Our work shows folate improves atypical antipsychotic (AAP) CV effects in schizophrenia specifically improving endothelial functioning. Reducing AAP linked metabolic risks may help cut the 30 years of life lost within this population. Supplemental folate may be a cost effective and low risk method to reduce AAP CVD morbidity and mortality. Folate pharmacogenetics, allows us to mechanistically study AAP metabolic complications and develop personalized medicine within clinical practice. The objective of this project is to compare the effect of folate versus placebo on measures of the metabolic syndrome and CVD risk factors. We will evaluate metabolic laboratory components, and endothelial functioning, in schizophrenia patients receiving AAPs, taking into account pharmacogenetic differences related to folate metabolism. Our primary hypothesis is that folate will attenuate metabolic changes associated with AAP use, thereby contributing to improve endothelial functioning. Variation within the genes facilitating folate metabolism (methylenetetrahydrofolate reductase (MTHFR) and catechol-o-methyl transferase (COMT)) modulate these improvements. We have formulated this hypothesis based on our pilot data obtained during R01MH082784 showing AAPs increase metabolic syndrome risk due to an interaction with MTHFR and COMT. We performed an open-label 3-month folate supplement trial and found significant reductions in metabolic measures and significantly reduced the number of subjects meeting endothelial dysfunction criteria. These improvements were modulated through MTHFR and COMT.
The specific aims for this proposal are: 1) Evaluate the therapeutic effectiveness of folic acid supplementation (5mg/day) versus placebo for 16 weeks in schizophrenia subjects and measure sustainability of this effect 8 weeks after supplementation withdrawal, 2) Determine the role of MTHFR and COMT variants on endothelial functioning and metabolic improvements seen with folate supplementation. The innovative approach capitalizes upon a novel strategy to reduce AAP metabolic risks using a novel non-invasive endothelial functioning measurement as a biomarker. This allows for an overall CVD risk estimation compared to focusing on solely weight loss and glucose regulation. The inclusion of pharmacogenomics allows for potential innovative translation of personalized medicine outcomes into practice. Our expected outcomes will demonstrate folate's effectiveness in attenuating metabolic syndrome measures and improvements in endothelial functioning in AAP users with a randomized double blind longitudinal treatment design. Our follow up visit will allow for measurement of any sustained folate effects leading to future dose ranging studies. Successful completion of our pharmacogenetic analyses can be expected to provide a greater mechanistic understanding of AAP metabolic risks. The primary positive impact of our anticipated findings will be an evidence-based scientific framework for folate intervention development for AAP metabolic complications, which can be directly translated into clinical practice.

Public Health Relevance

The public health relevance of this proposed research is that its successful completion can be expected to provide a cost effective intervention that can be used to significantly reduce the risk of development of cardiovascular problems for patients taking antipsychotic medications to treat their serious mental illness. Ultimately this will help t markedly improve quality of life for such patients, significantly enhancing their expected life spa and reduce costs to the health care system.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Chavez, Mark
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University of Michigan Ann Arbor
Schools of Pharmacy
Ann Arbor
United States
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Burghardt, Kj; Grove, Tb; Ellingrod, Vl (2014) Endothelial nitric oxide synthetase genetic variants, metabolic syndrome and endothelial function in schizophrenia. J Psychopharmacol 28:349-56
Bly, Michael J; Taylor, Stephan F; Dalack, Gregory et al. (2014) Metabolic syndrome in bipolar disorder and schizophrenia: dietary and lifestyle factors compared to the general population. Bipolar Disord 16:277-88
Vassas, Thomas J; Burghardt, Kyle J; Ellingrod, Vicki L (2014) Pharmacogenomics of sterol synthesis and statin use in schizophrenia subjects treated with antipsychotics. Pharmacogenomics 15:61-7
Hicks, J K; Swen, J J; Thorn, C F et al. (2013) Clinical Pharmacogenetics Implementation Consortium guideline for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants. Clin Pharmacol Ther 93:402-8
Lott, S A; Burghardt, P R; Burghardt, K J et al. (2013) The influence of metabolic syndrome, physical activity and genotype on catechol-O-methyl transferase promoter-region methylation in schizophrenia. Pharmacogenomics J 13:264-71
Burghardt, Kyle J; Ellingrod, Vicki L (2013) Detection of metabolic syndrome in schizophrenia and implications for antipsychotic therapy : is there a role for folate? Mol Diagn Ther 17:21-30
Ellingrod, Vicki L; Taylor, Stephan F; Dalack, Gregory et al. (2012) Risk factors associated with metabolic syndrome in bipolar and schizophrenia subjects treated with antipsychotics: the role of folate pharmacogenetics. J Clin Psychopharmacol 32:261-5
Evans, Simon J; Prossin, Alan R; Harrington, Gloria J et al. (2012) Fats and factors: lipid profiles associate with personality factors and suicidal history in bipolar subjects. PLoS One 7:e29297
Ellingrod, Vicki L; Taylor, Stephan F; Brook, Robert D et al. (2011) Dietary, lifestyle and pharmacogenetic factors associated with arteriole endothelial-dependent vasodilatation in schizophrenia patients treated with atypical antipsychotics (AAPs). Schizophr Res 130:20-6