The Pharmacogenomics of Bipolar Disorder study (PGBD): identification of genes for lithium response in a prospective sample

Abstract

BackgroundBipolar 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/DesignThis 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.DiscussionLithium is an extraordinarily important therapeutic drug in the clinical mana...

Distinct lithium-induced gene expression effects in lymphoblastoid cell lines from patients with bipolar disorder

“…This goes along with the increasing body of evidence suggesting a key role of pharmacogenetics in the response to lithium (Pisanu et al, 2016a). Accordingly, different, more homogeneous phenotypes have been identified within patients regarding their likelihood of showing an adequate response to lithium treatment (responders vs. nonresponders) (Geoffroy et al, 2017; Oedegaard et al, 2016; Scott et al, 2017; Sportiche et al, 2016), and the genetic basis of lithium responsiveness has been consistently shown by several studies (Alda, 2015; Alda et al, 2005; Grof et al, 2009; Grof et al, 2002; Hou et al, 2016). This is also supported by in vitro studies performed with LCLs, in which lithium has been shown to exert specific effects based on the donor’s treatment responsiveness (Hunsberger et al, 2015; Milanesi et al, 2015; Squassina et al, 2013).…”

Don’t stress about CRF: assessing the translational failures of CRF1antagonists

“…Additionally, in general, individual genetic variants are associated with a low percentage of psychiatric disease prevalence. Furthermore, with only a few recent exceptions (see Clarke et al 2014, Crist et al 2016, Crist et al 2013 Heinzerling et al 2013) genetic variants have not yet reliably and reproducibly predicted treatment response in psychiatric diseases (Jones and Comer 2015 Berrettini 2016 Qedegaard et al 2016) A molecular, and not only phenotype-based, understanding, of a variant’s functional effect (if any) may ultimately be needed to understand its prognostic relation to CRF 1 antagonist treatment response.…”

Entrainment of Circadian Rhythms to Temperature Reveals Amplitude Deficits in Fibroblasts from Patients with Bipolar Disorder and Possible Links to Calcium Channels

“…Established cell lines were frozen in cryovials and stored in liquid nitrogen until use. BD subjects were evaluated in detail as described previously [23]. The majority of BD cell line donors (95%) were of Caucasian ancestry.…”

“…Skin biopsies were obtained from healthy controls or deidentified patients with BD type I who consented to research while participating in the Pharmacogenomics of Bipolar Disorder (PGBD) trial [23]. The majority of the donors were Caucasian, and most BD patients were on medication at the time of the biopsy.…”