Genetic Predictors of Lithium Response in Bipolar Disorder

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障碍，其特征是躁狂和抑郁的极端情绪状态之间的交替。有许多有效的治疗方法；然而，个体反应有很大的变异性。这经常导致治疗优化的漫长试验和错误过程，这可能需要数年时间。锂是第一种稳定情绪的药物，现在仍然是治疗的黄金标准。现有数据表明，锂敏感型双相情感障碍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。这些患者往往有双相情感障碍的家族史，表现为欣快而不是易怒的躁狂。锂的反应也被证明是家族性的。该项目的目标一直是确定与双相情感障碍患者对锂的反应相关的基因。在上一个资助期，我们对184名患者进行了回顾性评估，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编码TrkB受体，它是BDNF的受体，也与双相情感障碍有关。我们发现NTRK2基因中的SNPs与快乐性躁狂症患者对锂的反应有关，而与易怒躁狂症患者无关。相反，磷酸二酯酶PDE11A基因与所有形式的躁狂症的反应有关。这些数据支持这样的观点，即锂敏感型双相情感障碍在基因上是不同的。回溯性数据有很多局限性。出于这个原因，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接受为期三个月的锂单一疗法的稳定治疗，然后进入研究的维持阶段。然后对患者进行为期两年的跟踪调查，以发现患者是否复发为躁狂或抑郁。使用生存曲线分析测试SNPs与复发时间测量的反应的关联性。到目前为止，已有75名受试者进入了该方案。在这次更新中，我们建议：1)将回溯样本扩大到500名受试者；2)在回溯样本中增加50个基因；3)在预期样本中再招募125名受试者，总共200个；以及4)在预期样本中复制回溯样本中最重要的SNP。 公共卫生相关性： 项目简介：双相情感障碍是一种常见的精神障碍，其特征是躁狂和抑郁的极端情绪状态之间的交替。尽管它影响了1-3%的退伍军人，但从伊拉克回国的退伍军人中，这一比例可能会高出几倍。有几种好的治疗方法，但对不同药物的反应有很高的变异性，因为治疗往往是一个漫长的试验和错误过程。这项研究的目标是确定与锂在双相情感障碍中的良好治疗反应相关的遗传变异。这项研究的结果可以用来开发一种基于DNA的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。

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.