Pharmacogenomics of Mood Stabilizer response I Bipolar Disorder
Prosjekt
- Prosjektnummer
- 911676
- Ansvarlig person
- Ketil J. Ødegaard
- Institusjon
- Helse Bergen HF
- Prosjektkategori
- Strategiske midler - psykisk helse
- Helsekategori
- Mental Health
- Forskningsaktivitet
- 1. Underpinning
Rapporter
A prospective trial of mood stabilizer response will be conducted in 800 BP patients, and the sample genotyped for GWAS. Positive SNPs from ConLiGen, will first be tested, before a complete GWAS on the prospective sample and a meta-analyses with with ConLiGen is performed.Bipolar Disorder (BD) is a serious common psychiatric disorder with a relapsing and remitting course. The cornerstone of clinical management is stabilization and prophylaxis using mood stabilization agents to prevent both mania and depression. Lithium remains the gold standard of treatment with the strongest data for both efficacy and reduction of suicide. Tools to aid the clinician in selection of mood stabilizers are needed. This project is a prospective study of the pharmacogenomics of moodstabilizer response in 800 patients with bipolar I disorder recruited from 13 sites and genotyped with GWAS. Positive genes from past genetic retrospective studies of Lithium response (ConLiGen), will be tested in this prospective sample; successively meta-analyses of these samples will be performed. Finally, neurons will be derived from pluripotent stem cells from lithium responders and non-responders and tested in vivo for response to lithium by gene expression studies. The study has received funding from NIMH to cover the expenses of the US clinical sites, and general project infrastructure, including data management, data analyses and genotyping.
The goal of the current study is to collect a sample of 800 patients with BD on lithium monotherapy by the end of 2014. By the end of 2013 about 400 patients (40 in Bergen) are included. To increase inclusion 3 new study sites have been added in 2013, 1 at the Mayo Clinic in the US and 2 sites in Norway (Trondheim and Stavanger). 2014 will be essential for the recruitment of the last patients in the sample. Funding in 2014 will be used to maximize the patient inclusion in the Norwegian sites and thus the impact of the Norwegian contributions.
This study is a clinical trail designed to identify genetic predictors of lithium repsons in Bipolar 1 disorder. The study has 10 international sites (8 in the US, 1 in Canada and 1 in Bergen, Norway). The study is funded by the NIMH and Health- West, and is part of the national network for research in severe mental disorders in Norway (NORSMI).Bipolar Disorder (BD) is a serious common psychiatric disorder with a relapsing and remitting course. The
cornerstone of clinical management is stabilization and prophylaxis using mood stabilization agents whose
function is to prevent both mania and depression. Lithium remains the gold standard of treatment with the
strongest data for both efficacy and reduction of suicide. Clinically there is a great need for tools to aid the
clinician in selection of mood stabilizers. Currently, this is a trial and error approach with each trial requiring
3-6 months and several trials of different medications are frequently required. This project description
describes a prospective study of the pharmacogenomics of moodstabilizer response in 800 patients with
bipolar I disorder, to be conducted by our research group called PGBD (Pharmacogenetics of Bipolar
Disorder). The aim of this study is to recruit patients from ten closely collaborating sites and follow them up
for two years in order to identify genes that predict moodstabilizer response by genome- wide association
analyses. The study has received funding from NIMH to cover the expenses of the US clinical sites, and
general project infrastructure, including data management, data analyses and genotyping. The current
application seeks continuus funding for the Norwegian clinical research center of the PGBD, located in Health-
Bergen.
REPORT DECEMBER 31th 2012
• Clinical trial: Pharmacogenomic prospective non-randomized open trial of lithium and valproate
• Eudract number: 2010-023740-32
• Approved Regional Ethics Committee South-East C:11-04-2011
• Approved Statens legemiddelverk (SLV): 18-05-2011
• Principle Investigator Norway: Ketil J. Oedegaard, Health-Bergen, Norway
• Principle Investigator International: John R. Kelsoe, USCD, USA
• Clinical Monitor Norway: Ingunn Anundsgård, Innovest
• Study Period: 2011-2016
• Total Number of Patients to be included: 800
• Total Patients Enrolled Norway by Dec 31st 2012: 26 (22 last 12 months)
• Total Patients Enrolled International by Dec 31st 2012: 267 (185 last 12 months)
Comments: This study is proceeding according to the protocol. Both in the Norwegian site and in the international sites the inclusion rates have been satisfactory. First planned publication will be developed in 2013.
This study is an international, NIMH sponsored, multicenter prospective clinical trial of medication response conducted by the PGBD (Pharmacogenetics of Bipolar Disorder) to identify genes that predict moodstabilizer response by genome-wide association analyses.SYNOPSIS OF THE STUDY BY 31.12.2011
Clinical trial: Pharmacogenomic prospective non-randomized open trial of lithium and valproate.
Eudract number: 2010-023740-32. Approved Regional Ethics Committee South-East C:11-04-2011.
Approved Statens legemiddelverk (SLV): 18-05-2011.
Principle Investigator Norway: Ketil J. Oedegaard, Health-Bergen, Norway. Principle Investigator International: John R. Kelsoe, USCD, USA.
Study Period: 2011-2016.
Total Number of Patients to be included: 800.
Total Patients Enrolled Norway 31.12.2011: 7.
Total Patients Enrolled International 31.12.2011: 90
Bipolar Disorder (BD) is a serious common psychiatric disorder with a relapsing and remitting course. Patients experience swings of mood from mania with symptoms of excitation, euphoria, increased activity and risk taking, to depression with sadness, apathy, anergy and anhedonia. It affects 1-3% of the population and consumes a substantial portion of annual mental health care expenditures. Psychosis can occur in either phase and 17% suicide at some point in their lives.
The cornerstone of clinical management is stabilization and prophylaxis using one of several mood stabilization agents whose function is to prevent both mania and depression. Lithium was the first mood stabilizing medication identified, and remains the gold standard of treatment with the strongest data for both efficacy and reduction of suicide. Patients have a wide range in response to these different agents and it is a common clinical experience to try several of them only to find a robust response to one agent. This heterogeneity of response is supported by data arguing that different clinical presentations are associated with response to different agents.Clinically there is a great need for tools to aid the clinician in selection of mood stabilizers. Currently, this is a trial and error approach with each trial requiring 3-6 months and several trials of different medications frequently required. A DNA test that provided a probabilistic predictor of response to different mood stabilizers could shorten the process of medication optimization by years with a corresponding reduction in patient suffering and suicidal risk. Towards that end, this study will be conducted as a 10 site clinical trial in which 800 subjects will be stabilized on lithium over 3 months and then followed for 2 years in order to document relapses. Genotypes at 1M SNPs will be correlated with time to relapse using survival methods.
In 2011 the study was approved by REK and SLV and a total of 90 patients have been enrolled. The start up meeting in Norway was held in Bergen in June 2011 where the internatonal PI and national collaborators participated with study related lectures to initiate local clinicians to identify subjects for study enrollment.
Vitenskapelige artikler
McCarthy Michael J, Nievergelt Caroline M, Kelsoe John R, Welsh David K
A survey of genomic studies supports association of circadian clock genes with bipolar disorder spectrum illnesses and lithium response.
PLoS One 2012;7(2):e32091. Epub 2012 feb 22
PMID: 22384149
Deltagere
- John Kelsoe Prosjektleder
- Helle Kristine Schøyen Prosjektdeltaker
- Gunnar Morken Prosjektdeltaker
- Ole Andreas Andreassen Prosjektdeltaker
- Ketil Joachim Ødegaard Prosjektleder
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