Antipsychotic and Folate Pharmacogenetics

Summary

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

Top Publications

  1. pmc Metabolic syndrome and insulin resistance in schizophrenia patients receiving antipsychotics genotyped for the methylenetetrahydrofolate reductase (MTHFR) 677C/T and 1298A/C variants
    Vicki 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
  2. pmc Pharmacogenomics of sterol synthesis and statin use in schizophrenia subjects treated with antipsychotics
    Thomas 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
  3. pmc Clinical Pharmacogenetics Implementation Consortium guideline for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants
    J K Hicks
    Department of Pharmaceutical Sciences, St Jude Children s Research Hospital, Memphis, Tennessee, USA
    Clin Pharmacol Ther 93:402-8. 2013
  4. pmc 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
  5. ncbi The influence of the brain-derived neurotropic factor Val66Met genotype and HMG-CoA reductase inhibitors on insulin resistance in the schizophrenia and bipolar populations
    K 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
  6. pmc DNA methylation in schizophrenia subjects: gender and MTHFR 677C/T genotype differences
    Kyle 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
  7. pmc The influence of metabolic syndrome, physical activity and genotype on catechol-O-methyl transferase promoter-region methylation in schizophrenia
    S 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
  8. pmc Risk factors associated with metabolic syndrome in bipolar and schizophrenia subjects treated with antipsychotics: the role of folate pharmacogenetics
    Vicki 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
  9. pmc Fats and factors: lipid profiles associate with personality factors and suicidal history in bipolar subjects
    Simon J Evans
    Department of Psychiatry, University of Michigan, Ann Arbor, Michigan, United States of America
    PLoS ONE 7:e29297. 2012
  10. pmc 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

Detail Information

Publications13

  1. pmc Metabolic syndrome and insulin resistance in schizophrenia patients receiving antipsychotics genotyped for the methylenetetrahydrofolate reductase (MTHFR) 677C/T and 1298A/C variants
    Vicki 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
    ....
  2. pmc Pharmacogenomics of sterol synthesis and statin use in schizophrenia subjects treated with antipsychotics
    Thomas 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...
  3. pmc Clinical Pharmacogenetics Implementation Consortium guideline for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants
    J 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...
  4. pmc 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...
  5. ncbi The influence of the brain-derived neurotropic factor Val66Met genotype and HMG-CoA reductase inhibitors on insulin resistance in the schizophrenia and bipolar populations
    K 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)...
  6. pmc DNA methylation in schizophrenia subjects: gender and MTHFR 677C/T genotype differences
    Kyle 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...
  7. pmc The influence of metabolic syndrome, physical activity and genotype on catechol-O-methyl transferase promoter-region methylation in schizophrenia
    S 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...
  8. pmc Risk factors associated with metabolic syndrome in bipolar and schizophrenia subjects treated with antipsychotics: the role of folate pharmacogenetics
    Vicki 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...
  9. pmc Fats and factors: lipid profiles associate with personality factors and suicidal history in bipolar subjects
    Simon J Evans
    Department of Psychiatry, University of Michigan, Ann Arbor, Michigan, United States of America
    PLoS ONE 7:e29297. 2012
    ....
  10. pmc 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...
  11. pmc Association between type-three metabotropic glutamate receptor gene (GRM3) variants and symptom presentation in treatment refractory schizophrenia
    Jeffrey R Bishop
    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...
  12. pmc Metabolic syndrome in bipolar disorder and schizophrenia: dietary and lifestyle factors compared to the general population
    Michael 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
    ....

