The Pharmacogenomics of Bipolar Disorder study (PGBD)

Identification of genes for lithium response in a prospective sample

Ketil J. Oedegaard, Martin Alda, Anit Anand, Ole A. Andreassen, Yokesh Balaraman, Wade H. Berrettini, Abesh Bhattacharjee, Kristen J. Brennand, Katherine E. Burdick, Joseph R. Calabrese, Cynthia V. Calkin, Ana Claasen, William H. Coryell, David Craig, Anna DeModena, Mark Frye, Fred H. Gage, Keming Gao, Julie Garnham, Elliot Gershon & 18 others Petter Jakobsen, Susan G. Leckband, Michael J. McCarthy, Melvin G. McInnis, Adam X. Maihofer, Jerome Mertens, Gunnar Morken, Caroline M. Nievergelt, John Nurnberger, Son Pham, Helle Schoeyen, Tatyana Shekhtman, Paul D. Shilling, Szabolcs Szelinger, Bruce Tarwater, Jun Yao, Peter P. Zandi, John R. Kelsoe

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Background: Bipolar disorder is a serious and common psychiatric disorder characterized by manic and depressive mood switches and a relapsing and remitting course. The cornerstone of clinical management is stabilization and prophylaxis using mood-stabilizing medications to reduce both manic and depressive symptoms. Lithium remains the gold standard of treatment with the strongest data for both efficacy and suicide prevention. However, many patients do not respond to this medication, and clinically there is a great need for tools to aid the clinician in selecting the correct treatment. Large genome wide association studies (GWAS) investigating retrospectively the effect of lithium response are in the pipeline however, few large prospective studies on genetic predictors to of lithium response have yet been conducted. The purpose of this project is to identify genes that are associated with lithium response in a large prospective cohort of bipolar patients and to better understand the mechanism of action of lithium and the variation in the genome that influences clinical response. Methods/Design: This study is an 11-site prospective non-randomized open trial of lithium designed to ascertain a cohort of 700 subjects with bipolar I disorder who experience protocol-defined relapse prevention as a result of treatment with lithium monotherapy. All patients will be diagnosed using the Diagnostic Interview for Genetic Studies (DIGS) and will then enter a 2-year follow-up period on lithium monotherapy if and when they exhibit a score of 1 (normal, not ill), 2 (minimally ill) or 3 (mildly ill) on the Clinical Global Impressions of Severity Scale for Bipolar Disorder (CGI-S-BP Overall Bipolar Illness) for 4 of the 5 preceding weeks. Lithium will be titrated as clinically appropriate, not to exceed serum levels of 1.2mEq/L. The sample will be evaluated longitudinally using a wide range of clinical scales, cognitive assessments and laboratory tests. On relapse, patients will be discontinued or crossed-over to treatment with valproic acid (VPA) or treatment as usual (TAU). Relapse is defined as a DSM-IV manic, major depressive or mixed episode or if the treating physician decides a change in medication is clinically necessary. The sample will be genotyped for GWAS. The outcome for lithium response will be analyzed as a time to event, where the event is defined as clinical relapse, using a Cox Proportional Hazards model. Positive single nucleotide polymorphisms (SNPs) from past genetic retrospective studies of lithium response, the Consortium on Lithium Genetics (ConLiGen), will be tested in this prospective study sample a meta-analysis of these samples will then 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. SNPs in genes identified in these cellular studies will also be tested for association to response. Discussion: Lithium is an extraordinarily important therapeutic drug in the clinical management of patients suffering from bipolar disorder. However, a significant proportion of patients, 30-40%, fail to respond, and there is currently no method to identify the good lithium responders before initiation of treatment. Converging evidence suggests that genetic factors play a strong role in the variation of response to lithium, but only a few genes have been tested and the samples have largely been retrospective or quite small. The current study will collect an entirely unique sample of 700 patients with bipolar disorder to be stabilized on lithium monotherapy and followed for up to 2years. This study will produce useful information to improve the understanding of the mechanism of action of lithium and will add to the development of a method to predict individual response to lithium, thereby accelerating recovery and reducing suffering and cost. Trial registration: ClinicalTrials.gov Identifier: NCT01272531Registered: January 6, 2011.

