Although
antipsychotic medication contributed to the improvement of psychotic symptoms and reduced relapse, it induced
weight gain and
metabolic syndrome during
antipsychotic medication treatment, which was seriously concerning. To investigate the association of
methylenetetrahydrofolate reductase (MTHFR) gene C677T (rs1801133) polymorphism with
antipsychotic-induced
weight gain and metabolism parameter change, we employed 1,868 patients with
schizophrenia in this study and randomly allocated them to seven
antipsychotic medication treatment groups. All patients received
antipsychotics monotherapy and were followed up for 6 weeks. Height, body weight, and metabolic parameters of the patients were measured at baseline and at 2, 4, and 6 weeks after
antipsychotic treatment. We genotyped blood
DNA from patients for MTHFR C677T polymorphisms and performed quantitative analyses using analysis of variance (ANOVA) and the analysis of covariance (ANCOVA) among three genotype groups. We found a predominant association between MTHFR C677T and
body weight mass index (BMI) change after 6-week
risperidone treatment. After 6-week treatment of
risperidone, the BMI change rate (%) of MTHFR C677 carriers was significantly higher than that of MTHFR TT genotype carriers [CC (2.81 ± 6.77)%, CT (3.79 ± 5.22)%, TT (1.42 ± 3.53)%, F = 4.749, P = 0.009]. Some of the abnormal metabolic parameters were found to be associated with the MTHFR 677T, including higher levels of
low-density lipoprotein and waist circumference. Validation was performed in an independent cohort, consisting of 252 patients with
schizophrenia treated with three atypical
antipsychotic drugs. Overall, the MTHFR C677 was associated with high risk of
antipsychotic-induced
weight gain and metabolism abnormalities.