Pharmacogenomics of Mood Stabilizer Response in Bipolar Disorder

Summary

Principal Investigator: John R Kelsoe
Abstract: DESCRIPTION (provided by applicant): Mood stabilizer treatment is central to the pharmacological management of patients with bipolar disorder. However, response to such agents is highly variable between individuals often resulting in a lengthy trial and error process of medication optimization that can last years. There is a great need for a better predictor of response which would guide physicians to the optimum medication in a more efficient fashion. Genetic differences likely explain a substantial portion of this variability. The goal of this project is to identify genetic variants that are associated with response to mood stabilizer medications that might ultimately be useful as a predictive test. Studies to date by our group have implicated two genes, NTRK2 and PDE11A as predicting response to lithium. In this project, we propose a two pronged approach: genes will first be sought in an exploratory fashion in a larger retrospective sample and then tested for replication in a smaller prospective sample. Larger samples are more easily obtainable in a retrospective study, however, prospective designs though more difficult, provide better and more quantitative data. Our 11 site consortium has recently completed collection of over 4,500 bipolar subjects for a large genetic study. 2,000 retrospective subjects will be collected from both recontact of these previous cases and recruitment of new retrospective cases. The prospective sample of 960 subjects will be collected through an eight site multicenter trial. Patients will be recruited, screened and stabilized first on lithium monotherapy over a 3 month period. After one month observation, they will enter the maintenance phase and followed for 2 years. The primary outcome measure will be time to relapse. Patients who fail lithium will be crossed over to valproic acid, those failing both drugs will enter the treatment as usual arm. Genomewide association will be performed on the retrospective sample and positive SNPs replicated in the prospective sample. Secondary analyses will include genomewide association ofthe prospective sample alone and in meta-analysis with the retrospective sample. These analyses will be guided in part by studies of lithium's mechanism of action in neuronal cells derived from induced pluripotent stem cells in turn derived from skin fibroblasts from lithium responders and non-responders. RELEVANCE (See instructions): This multi-site collaborative project aims to identify genetic variants in individuals with bipolar disorder that predict response to lithium. We will do this with a combination of retrospective assessment of lithium response in 1600 individuals with BP disorder and analysis of genotype data, as well as a prospective study of 1000 BP individuals who begin an open trial with lithium. Our hypothesis is that genetic variants at several loci predict treatment outcomes with lithium.
Funding Period: 2010-09-10 - 2015-05-31
more information: NIH RePORT

Top Publications

  1. ncbi Pharmacogenetics of lithium response in bipolar disorder
    Michael J McCarthy
    Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA
    Pharmacogenomics 11:1439-65. 2010
  2. ncbi Biomarkers of PTSD: neuropeptides and immune signaling
    Dewleen G Baker
    Veterans Affairs Center of Excellence for Stress and Mental Health, VA San Diego, CA, USA
    Neuropharmacology 62:663-73. 2012
  3. pmc Functional genetic variation in the Rev-Erbα pathway and lithium response in the treatment of bipolar disorder
    M J McCarthy
    Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA
    Genes Brain Behav 10:852-61. 2011
  4. pmc A survey of genomic studies supports association of circadian clock genes with bipolar disorder spectrum illnesses and lithium response
    Michael J McCarthy
    Veterans Affairs San Diego Healthcare System, San Diego, California, United Sates of America
    PLoS ONE 7:e32091. 2012
  5. pmc Clinical Pharmacogenetics Implementation Consortium guidelines for HLA-B genotype and carbamazepine dosing
    S G Leckband
    Veterans Affairs San Diego Healthcare System, San Diego, California, USA
    Clin Pharmacol Ther 94:324-8. 2013
  6. pmc Neuroimaging in psychiatric pharmacogenetics research: the promise and pitfalls
    Mary Falcone
    1 Department of Pharmacology, University of Pennsylvania, Philadelphia, PA, USA 2 Center for Interdisciplinary Research on Nicotine Addiction, Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA
    Neuropsychopharmacology 38:2327-37. 2013

