In schizophrenia patients treated with atypical antipsychotics (AAPs), metabolic syndrome and insulin resistance/diabetes mellitus (DM) incidence is two to four fold higher than the general population. Aberrant folate metabolism is linked to a greater risk for CVD, DM, and endothelial dysfunction. Specifically the methylenetetrahydrofolate reductase (MTHFR) 677C/T variant has been associated with a 14% increase in CVD risk in the general population and a 36% greater risk for schizophrenia, although these relationships are highly dependent on dietary folate intake. This variant has not been investigated with metabolic syndrome and DM seen in schizophrenia. Our research group is the first to investigate the relationship between MTHFR, metabolic syndrome, and insulin resistance in schizophrenia. The objective of this application is to better understand the interplay of folate pharmacogenetics and diet and lifestyle factors on developing AAP-associated metabolic complications;metabolic syndrome, and insulin resistance. Additionally we will systematically measure endothelial functioning in this population and determine the role of supplemental folate administration on attenuation of these metabolic consequences. Our primary hypothesis is that MTHFR confounds inadequate folate intake and confers a greater risk for insulin resistance from AAP use. This contributes to the metabolic syndrome, endothelial dysfunction, and CVD in this population. We have formulated this hypothesis based on our pilot data (from a NIMH Career Development Award) showing a relationship between the MTHFR T allele and a greater risk for metabolic syndrome and insulin resistance in schizophrenia patients receiving AAPs. Our rationale is that the MTHFR T allele combined with inadequate diet, increases insulin resistance risk with AAP use, contributing to the metabolic syndrome, which facilitates endothelial dysfunction, leading to CVD. Thus, supplemental folate may be a realistic treatment option to reduce AAP-associated cardiovascular complications. Successful completion of this study would fundamentally advance schizophrenia treatment as we learn more about genetic, dietary, and lifestyle factors that relate to AAP-associated metabolic complications, as well as measuring the incidence of endothelial dysfunction in this population, and identifying potential ameliorating factors such as supplemental folate in an effort to attenuate the overall cardiovascular burden associated with AAP use.

Public Health Relevance

This proposal will help clinicians gain a better understanding of how genetics, dietary and lifestyle factors interact to place patients with schizophrenia at increased risk for metabolic syndrome, insulin resistance, and endothelial dysfunction from atypical antipsychotic use.

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)
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Chavez, Mark
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University of Michigan Ann Arbor
Schools of Pharmacy
Ann Arbor
United States
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Grove, Tyler B; Tso, Ivy F; Chun, Jinsoo et al. (2016) Negative affect predicts social functioning across schizophrenia and bipolar disorder: Findings from an integrated data analysis. Psychiatry Res 243:198-206
Flowers, Stephanie A; Ryan, Kelly A; Lai, Zongshan et al. (2016) Interaction between COMT rs5993883 and second generation antipsychotics is linked to decreases in verbal cognition and cognitive control in bipolar disorder. BMC Psychol 4:14
Fiedorowicz, Jess G; Ellingrod, Vicki L; Kaplan, Mariana J et al. (2015) The development of depressive symptoms during medical internship stress predicts worsening vascular function. J Psychosom Res 79:243-5
Burghardt, Kyle J; Evans, Simon J; Wiese, Kristen M et al. (2015) An Untargeted Metabolomics Analysis of Antipsychotic Use in Bipolar Disorder. Clin Transl Sci 8:432-40
Ellingrod, Vicki L; Grove, Tyler B; Burghardt, Kyle J et al. (2015) The effect of folate supplementation and genotype on cardiovascular and epigenetic measures in schizophrenia subjects. NPJ Schizophr 1:15046
Grove, Tyler; Taylor, Stephan; Dalack, Gregory et al. (2015) Endothelial function, folate pharmacogenomics, and neurocognition in psychotic disorders. Schizophr Res 164:115-21
Burghardt, Kyle J; Goodrich, Jacyln M; Dolinoy, Dana C et al. (2015) DNA methylation, insulin resistance and second-generation antipsychotics in bipolar disorder. Epigenomics 7:343-52
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
Hirasawa-Fujita, Mika; Bly, Michael J; Ellingrod, Vicki L et al. (2014) Genetic Variation of the Mu Opioid Receptor (OPRM1) and Dopamine D2 Receptor (DRD2) is Related to Smoking Differences in Patients with Schizophrenia but not Bipolar Disorder. Clin Schizophr Relat Psychoses :1-27

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