Original languageEnglish (US)
Article number129
JournalBMC Psychiatry
Volume16
Issue number1
DOIs
StatePublished - May 5 2016

Fingerprint

Pharmacogenetics
Bipolar Disorder
Lithium
Genes
Genome-Wide Association Study
Recurrence
Therapeutics
Single Nucleotide Polymorphism
Prospective Studies
Pluripotent Stem Cells

Keywords

  • Bipolar disorder
  • GWAS
  • Lithium
  • Mood stabilizer
  • Personalized medicine
  • Pharmacogenetics
  • Precision medicine
  • Prospective trial

ASJC Scopus subject areas

  • Psychiatry and Mental health

Cite this

Oedegaard, K. J., Alda, M., Anand, A., Andreassen, O. A., Balaraman, Y., Berrettini, W. H., ... Kelsoe, J. R. (2016). The Pharmacogenomics of Bipolar Disorder study (PGBD): Identification of genes for lithium response in a prospective sample. BMC Psychiatry, 16(1), [129]. https://doi.org/10.1186/s12888-016-0732-x

The Pharmacogenomics of Bipolar Disorder study (PGBD) : Identification of genes for lithium response in a prospective sample. / Oedegaard, Ketil J.; Alda, Martin; Anand, Anit; Andreassen, Ole A.; Balaraman, Yokesh; Berrettini, Wade H.; Bhattacharjee, Abesh; Brennand, Kristen J.; Burdick, Katherine E.; Calabrese, Joseph R.; Calkin, Cynthia V.; Claasen, Ana; Coryell, William H.; Craig, David; DeModena, Anna; Frye, Mark; Gage, Fred H.; Gao, Keming; Garnham, Julie; Gershon, Elliot; Jakobsen, Petter; Leckband, Susan G.; McCarthy, Michael J.; McInnis, Melvin G.; Maihofer, Adam X.; Mertens, Jerome; Morken, Gunnar; Nievergelt, Caroline M.; Nurnberger, John; Pham, Son; Schoeyen, Helle; Shekhtman, Tatyana; Shilling, Paul D.; Szelinger, Szabolcs; Tarwater, Bruce; Yao, Jun; Zandi, Peter P.; Kelsoe, John R.

In: BMC Psychiatry, Vol. 16, No. 1, 129, 05.05.2016.

Research output: Contribution to journalArticle

Oedegaard, KJ, Alda, M, Anand, A, Andreassen, OA, Balaraman, Y, Berrettini, WH, Bhattacharjee, A, Brennand, KJ, Burdick, KE, Calabrese, JR, Calkin, CV, Claasen, A, Coryell, WH, Craig, D, DeModena, A, Frye, M, Gage, FH, Gao, K, Garnham, J, Gershon, E, Jakobsen, P, Leckband, SG, McCarthy, MJ, McInnis, MG, Maihofer, AX, Mertens, J, Morken, G, Nievergelt, CM, Nurnberger, J, Pham, S, Schoeyen, H, Shekhtman, T, Shilling, PD, Szelinger, S, Tarwater, B, Yao, J, Zandi, PP & Kelsoe, JR 2016, 'The Pharmacogenomics of Bipolar Disorder study (PGBD): Identification of genes for lithium response in a prospective sample', BMC Psychiatry, vol. 16, no. 1, 129. https://doi.org/10.1186/s12888-016-0732-x
Oedegaard, Ketil J. ; Alda, Martin ; Anand, Anit ; Andreassen, Ole A. ; Balaraman, Yokesh ; Berrettini, Wade H. ; Bhattacharjee, Abesh ; Brennand, Kristen J. ; Burdick, Katherine E. ; Calabrese, Joseph R. ; Calkin, Cynthia V. ; Claasen, Ana ; Coryell, William H. ; Craig, David ; DeModena, Anna ; Frye, Mark ; Gage, Fred H. ; Gao, Keming ; Garnham, Julie ; Gershon, Elliot ; Jakobsen, Petter ; Leckband, Susan G. ; McCarthy, Michael J. ; McInnis, Melvin G. ; Maihofer, Adam X. ; Mertens, Jerome ; Morken, Gunnar ; Nievergelt, Caroline M. ; Nurnberger, John ; Pham, Son ; Schoeyen, Helle ; Shekhtman, Tatyana ; Shilling, Paul D. ; Szelinger, Szabolcs ; Tarwater, Bruce ; Yao, Jun ; Zandi, Peter P. ; Kelsoe, John R. / The Pharmacogenomics of Bipolar Disorder study (PGBD) : Identification of genes for lithium response in a prospective sample. In: BMC Psychiatry. 2016 ; Vol. 16, No. 1.
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TY - JOUR

T1 - The Pharmacogenomics of Bipolar Disorder study (PGBD)

T2 - Identification of genes for lithium response in a prospective sample

AU - Oedegaard, Ketil J.

