The Pharmacogenomics of Bipolar Disorder study (PGBD): identification of genes for lithium response in a prospective sample.
The Pharmacogenomics of Bipolar Disorder study (PGBD): identification of genes for lithium response in a prospective sample.
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DOI：
10.1186/s12888-016-0732-x
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发表时间：
2016-05-05
期刊：
影响因子：
4.4
通讯作者：
Kelsoe JR
中科院分区：
文献类型：
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作者：
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
双相情感障碍是一种严重而常见的精神疾病，其特征是躁狂和抑郁情绪转换以及复发和缓解过程。临床管理的基石是稳定和预防使用情绪稳定药物，以减少躁狂和抑郁症状。锂仍然是治疗的金标准，在疗效和自杀预防方面都有最强的数据。然而，许多患者对这种药物没有反应，临床上非常需要工具来帮助临床医生选择正确的治疗方法。大型全基因组关联研究（GWAS）回顾性调查锂反应的影响正在进行中;然而，很少有关于锂反应遗传预测因子的大型前瞻性研究。该项目的目的是在一个大型前瞻性双相患者队列中鉴定与锂反应相关的基因，并更好地了解锂的作用机制和影响临床反应的基因组变异。本研究是一项11个中心的前瞻性非随机开放性锂试验，旨在确定700例双相I型障碍受试者的队列，这些受试者由于锂单药治疗而经历了方案定义的复发预防。所有患者将使用遗传学研究诊断访谈（DIGS）进行诊断，然后如果患者在前5周中的4周内双相情感障碍临床总体严重程度量表（CGI-S-BP总体双相情感障碍）评分为1分（正常，未患病）、2分（轻度患病）或3分（轻度患病），则将进入锂单药治疗的2年随访期。将根据临床需要滴定锂，不超过1.2 mEq/L的血清水平。将使用广泛的临床量表、认知评估和实验室检查对样本进行纵向评价。复发时，患者将停药或交叉至丙戊酸（VPA）治疗或常规治疗（TAU）。复发被定义为DSM-IV躁狂，重度抑郁或混合发作，或者如果治疗医生决定改变药物治疗是临床必要的。将对样本进行GWAS基因分型。将使用考克斯比例风险模型，将锂盐缓解的结局分析为至事件的时间，其中事件定义为临床复发。将在本前瞻性研究样本中检测锂反应的既往遗传回顾性研究（锂遗传学联盟（ConLiGen））中的阳性单核苷酸多态性（SNP）;然后将对这些样本进行荟萃分析。最后，神经元将来自锂反应者和非反应者的多能干细胞，并通过基因表达研究在体内测试对锂的反应。还将检测在这些细胞研究中鉴定的基因中的SNP与反应的关联。锂在双相情感障碍患者的临床管理中是一种非常重要的治疗药物。然而，相当大比例的患者（30- 40%）没有反应，目前还没有方法在开始治疗前确定良好的锂反应者。越来越多的证据表明，遗传因素在对锂的反应变化中起着重要作用，但只有少数基因得到了测试，而且样本在很大程度上是回顾性的或相当小。目前的研究将收集700名双相情感障碍患者的完全独特的样本，这些患者将接受锂单药治疗并随访长达2年。这项研究将产生有用的信息，以提高对锂作用机制的理解，并将有助于开发一种预测个人对锂反应的方法，从而加速康复，减少痛苦和成本。ClinicalTrials.gov标识符：NCT 01272531注册日期：2011年1月6日
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. 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. 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. ClinicalTrials.gov Identifier: NCT01272531 Registered: January 6, 2011