissue, is one of the most important components of MetS. In rodents, models of brain-derived neurotrophic factor disruption all exhibited increased food AbMole Nodakenin intake, obesity, and hyperphagia, whereas calorie restriction in heterozygous BDNF+/2 mice can increase expression of BDNF and reduce obesity. In humans, BDNF was found 
to be associated with eating disorders, such as restrictive anorexia nervosa, as well as antipsychoticinduced body weight gain. In a recent pharmacogenetic study, BDNF was reported to regulate the clozapine treatment response, suggesting that BDNF may be a pharmacological target of clozapine. Given these findings, it seems plausible that a deficiency in BDNF may be a potential biological mechanism that underlies clozapine-induced MetS. At the molecular level, a common functional polymorphism of BDNF, leading to a valine to methionine substitution at codon 66, is known to alter the intracellular trafficking and activitydependent secretion of BDNF. Recently, the Val66Met polymorphism was identified as a risk factor for metabolic traits, such as obesity and insulin resistance in several human populations. Based on the findings from abovementioned studies, we hypothesized that the BDNF Val66Met polymorphism may confer susceptibility to clozapine-induced MetS. To test this potential association, we conducted a pharmacogenetic study to investigate the association between the Val66Met polymorphism and MetS in a population of Han Chinese under long-term clozapine treatment. Taking into consideration the interaction between the Val66Met polymorphism and sex observed in our previous studies, we also aimed to evaluate potential differences in the effect of this variant on males and females. BDNF is a member of the neurotrophin family, which regulates various neurodevelopmental processes, such as neuronal differentiation, neurite outgrowth and neuronal survival. Altered BDNF signaling has been shown to involved in a variety of peripheral and central nervous system disorders, including dementia, amyotrophic lateral sclerosis, depression and schizophrenia, etc. A recent study implicated BDNF in the control of GLU, lipid and antioxidant metabolism, which is considered an anorexigenic signal in the central control of food intake.