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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH082784-04
Application #
8019472
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Chavez, Mark
Project Start
2008-05-01
Project End
2013-01-31
Budget Start
2011-02-01
Budget End
2012-01-31
Support Year
4
Fiscal Year
2011
Total Cost
$334,288
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Kraal, A Zarina; Ward, Kristen M; Ellingrod, Vicki L (2017) Sex Differences in Antipsychotic Related Metabolic Functioning in Schizophrenia Spectrum Disorders. Psychopharmacol Bull 47:8-21
Burghardt, Kyle J; Goodrich, Jacyln M; Dolinoy, Dana C et al. (2016) Gene-specific DNA methylation may mediate atypical antipsychotic-induced insulin resistance. Bipolar Disord 18:423-32
Grove, Tyler B; Burghardt, Kyle J; Kraal, A Zarina et al. (2016) Oxytocin Receptor (OXTR) Methylation and Cognition in Psychotic Disorders. Mol Neuropsychiatry 2:151-160
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
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
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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

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