Methylenetetrahydrofolate reductase gene variants and antipsychotic-induced weight gain and metabolic disturbances

A. C.C. Kao, M. Rojnic Kuzman, A. K. Tiwari, M. V. Zivkovic, N. I. Chowdhury, V. Medved, I. Kekin, C. C. Zai, J. A. Lieberman, H. Y. Meltzer, T. Bozina, N. Bozina, J. L. Kennedy, J. Sertic, D. J. Müller*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


Weight gain and metabolic disturbances represent serious side-effects in antipsychotic (AP) treatment, particularly with clozapine and olanzapine. The methylenetetrahydrofolate reductase (MTHFR) gene is a key determinant in the folate metabolism and previous studies reported a significant effect on AP-induced weight gain and related metabolic abnormalities. Thus, we investigated MTHFR gene variants and changes in several important metabolic parameters in AP-treated patients. In this study, two functional MTHFR polymorphisms, rs1801133 (C677T) and rs1801131 (A1298C), were investigated for changes in weight and metabolic parameters. Genotypic associations were evaluated in a large population (n = 347 including 66 first episode psychosis, FEP patients) treated mostly with clozapine and olanzapine. We did not detect any genotypic association with weight changes (p > 0.05) in our total sample and in the sample refined for ancestry and medication. In our allelic analyses, we observed a trend for the 677-C allele to be associated with weight gain in the total sample (p = 0.03). This effect appeared to be driven by the FEP patients where those carrying the C-allele gained, on average, twice as much weight. Exploratory analyses revealed a significant association between the C677T and the A1298C polymorphism with HDL cholesterol serum levels in patients (p = 0.031). Overall we did not detect a major effect of two functional MTHFR gene variants and AP-induced weight gain. However, our findings suggest an effect of the C677T polymorphism in FEP patients and changes in weight and cholesterol levels. Further investigations in a larger sample are required.

Original languageEnglish (US)
Pages (from-to)36-42
Number of pages7
JournalJournal of Psychiatric Research
Issue number1
StatePublished - 2014


  • A1298C
  • Antipsychotic
  • C677T
  • Weight gain

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Biological Psychiatry


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