AU - Alda, Martin

AU - Anand, Anit

AU - Andreassen, Ole A.

AU - Balaraman, Yokesh

AU - Berrettini, Wade H.

AU - Bhattacharjee, Abesh

AU - Brennand, Kristen J.

AU - Burdick, Katherine E.

AU - Calabrese, Joseph R.

AU - Calkin, Cynthia V.

AU - Claasen, Ana

AU - Coryell, William H.

AU - Craig, David

AU - DeModena, Anna

AU - Frye, Mark

AU - Gage, Fred H.

AU - Gao, Keming

AU - Garnham, Julie

AU - Gershon, Elliot

AU - Jakobsen, Petter

AU - Leckband, Susan G.

AU - McCarthy, Michael J.

AU - McInnis, Melvin G.

AU - Maihofer, Adam X.

AU - Mertens, Jerome

AU - Morken, Gunnar

AU - Nievergelt, Caroline M.

AU - Nurnberger, John

AU - Pham, Son

AU - Schoeyen, Helle

AU - Shekhtman, Tatyana

AU - Shilling, Paul D.

AU - Szelinger, Szabolcs

AU - Tarwater, Bruce

AU - Yao, Jun

AU - Zandi, Peter P.

AU - Kelsoe, John R.

PY - 2016/5/5

Y1 - 2016/5/5

N2 - Background: Bipolar disorder is a serious and common psychiatric disorder characterized by manic and depressive mood switches and a relapsing and remitting course. The cornerstone of clinical management is stabilization and prophylaxis using mood-stabilizing medications to reduce both manic and depressive symptoms. Lithium remains the gold standard of treatment with the strongest data for both efficacy and suicide prevention. However, many patients do not respond to this medication, and clinically there is a great need for tools to aid the clinician in selecting the correct treatment. Large genome wide association studies (GWAS) investigating retrospectively the effect of lithium response are in the pipeline however, few large prospective studies on genetic predictors to of lithium response have yet been conducted. The purpose of this project is to identify genes that are associated with lithium response in a large prospective cohort of bipolar patients and to better understand the mechanism of action of lithium and the variation in the genome that influences clinical response. Methods/Design: This study is an 11-site prospective non-randomized open trial of lithium designed to ascertain a cohort of 700 subjects with bipolar I disorder who experience protocol-defined relapse prevention as a result of treatment with lithium monotherapy. All patients will be diagnosed using the Diagnostic Interview for Genetic Studies (DIGS) and will then enter a 2-year follow-up period on lithium monotherapy if and when they exhibit a score of 1 (normal, not ill), 2 (minimally ill) or 3 (mildly ill) on the Clinical Global Impressions of Severity Scale for Bipolar Disorder (CGI-S-BP Overall Bipolar Illness) for 4 of the 5 preceding weeks. Lithium will be titrated as clinically appropriate, not to exceed serum levels of 1.2mEq/L. The sample will be evaluated longitudinally using a wide range of clinical scales, cognitive assessments and laboratory tests. On relapse, patients will be discontinued or crossed-over to treatment with valproic acid (VPA) or treatment as usual (TAU). Relapse is defined as a DSM-IV manic, major depressive or mixed episode or if the treating physician decides a change in medication is clinically necessary. The sample will be genotyped for GWAS. The outcome for lithium response will be analyzed as a time to event, where the event is defined as clinical relapse, using a Cox Proportional Hazards model. Positive single nucleotide polymorphisms (SNPs) from past genetic retrospective studies of lithium response, the Consortium on Lithium Genetics (ConLiGen), will be tested in this prospective study sample a meta-analysis of these samples will then 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. SNPs in genes identified in these cellular studies will also be tested for association to response. Discussion: Lithium is an extraordinarily important therapeutic drug in the clinical management of patients suffering from bipolar disorder. However, a significant proportion of patients, 30-40%, fail to respond, and there is currently no method to identify the good lithium responders before initiation of treatment. Converging evidence suggests that genetic factors play a strong role in the variation of response to lithium, but only a few genes have been tested and the samples have largely been retrospective or quite small. The current study will collect an entirely unique sample of 700 patients with bipolar disorder to be stabilized on lithium monotherapy and followed for up to 2years. This study will produce useful information to improve the understanding of the mechanism of action of lithium and will add to the development of a method to predict individual response to lithium, thereby accelerating recovery and reducing suffering and cost. Trial registration: ClinicalTrials.gov Identifier: NCT01272531Registered: January 6, 2011.

