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）： 项目摘要躁郁症是一种主要的精神疾病，其特征是躁狂和抑郁症的极端情绪状态之间的交替。存在许多有效的治疗方法；但是，个体反应有很高的可变性。这通常会导致长期的治疗优化过程，这可能需要数年。锂是第一个稳定药物的情绪，仍然是治疗的金标准。现有数据表明锂反应性躁郁症可能是一种不同的疾病形式。有一部分患者对锂的反应非常好。这些患者倾向于患有躁郁症的家族病史，并出现欣快而不是易怒的躁狂症。锂反应也已被证明是家族性的。该项目的目的是鉴定与躁郁症中对锂反应有关的基因。在最后的资金期间，我们在回顾性评估了184名患者的样本中研究了一系列候选基因。这些研究发现了两个预测锂反应的基因的证据。 NTRK2代码为TRKB受体，这是BDNF的受体，也与双相情感障碍有关。我们在NTRK2基因中发现SNP与欣快躁狂症的患者的反应有关，但在躁狂症患者中无关。相反，磷酸二酯酶PDE11a的基因与所有形式的躁狂症的反应有关。这些数据支持锂反应性躁郁症在遗传上与众不同的想法。回顾性数据有许多局限性。因此，我们还进行了二极化症中锂的前瞻性临床试验。首先在三个月内对锂单一疗法稳定患有躁郁症的患者，然后进入研究的维护阶段。然后跟踪患者2年，以检测到躁狂症或抑郁症的复发。测试了SNP与使用生存曲线分析的响应的关联，以测量作为复发的时间。迄今为止，已有75名受试者输入了协议。在此续约中，我们建议：1）将回顾性样本扩展到500名受试者； 2）基因型在另外50个基因上的回顾样本； 3）将额外的125名受试者招募到前瞻性样本中，总计200和4）复制前瞻性样本中回顾性样本中最重要的SNP。 公共卫生相关性： 项目叙事：躁郁症是一种常见的精神疾病，其特征是躁狂和抑郁症的极端情绪状态之间的交替。尽管它影响了总体退伍军人的1-3％，但对于从伊拉克返回的战斗暴露的退伍军人来说，速率可能会高出几倍。存在几种良好的治疗方法，但是在这种治疗中对不同药物的响应有很高的可变性，通常是一个漫长的试验和错误过程。这项研究的目的是确定与对二极性疾病中对锂的良好治疗反应有关的遗传变异。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指标。这可以帮助临床医生选择药物，并导致更快的稳定和减少退伍军人的痛苦。