Detail Information

Publications6

  1. ncbi Pharmacogenetics of lithium response in bipolar disorder
    Michael J McCarthy
    Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA
    Pharmacogenomics 11:1439-65. 2010
    ..Finally, a framework is proposed by which future pharmacogenetic studies can incorporate advances in genetics, molecular biology and bioinformatics in a pathway-based approach to predicting lithium treatment response...
  2. ncbi Biomarkers of PTSD: neuropeptides and immune signaling
    Dewleen G Baker
    Veterans Affairs Center of Excellence for Stress and Mental Health, VA San Diego, CA, USA
    Neuropharmacology 62:663-73. 2012
    ..Potential research implications and directions are discussed. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'...
  3. pmc Functional genetic variation in the Rev-Erbα pathway and lithium response in the treatment of bipolar disorder
    M J McCarthy
    Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA
    Genes Brain Behav 10:852-61. 2011
    ..Our findings support a role for Rev-Erbα in the therapeutic mechanism of lithium and suggest that the interaction between Rev-Erbα and GSK3β may warrant further study...
  4. pmc A survey of genomic studies supports association of circadian clock genes with bipolar disorder spectrum illnesses and lithium response
    Michael J McCarthy
    Veterans Affairs San Diego Healthcare System, San Diego, California, United Sates of America
    PLoS ONE 7:e32091. 2012
    ..Our analysis reveals previously unrecognized associations between clock genes and BD-spectrum illnesses, partly reconciling previously discordant results from past GWAS and candidate gene studies...
  5. pmc Clinical Pharmacogenetics Implementation Consortium guidelines for HLA-B genotype and carbamazepine dosing
    S G Leckband
    Veterans Affairs San Diego Healthcare System, San Diego, California, USA
    Clin Pharmacol Ther 94:324-8. 2013
    ..Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines are published and updated periodically on the PharmGKB website at (http://www.pharmgkb.org)...
  6. pmc Neuroimaging in psychiatric pharmacogenetics research: the promise and pitfalls
    Mary Falcone
    1 Department of Pharmacology, University of Pennsylvania, Philadelphia, PA, USA 2 Center for Interdisciplinary Research on Nicotine Addiction, Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA
    Neuropsychopharmacology 38:2327-37. 2013
    ..Future studies that pre-screen participants for genetic variants selected a priori based on drug metabolism and targets have the greatest potential to advance the science and practice of psychiatric treatment. ..

Research Grants30

  1. Comprehensive NeuroAIDS Core Center
    Kamel Khalili; Fiscal Year: 2013
    ..abstract_text> ..
  2. Translational Methamphetamine AIDS Research Center (TMARC)
    Igor Grant; Fiscal Year: 2013
    ..TMARC's ultimate vision is to become a national resource for translational multidisciplinary research and training in the neuropathogenesis of HIV and substance use. ..
  3. Genetic Predictors of Lithium Response in Bipolar Disorder
    John R Kelsoe; Fiscal Year: 2013
    ..The results of this study could be used to develop a DNA based predictor of response to different medications. This could aid clinicians in the selection of medications and lead to faster stabilization and reduced suffering of veterans. ..
  4. Modeling anorexia nervosa with human pluripotent stem cells
    Alysson R Muotri; Fiscal Year: 2013
    ....
  5. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
    ..abstract_text> ..
  6. Hopkins Center for Eliminate Cardiovascular Health Disparities
    Lisa A Cooper; Fiscal Year: 2013
    ..abstract_text> ..
  7. Circadian Clock Genes in Bipolar Disorder
    MICHAEL JOSEPH MCCARTHY; Fiscal Year: 2013
    ..abstract_text> ..
  8. Genomic Studies of Bipolar Disorder in a Large Cohort from The Netherlands
    Roel A Ophoff; Fiscal Year: 2013
    ..Since these diseases are known to be related and yet have different characteristics, our study provides a unique opportunity to systematically study differences and overlapping features of these neuropsychiatric disorders. ..
  9. Treatment of Bipolar Disorder in Old Age
    Robert C Young; Fiscal Year: 2013
    ..These studies can provide findings that use relatively non- invasive and cost effective methods, derived from neuroscience and neurobiology, to develop safe and effective treatment approaches. ..
  10. The Pathogenesis of Facioscapulohumeral Muscular Dystrophy
    Stephen J Tapscott; Fiscal Year: 2013
    ..Together, these studies combine genetic, epigenetic, transcriptional and developmental approaches to defining the molecular deficits that cause FSHD and will provide a new basis for developing therapies. ..
  11. In vitro and in vivo study of simvastatin plus lithium in bipolar depression
    Roy H Perlis; Fiscal Year: 2013
    ....
  12. BIOLOGY OF NEUROENDOCRINE PEPTIDES
    Marc R Montminy; Fiscal Year: 2013
    ..Specifying the contributions of the CRF family of ligands and receptors to the maintenance of homeostasis and to stress-linked allostasis may improve our ability to manage diseases, including mood and metabolic disorders ..
  13. Washington National Primate Research Center
    David M Anderson; Fiscal Year: 2013
    ..All lentivirus-infected primates are housed in ABSL2/3 containment facilities with appropriate biosafety procedures. The University of Washington, including the WaNPRC, is fully accredited by AAALAC International. ..