PGBD Profile
Pharmacogenomics of Mood Stabilizer Response in Bipolar Disorder
| Principal Investigator | John R. Kelsoe, M.D. |
|---|---|
| Host Institution | University California, San Diego |
| Grant Number | 1 U01 MH092758-01 |
| PGRN 2011 Retreat Poster | PGBD Poster |
| PGBD Publications | PGBD Publications |
Abstract (Updated, May 2011)
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 will conduct a prospective trial of two common mood stabilizing medications, lithium and valproate, in 700 subjects studied at 10 sites. Subjects with bipolar disorder will be treated initially with lithium and stabilized on monotherapy over 3-4 months. They will then be followed for 2 years and monitored for relapse. Those who fail lithium will be crossed-over to valproate and similarly studied. Most studies to date have employed retrospective assessment, we hope this will establish a large sample with "gold standard" clinical trial prospective assessment methods. Samples will be genotyped for GWAS and survival analysis methods used to test for association of genotype to time to relapse as the primary outcome measure. Positive SNPs from a collaborating retrospective lithium project (ConLiGen) will first be tested for replication in our prospective sample. Subsequently, all SNPs genotyped will be tested for association. 150 of the 700 subjects will also undergo skin biopsy for skin fibroblasts. These fibroblasts will be reprogrammed into induced pluripotent stem cells (iPS) and then differentiated into neurons. This powerful method allows for the functional testing of living neurons from specific individuals. iPS derived neurons from lithium responders and non-responders will each be challenged with lithium and expression profiling conducted. This will help identify genes involved in lithium response that can be compared with the GWAS data. It also will facilitate functional mutation studies in lithium related genes.
Team Members
Project Management
|
John Kelsoe, M.D. Principle Investigator; Professor of Psychiatry; Director, Laboratory of Psychiatric Genomics Institute for Genomic Medicine University of California, San Diego Email: jkelsoe@ucsd.edu Phone: (858) 534-5927 |
Susan Leckband, R.Ph., B.C.P.P. Co-Investigator; Psychiatric Clinical Pharmacist, University of California, San Diego Email: Susan.Leckband@va.gov Phone: (858) 552-8585 ext. 5337 |
Clinical Sites
|
Joseph Calabrese, M.D. Co-Investigator; Director, University Hospitals, Case Medical Center, Case Western Reserve University Email: joseph.calabrese@UHhospitals.org Phone: (216) 844-2865 |
John Nurnberger, M.D., Ph.D. Co-Investigator; Professor, Indiana University Email: jnurnber@iupui.edu Phone: (317) 274-8382 |
Amit Anand, M.D. Co-Investigator; Professor, Indiana University Email: aanand@iupui.edu Phone: (317) 274-0726 |
Peter Zandi, M.D., Ph.D. Director/Data Analysis; Professor, Johns Hopkins Hospital Email: pzandi@jhsph.edu Phone: (410) 614-2686 |
|
Elliot Gershon, M.D. Co-Investigator; Professor, University of Chicago Email: egershon@yoda.bsd.uchicago.edu Phone: (773) 834-2660 |
William Coryell, M.D. Co-Investigator; Professor, University of Iowa Email: william-coryell@uiowa.edu Phone: (319) 353-4434 |
Melvin McInnis, M.D. Co-Investigator; Professor, University of Michigan Email: mmcinnis@umich.edu Phone: (734) 936-6018 |
Martin Alda, M.D. Collaborator; Professor, Dalhousie University, Halifax, Canada Email: malda@dal.ca Phone: (902) 473-2712 |
|
Wade Berrettini, M.D. Co-Investigator; Professor, University of Pennsylvania Email: wadeb@mail.med.upenn.edu Phone: (215) 898-0092 |
Ketil Odegaard, M.D., Ph.D. Collaborator; University of Bergen, Norway Email: ketil.odegaard@helse-bergen.no Phone: +47 5595 8400 |
iPS Functional Study Team
|
Fred Gage, Ph.D. Director/iPS Functional Studies; Director, Salk Institute for Biological Studies Email: gage@salk.edu Phone: (858) 453-4100 |
Kristen Brennand, Ph.D. Co-Investigator/iPS Functional Studies; Salk Institute for Biological Studies Email: kristen.brennand@gmail.com Phone: (858) 453-4100 |
Data Analysis Team
|
Peter Zandi, M.D, Ph.D. Director/Data Analysis; Professor, Johns Hopkins Hospital Email: pzandi@jhsph.edu Phone: (410) 614-2686 |
Pamela B. Mahon, Ph.D. Co-Investigator/Data Analysis; Assistant Professor, Johns Hopkins Hospital Email: pbelmon2@jhmi.edu Phone: (410) 955-1382 |
Nicholas Schork, Ph.D. Consultant/Data Analysis; Director, Scripps Translational Sciences Institute Email: nschork@scripps.edu Phone: (858) 554-5709 |
Data Management Team
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Caroline Nievergelt, Ph.D. Director/Data Management; Assistant Adjunct Professor, University of California, San Diego Email: cnieverg@ucsd.edu Phone: (858) 246-0399 |
Paul Shilling, Ph.D. Co-Investigator/Data Management; Associate Project Scientist, University of California, San Diego Email: pshilling@ucsd.edu Phone: (858) 535-4791 |
Genomics
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David Craig, Ph.D. Director of Genomics; Director, Translational Genomics Research Email: dcraig@tgen.org Phone: (602) 343-8747 |
Szabolcs Szelinger Research Associate, Translational Genomics Research Email: sszelinger@tgen.org Phone: (602) 343-8400 |
Neurocognitive Assessment
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Katherine Burdick, Ph.D. Neurocognitive Assessment Consultant; Director of Neurocognitive Assessment Laboratory, North Shore-Long Island Jewish Health System Email: KBurdick@NSHS.edu Phone: (718) 470-8167 |
ConLiGen Collaborators
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Thomas G. Schulze, M.D. Director, ConLiGen/Consultant; Director Clinical Research, NIMH/NIH Email: schulzet@mail.nih.gov Phone: (301) 451-7213 |