Detection of metabolic syndrome in schizophrenia and implications for antipsychotic therapy : is there a role for folate?

Mol Diagn Ther. 2013 Feb;17(1):21-30. doi: 10.1007/s40291-013-0017-8.


In general, the presence of metabolic syndrome is associated with significant cardiovascular mortality and represents a growing public health concern in the USA. Patients with schizophrenia have a three times greater risk of death than the general population, with cardiovascular disease being the most common cause of this mortality. Use of atypical antipsychotics (AAPs) to treat schizophrenia contributes significantly to this cardiovascular risk. While several different clinical guidelines currently exist to monitor the metabolic consequences of AAP use, implementation is lacking. Because of under-monitoring of side effects and the lack of alternative treatment choices in schizophrenia, research has focused on identification of various biomarkers and pharmacogenomic targets to focus on the patients at greatest risk of metabolic syndrome, thus aiming to increase the efficacy and minimize the side effects of AAPs. This has led to several different lines of research. This review focuses on summarizing the differing metabolic syndrome criteria, monitoring guidelines for use of AAPs, and the role of folic acid as it relates to metabolic syndrome within the schizophrenia population. It concentrates not only on the pharmacogenomics of folic acid metabolism but also on its epigenetic interaction with the environment. From this work, genetic variation within both the methylenetetrahydrofolate reductase (MTHFR) gene and the catechol-O-methyltransferase (COMT) gene has been associated with an increased risk of metabolic syndrome in schizophrenia patients treated with AAPs. Furthermore, work on the combination of folate pharmacogenetics and epigenetics has uncovered relationships between methylation, schizophrenia disease, treatment type, and metabolic syndrome. Despite several areas of biomarker research into schizophrenia-related metabolic syndrome, translation into the clinical setting is still lacking, and further studies are needed to bridge this gap. In the future, folate supplementation may prove to be an easy and effective clinical tool for prevention and/or treatment of metabolic syndrome associated with AAP treatment, but clearly more research needs to be done in this area.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Antipsychotic Agents / adverse effects*
  • Antipsychotic Agents / therapeutic use
  • Cardiovascular Diseases / etiology
  • Cardiovascular Diseases / prevention & control
  • Catechol O-Methyltransferase / genetics
  • Catechol O-Methyltransferase / metabolism
  • Dietary Supplements*
  • Epigenomics / methods
  • Folic Acid / administration & dosage*
  • Humans
  • Metabolic Syndrome / complications
  • Metabolic Syndrome / drug therapy*
  • Methylenetetrahydrofolate Reductase (NADPH2) / genetics
  • Methylenetetrahydrofolate Reductase (NADPH2) / metabolism
  • Pharmacogenetics
  • Risk Factors
  • Schizophrenia / complications
  • Schizophrenia / drug therapy*


  • Antipsychotic Agents
  • Folic Acid
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • Catechol O-Methyltransferase