Research Grants30

  1. Understanding Providers Stigmatization of SMI Among Veterans
    JAN GREER SULLIVAN; Fiscal Year: 2013
    ..A series of standard ordinary least squares analysis will be used to examine the outcomes of interest. ..
  2. Substance Abuse Research - Medications Development Center
    JOY MARIE SCHMITZ; Fiscal Year: 2013
    ..abstract_text> ..
  3. Comprehensive NeuroAIDS Core Center
    Kamel Khalili; Fiscal Year: 2013
    ..abstract_text> ..
  4. The Conte Center for Schizophrenia Research
    Daniel C Javitt; Fiscal Year: 2013
    ..The overall goal of the Center is to develop new assessment and intervention approaches for schizophrenia based upon glutamatergic models. ..
  5. Penn TREC Survivor Center
    Kathryn H Schmitz; Fiscal Year: 2013
    ..abstract_text> ..
  6. Clozapine for Cannabis Use Disorder in Schizophrenia
    Alan I Green; Fiscal Year: 2013
    ..Lastly, CLOZ's use in this study may also reflect its potential to serve as a prototype of the next generation of medications for treatment of SCZ and co-occurring CUD. ..
  7. Program Project: GENE MUTATION AND RESCUE IN HUMAN DIAPHRAGMATIC HERNIA
    Patricia K Donahoe; Fiscal Year: 2013
    ..Further, the methods devised for this study of CDH may have broader implications across other congenital anomalies. ..
  8. Quetiapine Pharmacotherapy for Cannabis Dependence
    John J Mariani; Fiscal Year: 2013
    ..The specific aims of the projects are to determine whether quetiapine is superior to placebo in 1) reducing marijuana use and 2) achieving abstinence. ..
  9. Notch-Mediated Expansion of Cord Blood Progenitors for Stem Cell Transplant
    Colleen Delaney; Fiscal Year: 2013
    ..Our goal is to now determine the clinical efficacy of this approach in a phase II clinical trial. ..
  10. Statewide Intervention to Reduce Early Mortality in Persons with Mental Illness
    Stephen J Bartels; Fiscal Year: 2013
    ..We propose to track the outcomes of this state program so that useful lessons can be drawn for similar, future efforts in other states. ..
  11. Defining and Treating Written Language Disabilities
    VIRGINIA WISE BERNINGER; Fiscal Year: 2013
    ..The proposed multidisciplinary research has practical significance for improving diagnosis and providing more effective services which may lower such risks. ..
  12. Implementing Health Care Interventions for Hispanics with Serious Mental Illness
    Leopoldo J Cabassa; Fiscal Year: 2013
    ..The research plan will yield pilot data for a subsequent R01 to conduct a randomized controlled trial to test the effectiveness and implementation of the modified intervention. ..
  13. OUHSC Specific Pathogen Free Baboon Research Resource
    Roman F Wolf; Fiscal Year: 2013
    ..The long term objective is for the SPF baboon colony to be a stable, self-sustaining breeding colony that produces ~100 SPF baboons/year for use in NIH-funded biomedical research. ..
  14. COBRE Center for Central Nervous System Function
    Jerome N Sanes; Fiscal Year: 2013
    ..The COBRE Center will leverage the administrative resources available through the Brown Institute for Brain Science to ensure efficient operation and coordinate with other brain science research activities at Brown. ..
  15. JHU-UMD Diabetes Research Center
    Fredric E Wondisford; Fiscal Year: 2013
    ..The Enrichment Program will facilitate the interaction within and between Johns Hopkins University and the University of Maryland. ..
  16. NALTREXONE FOR ANTIPSYCHOTIC-INDUCED WEIGHT GAIN
    Cenk Tek; Fiscal Year: 2013
    ....
  17. 1/2-A Comparison of Long-Acting Injectable Medications for Schizophrenia -ACLAIMS
    JOSEPH PATRICK MCEVOY; Fiscal Year: 2013
    ..abstract_text> ..
  18. Pharmacogenetics of Antipsychotic Drug Response
    Jianping Zhang; Fiscal Year: 2013
    ....
  19. Hopkins Center for Eliminate Cardiovascular Health Disparities
    Lisa A Cooper; Fiscal Year: 2013
    ..abstract_text> ..
  20. Early Phase Psychosis: Informing Treatment Decisions
    John M Kane; Fiscal Year: 2013
    ..Our ability to intervene appropriately, effectively and consistently in this population can have profound long-term public health consequences. ..
  21. 2/2-A Comparison of Long-Acting Injectable Medications for Schizophrenia -ACLAIMS
    THOMAS SCOTT STROUP; Fiscal Year: 2013
    ..abstract_text> ..