Genetic Predictors of Lithium Response in Bipolar Disorder

双相情感障碍锂反应的遗传预测因素

• 批准号: 7931543
• 负责人: John R. Kelsoe
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-10-01 至 2015-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7931543
• 关键词: Adopted; Bipolar Disorder; Candidate Disease Gene; Clinical Trials; Code; Communities; DNA; Data; Disease Pathway; Double-Blind Method; Drug Delivery Systems; Family history of; Funding; Genes; Genetic; Genetic Variation; Genotype; Goals; Gold; Individual; Lithium; Maintenance; Manic; Measures; Mental Depression; Mental disorders; Moods; NTRK2 gene; Neurotrophic Tyrosine Kinase Receptor Type 2; Outcome Measure; Patients; Pharmaceutical Preparations; Pharmacogenetics; Phase; Phenotype; Process; Protocols documentation; Psychiatry; Randomized; Recruitment Activity; Relapse; Sampling; Series; Staging; Testing; Therapeutic; Time; abstracting; base; design; disorder later incidence prevention; novel; phosphodiesterase 11a; primary outcome; prospective; response; standard care

DESCRIPTION (provided by applicant): Project Abstract Bipolar Disorder is a major psychiatric disorder characterized by alternation between the extreme mood states of mania and depression. Many efficacious treatments exist; however, there is a high degree of variability in individual response. This frequently results in a lengthy trial and error process of treatment optimization which may take years. Lithium was the first mood stabilizing medication and is still the gold standard for treatment. Existing data suggests that lithium responsive bipolar disorder may be a distinct form of illness. There is a subset of patients who have a remarkably good response to lithium. These patients tend to have a family history of bipolar disorder and present with euphoric rather than irritable mania. Lithium response has also been shown to be familial. The goal of this project has been the identification of genes associated with response to lithium in bipolar disorder. In the last funding period, we studied a series of candidate genes in our retrospectively assessed sample of 184 patients. These studies found evidence for two genes predicting response to lithium. NTRK2 codes for the trkb receptor which is the receptor for BDNF also implicated in bipolar disorder. We found SNPs in the NTRK2 gene that were associated with response to lithium in those with euphoric mania but not associated in those with irritable mania. Conversely, the gene for the phosphodiesterase PDE11A was associated with response for all forms of mania. These data support the idea that lithium responsive bipolar disorder is genetically distinct. Retrospective data has numerous limitations. For this reason, we have also conducted a prospective clinical trial of lithium in bipolar disorder. Patients with bipolar disorder are first stabilized on lithium monotherapy over a three month period and then entered into the maintenance phase of the study. Patients are then followed for 2 years in order to detect relapse into mania or depression. SNPs are tested for association to response measured as time to relapse using a survival curve analysis. 75 subjects have entered the protocol to date. In this renewal, we propose to: 1) expand the retrospective sample to 500 subjects; 2) genotype the retrospective sample at an additional 50 genes; 3) recruit an additional 125 subjects into the prospective sample for a total of 200 and 4) replicate the most significant SNPs from the retrospective sample in the prospective sample. PUBLIC HEALTH RELEVANCE: Project Narrative: Bipolar disorder is a common psychiatric disorder characterized by alternation between the extreme mood states of mania and depression. Though it affects 1 - 3% of veterans overall, the rate may be several fold higher for combat exposed veterans returning from Iraq. Several good treatments exist, but there is a high variability in response to different medications in that treatment is often a lengthy trial and error process. The goal of this study is to identify genetic variation that is associated with a good therapeutic response to lithium in bipolar disorder. The results of this study could be used to develop a DNA based predictor of response to different medications. This could aid clinicians in the selection of medications and lead to faster stabilization and reduced suffering of veterans.

描述（由申请人提供）： 项目摘要 双相情感障碍是一种主要的精神疾病，其特征是躁狂和抑郁两种极端情绪状态之间的交替。存在许多有效的治疗方法；然而，个体反应存在很大程度的差异。这通常会导致治疗优化的漫长试错过程，可能需要数年时间。锂是第一种稳定情绪的药物，并且仍然是治疗的黄金标准。现有数据表明，锂反应性双相情感障碍可能是一种独特的疾病形式。有一部分患者对锂的反应非常好。这些患者往往有双相情感障碍家族史，并表现为欣快型躁狂而不是烦躁性躁狂。锂反应也被证明具有家族性。该项目的目标是鉴定与躁郁症患者对锂反应相关的基因。在上一个资助期间，我们在 184 名患者的回顾性评估样本中研究了一系列候选基因。这些研究发现了两个基因预测对锂的反应的证据。 NTRK2 编码 trkb 受体，该受体是 BDNF 的受体，也与双相情感障碍有关。我们发现 NTRK2 基因中的单核苷酸多态性 (SNP) 与欣快性躁狂患者对锂的反应相关，但与烦躁性躁狂患者的锂反应无关。相反，磷酸二酯酶 PDE11A 基因与所有形式的躁狂症反应相关。这些数据支持锂反应性双相情感障碍具有独特遗传性的观点。回顾性数据有很多局限性。为此，我们还进行了锂治疗双相情感障碍的前瞻性临床试验。双相情感障碍患者首先通过锂单药疗法在三个月内稳定下来，然后进入研究的维持阶段。然后对患者进行两年的随访，以检测是否复发为躁狂或抑郁。使用生存曲线分析测试 SNP 与以复发时间测量的反应的关联。迄今为止，已有 75 名受试者进入该方案。在本次更新中，我们建议：1）将回顾性样本扩大到500名受试者； 2) 对回顾性样本另外 50 个基因进行基因分型； 3) 在前瞻性样本中再招募 125 名受试者，总数为 200 名；4) 将回顾性样本中最显着的 SNP 复制到前瞻性样本中。 公共卫生相关性： 项目叙述：双相情感障碍是一种常见的精神疾病，其特征是躁狂和抑郁两种极端情绪状态之间的交替。虽然它影响了 1-3% 的退伍军人，但对于从伊拉克返回的经历过战斗的退伍军人来说，这一比例可能要高出几倍。存在几种好的​​治疗方法，但对不同药物的反应存在很大差异，因为治疗通常是一个漫长的试错过程。本研究的目的是确定与双相情感障碍患者对锂的良好治疗反应相关的遗传变异。这项研究的结果可用于开发基于 DNA 的对不同药物反应的预测因子。这可以帮助临床医生选择药物，并导致退伍军人更快稳定并减少痛苦。