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, 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, 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, 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

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 1.2 mEq/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 2 years. 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: NCT01272531 Registered: January 6, 2011.

Keywords: Bipolar disorder; GWAS; Lithium; Mood stabilizer; Personalized medicine; Pharmacogenetics; Precision medicine; Prospective trial.

Figures

Fig. 1
Fig. 1
iPSC-derived neurons as a cellular model of bipolar disorder and lithium response. Fibroblasts are grown from skin biopsies taken from participating subjects. These cells are treated with a combination of four transcription factors that reprogram the cells to stem cells. These iPSCs are then treated with a series of growth factors to differentiate them into a variety of neuronal types. In this way, neurons from patients can be compared to controls or lithium responders to non-responders
Fig. 2
Fig. 2
Using cellular phenotypes to identify likely lithium-responsive genes. To reduce the number of comparisons and preserve statistical power, iPSC-derived neurons will be used to identify a smaller number of genes likely to be involved in lithium’s action. iPSC-derived neurons from lithium responders and non-responders will be treated both with and without lithium. RNAseq will be conducted and genes sought whose expression changes in responders but not non-responders. These genes will comprise a limited number of a priori hypotheses for initial testing
Fig. 3
Fig. 3
Power of survival analysis as a function of hazard ratio and allele frequency for 700 subjects. Power analyses indicate that a sample of 700 subjects will have about 80 % power to detect a hazard ratio of 1.4

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