Pharmacogenomics of Mood Stabilizer Response in Bipolar Disorder

双相情感障碍情绪稳定剂反应的药物基因组学

• 批准号: 8509307
• 负责人: John R. Kelsoe
• 金额: $ 6.24万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-10 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8509307
• 关键词: Biopsy; Bipolar Disorder; Cell Culture Techniques; Cells; Collaborations; Collection; Data; Disease; Fibroblasts; Gene Expression; Genes; Genetic; Genetic Crossing Over; Genomics; Genotype; Goals; Human; In Vitro; Individual; Instruction; Lead; Lithium; Maintenance; Meta-Analysis; Modeling; Molecular Profiling; Mood stabilizers; Multicenter Trials; NTRK2 gene; Neurons; Outcome Measure; Pathway Analysis; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacogenomics; Phase; Phenotype; Physicians; Process; Prospective Studies; Recontacts; Recording of previous events; Recruitment Activity; Relapse; Relative (related person); Research Institute; Retrospective Studies; Sampling; Site; Skin; Surveys; Testing; Time; Treatment outcome; Valproic Acid; arm; design; disorder later incidence prevention; genetic variant; genome wide association study; genome-wide; human data; induced pluripotent stem cell; nerve stem cell; phosphodiesterase 11a; primary outcome; prospective; response; treatment as usual

DESCRIPTION (provided by applicant): Mood stabilizer treatment is central to the pharmacological management of patients with bipolar disorder. However, response to such agents is highly variable between individuals often resulting in a lengthy trial and error process of medication optimization that can last years. There is a great need for a better predictor of response which would guide physicians to the optimum medication in a more efficient fashion. Genetic differences likely explain a substantial portion of this variability. The goal of this project is to identify genetic variants that are associated with response to mood stabilizer medications that might ultimately be useful as a predictive test. Studies to date by our group have implicated two genes, NTRK2 and PDE11A as predicting response to lithium. In this project, we propose a two pronged approach: genes will first be sought in an exploratory fashion in a larger retrospective sample and then tested for replication in a smaller prospective sample. Larger samples are more easily obtainable in a retrospective study, however, prospective designs though more difficult, provide better and more quantitative data. Our 11 site consortium has recently completed collection of over 4,500 bipolar subjects for a large genetic study. 2,000 retrospective subjects will be collected from both recontact of these previous cases and recruitment of new retrospective cases. The prospective sample of 960 subjects will be collected through an eight site multicenter trial. Patients will be recruited, screened and stabilized first on lithium monotherapy over a 3 month period. After one month observation, they will enter the maintenance phase and followed for 2 years. The primary outcome measure will be time to relapse. Patients who fail lithium will be crossed over to valproic acid, those failing both drugs will enter the treatment as usual arm. Genomewide association will be performed on the retrospective sample and positive SNPs replicated in the prospective sample. Secondary analyses will include genomewide association ofthe prospective sample alone and in meta-analysis with the retrospective sample. These analyses will be guided in part by studies of lithium's mechanism of action in neuronal cells derived from induced pluripotent stem cells in turn derived from skin fibroblasts from lithium responders and non-responders. RELEVANCE (See instructions): This multi-site collaborative project aims to identify genetic variants in individuals with bipolar disorder that predict response to lithium. We will do this with a combination of retrospective assessment of lithium response in 1600 individuals with BP disorder and analysis of genotype data, as well as a prospective study of 1000 BP individuals who begin an open trial with lithium. Our hypothesis is that genetic variants at several loci predict treatment outcomes with lithium.

描述（由申请人提供）： 情绪稳定剂治疗对躁郁症患者的药理管理至关重要。但是，对这种药物的反应是个体之间的高度变化，通常会导致可以持续几年的药物优化的长期试验和错误过程。非常需要更好地预测反应指标，这将以更有效的方式指导医生到最佳药物。遗传差异可能解释了这种变异性的很大一部分。该项目的目的是确定与对情绪稳定药物的反应相关的遗传变异，这些变异最终可能是预测性测试。迄今为止，我们小组的研究暗示了两个基因NTRK2和PDE11a是预测对锂的反应。在这个项目中，我们提出了一种两种统治方法：首先以较大的回顾性样本以探索性方式寻求基因，然后在较小的前瞻性样本中测试复制。在回顾性研究中，更容易获得较大的样本，但是，前瞻性设计虽然更加困难，但提供了更好，更定量的数据。我们的11个地点财团最近完成了4,500多名双极受试者的收集，以进行大型遗传研究。从这些先前病例的重新连接以及招募新的回顾性案件中，将收集2,000名回顾性受试者。 960名受试者的前瞻性样本将通过八个站点多中心试验收集。将在3个月内首先在锂单药治疗上招募，筛查和稳定患者。经过一个月的观察，他们将进入维护阶段，然后进行2年。主要结果度量将是该复发的时间。失败锂的患者将越过丙戊酸，两种药物失败的患者将像往常一样进入治疗。全基因组的关联将在回顾性样本上进行，并在前瞻性样本中复制的阳性SNP进行。次级分析将包括单独的前瞻性样本和荟萃分析与回顾性样本的全基因组关联。这些分析将部分通过研究锂在诱导的多能干细胞衍生的神经元细胞中的作用机理，反过来又来自于锂反应者和非反应者的皮肤成纤维细胞。相关性（请参阅说明）：这个多站点的协作项目旨在识别躁郁症患者的遗传变异，以预测对锂反应的反应。我们将通过回顾性评估锂反应的回顾性评估和对基因型数据分析的分析以及对1000个BP个体开始使用锂进行开放试验的前瞻性研究的回顾性评估。我们的假设是，几个基因座的遗传变异预测锂的治疗结果。