AB - Background: Bipolar disorder is a serious and common psychiatric disorder characterized by manic and depressive mood switches and a relapsing and remitting course. The cornerstone of clinical management is stabilization and prophylaxis using mood-stabilizing medications to reduce both manic and depressive symptoms. Lithium remains the gold standard of treatment with the strongest data for both efficacy and suicide prevention. However, many patients do not respond to this medication, and clinically there is a great need for tools to aid the clinician in selecting the correct treatment. Large genome wide association studies (GWAS) investigating retrospectively the effect of lithium response are in the pipeline however, few large prospective studies on genetic predictors to of lithium response have yet been conducted. The purpose of this project is to identify genes that are associated with lithium response in a large prospective cohort of bipolar patients and to better understand the mechanism of action of lithium and the variation in the genome that influences clinical response. Methods/Design: This study is an 11-site prospective non-randomized open trial of lithium designed to ascertain a cohort of 700 subjects with bipolar I disorder who experience protocol-defined relapse prevention as a result of treatment with lithium monotherapy. All patients will be diagnosed using the Diagnostic Interview for Genetic Studies (DIGS) and will then enter a 2-year follow-up period on lithium monotherapy if and when they exhibit a score of 1 (normal, not ill), 2 (minimally ill) or 3 (mildly ill) on the Clinical Global Impressions of Severity Scale for Bipolar Disorder (CGI-S-BP Overall Bipolar Illness) for 4 of the 5 preceding weeks. Lithium will be titrated as clinically appropriate, not to exceed serum levels of 1.2mEq/L. The sample will be evaluated longitudinally using a wide range of clinical scales, cognitive assessments and laboratory tests. On relapse, patients will be discontinued or crossed-over to treatment with valproic acid (VPA) or treatment as usual (TAU). Relapse is defined as a DSM-IV manic, major depressive or mixed episode or if the treating physician decides a change in medication is clinically necessary. The sample will be genotyped for GWAS. The outcome for lithium response will be analyzed as a time to event, where the event is defined as clinical relapse, using a Cox Proportional Hazards model. Positive single nucleotide polymorphisms (SNPs) from past genetic retrospective studies of lithium response, the Consortium on Lithium Genetics (ConLiGen), will be tested in this prospective study sample a meta-analysis of these samples will then 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. SNPs in genes identified in these cellular studies will also be tested for association to response. Discussion: Lithium is an extraordinarily important therapeutic drug in the clinical management of patients suffering from bipolar disorder. However, a significant proportion of patients, 30-40%, fail to respond, and there is currently no method to identify the good lithium responders before initiation of treatment. Converging evidence suggests that genetic factors play a strong role in the variation of response to lithium, but only a few genes have been tested and the samples have largely been retrospective or quite small. The current study will collect an entirely unique sample of 700 patients with bipolar disorder to be stabilized on lithium monotherapy and followed for up to 2years. This study will produce useful information to improve the understanding of the mechanism of action of lithium and will add to the development of a method to predict individual response to lithium, thereby accelerating recovery and reducing suffering and cost. Trial registration: ClinicalTrials.gov Identifier: NCT01272531Registered: January 6, 2011.

KW - Bipolar disorder

KW - GWAS

KW - Lithium

KW - Mood stabilizer

KW - Personalized medicine

KW - Pharmacogenetics

KW - Precision medicine

KW - Prospective trial

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