Accordingly has been conceptually viewed not only as a neurotrophin, but also a metabotrophic factor. Several studies reported that serum concentrations decreased in subjects with MetS, and that a supplement of BDNF could reduce body weight. However, opposing results have also been reported. The Met allele has been known to significantly reduce activity-dependent secretion of BDNF as compared with the Val allele.The Met/Met genotype thus results in considerable low-activity of BDNF protein. In the present study, we observed a trend towards an association of the Met/Met genotype with clozapine-induced MetS in males. This finding is in agreement with the association between low BDNF concentration and MetS. Another major finding of this study is the association of the Val66Met polymorphism with clozapineinduced increased fasting GLU levels. BDNF has been reported to influence fasting GLU levels and insulin sensitivity, and decreased levels of the serum BDNF were found in the AbMole Gambogic-acid patients with MetS and type 2 diabetes mellitus. Mice with BDNF haploinsufficiency exhibited obesity and elevated levels of GLU, whereas systemic peripheral administration of BDNF contributed to the improvement of GLU metabolism and prevented the development of diabetes. In humans, there is a significant correlation between increased GLU levels and the BDNF Met allele in the general population. Insulin is critical for the body’s use of GLU as energy, and insulin resistance is a condition in which the body produces insulin but does not use it effectively, leading to increased levels of GLU. Clinical and preclinical studies have both documented that clozapine can result in marked IR. Burghardt et al. reported that the BDNF Met allele alone and in combination with AAP medications is associated with higher IR values. Similarly IR is well established as the major pathogenic feature of MetS. Taken together, we assume that the BDNF Val66Met genotype confers susceptibility to MetS by decreasing insulin action in the peripheral tissues. In this study, we found that the impact of the Met/Met genotype on MetS and increased levels of GLU is only seen in male patients. To our best knowledge, this is the first study to evaluate the sexual variation in the effects of the Val66Met polymorphism on MetS. Our previous studies also indicated that the Val66Met polymorphism may have sex-specific characteristics. A recent preclinical study showed that BDNF heterozygous mice have complex brain region-specific changes in neurotrophins and their receptors differ gender-specifically. This finding suggested that BDNF-TrkB signaling may be controlled in a sex-specific manner. Therefore, our findings in the present study imply that the effects of BDNF on MetS may be dependent on sex. The following question then arises naturally: do sex steroids contribute to this effect? Further studies are required for clarification, given the limited sample size and scope of this study.