Antipsychotic and Folate Pharmacogenetics
Principal Investigator: Vicki L Ellingrod
Abstract: DESCRIPTION (provided by applicant): 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.
Funding Period: 2008-05-01 - 2018-06-30
more information: NIH RePORT
- Metabolic syndrome and insulin resistance in schizophrenia patients receiving antipsychotics genotyped for the methylenetetrahydrofolate reductase (MTHFR) 677C/T and 1298A/C variantsVicki L Ellingrod
University of Michigan College of Pharmacy, Department of Clinical Sciences, School of Medicine, Ann Arbor 48109, USA
Schizophr Res 98:47-54. 2008....
- Pharmacogenomics of sterol synthesis and statin use in schizophrenia subjects treated with antipsychoticsThomas J Vassas
Clinical and Translational Pharmacy, University of Michigan College of Pharmacy, 428 Church Street, Ann Arbor, MI 48109, USA
Pharmacogenomics 15:61-7. 2014..Genetic variation within SREBF may contribute to dyslipidemias and lipid medication efficacy within schizophrenia...
- Clinical Pharmacogenetics Implementation Consortium guideline for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressantsJ K Hicks
Department of Pharmaceutical Sciences, St Jude Children s Research Hospital, Memphis, Tennessee, USA
Clin Pharmacol Ther 93:402-8. 2013..Evidence from published literature is presented for CYP2D6 and CYP2C19 genotype-directed dosing of tricyclic antidepressants...
- Detection of metabolic syndrome in schizophrenia and implications for antipsychotic therapy : is there a role for folate?Kyle J Burghardt
Department of Clinical Social and Administrative Sciences, College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, MI 48109, USA
Mol Diagn Ther 17:21-30. 2013..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...
- The influence of the brain-derived neurotropic factor Val66Met genotype and HMG-CoA reductase inhibitors on insulin resistance in the schizophrenia and bipolar populationsK J Burghardt
Department of Clinical Social and Administrative Sciences, College of Pharmacy, University of Michigan, Ann Arbor, USA
Clin Transl Sci 5:486-90. 2012..We sought to determine the effect of the BDNF Met variant and statin medication use on insulin resistance in schizophrenia and bipolar disorder using the homeostasis model assessment of insulin resistance (HOMA-IR)...
- DNA methylation in schizophrenia subjects: gender and MTHFR 677C/T genotype differencesKyle J Burghardt
College of Pharmacy, Department of Clinical Social and Administrative Sciences, University of Michigan, 428 Church Street, Ann Arbor, MI 48109, USA
Epigenomics 4:261-8. 2012..Pharmacogenetically regulated folic acid may be related to this risk. DNA methylation and metabolic syndrome within this group has not been previously studied...
- The influence of metabolic syndrome, physical activity and genotype on catechol-O-methyl transferase promoter-region methylation in schizophreniaS A Lott
Department of Clinical Social and Administrative Sciences, University of Michigan College of Pharmacy, Ann Arbor, MI, USA
Pharmacogenomics J 13:264-71. 2013..002; site 2: P=0.001). The results of this study suggest that COMT promoter region methylation is largely influenced by COMT genotype and that physical activity plays a significant role in epigenetic modulation of COMT...
- Risk factors associated with metabolic syndrome in bipolar and schizophrenia subjects treated with antipsychotics: the role of folate pharmacogeneticsVicki L Ellingrod
Department of Clinical Social and Administrative Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
J Clin Psychopharmacol 32:261-5. 2012..Use of this information clinically may help to reduce the risk for AAP metabolic complications in those whose clinical care necessitates the use of AAPs...
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Department of Psychiatry, University of Michigan, Ann Arbor, Michigan, United States of America
PLoS ONE 7:e29297. 2012....
- Dietary, lifestyle and pharmacogenetic factors associated with arteriole endothelial-dependent vasodilatation in schizophrenia patients treated with atypical antipsychotics (AAPs)Vicki L Ellingrod
University of Michigan, College of Pharmacy, Department of Clinical Social and Administrative Sciences, 428 Church Street, Ann Arbor, Michigan 48109, USA
Schizophr Res 130:20-6. 2011..This study examined the status of endothelial function within the schizophrenia population and determined pharmacogenetic, medication, dietary, and lifestyle factors associated with this functioning...
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Department of Pharmacy Practice, University of Illinois at Chicago College of Pharmacy, Chicago, Illinois 60612, USA
Hum Psychopharmacol 26:28-34. 2011..The objective of this study was to determine whether refractory psychiatric symptoms in antipsychotic non-responders are related to polymorphisms in GRM3...
- Metabolic syndrome in bipolar disorder and schizophrenia: dietary and lifestyle factors compared to the general populationMichael J Bly
Department of Clinical Social and Administrative Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA
Bipolar Disord 16:277-88. 2014....
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