Genetic Predictors of Lithium Response in Bipolar Disorder

描述（由申请人提供）： 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的极端情绪状态之间的交替。存在许多有效的治疗方法;然而，个体反应存在高度变异性。这通常导致可能需要数年时间的漫长的治疗优化试错过程。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，锂反应性双相情感障碍可能是一种独特的疾病形式。有一小部分患者对锂有非常好的反应。这些患者往往有双相情感障碍的家族史，表现为欣快而非易激躁狂。锂反应也被证明是家族性的。该项目的目标是鉴定与双相情感障碍中锂反应相关的基因。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锂反应的证据。NTRK 2编码trkb受体，其是BDNF的受体，也涉及双相情感障碍。我们发现NTRK 2基因中的SNPs与欣快性躁狂症患者对锂的反应相关，但与易激性躁狂症患者无关。相反，磷酸二酯酶PDE 11 A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双相情感障碍在遗传上是不同的这一观点。回顾性数据有许多局限性。出于这个原因，我们还进行了锂在双相情感障碍中的前瞻性临床试验。患有双相情感障碍的患者首先在三个月的时间内稳定锂单药治疗，然后进入研究的维持阶段。然后对患者随访2年，以检测是否复发为躁狂或抑郁。使用存活曲线分析测试SNP与作为复发时间测量的响应的关联。迄今为止，已有75例受试者进入方案。在此次更新中，我们建议：1）将回顾性样本扩展至500例受试者; 2）在另外50个基因处对回顾性样本进行基因分型; 3）在前瞻性样本中招募另外125例受试者，总计200例; 4）在前瞻性样本中复制来自回顾性样本的最显著SNP。 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的极端情绪状态之间的交替。虽然它影响了1 - 3%的退伍军人，但从伊拉克返回的战斗暴露退伍军人的比例可能要高出几倍。有几种很好的治疗方法，但对不同药物的反应存在很大的差异，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锂治疗反应良好相关的遗传变异。这项研究的结果可以用来开发一个基于DNA的预测对不同药物的反应。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.