Genetic Predictors of Lithium Response in Bipolar Disorder

双相情感障碍锂反应的遗传预测因素

基本信息

  • 批准号:
    7931543
  • 负责人:
  • 金额:
    --
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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。

项目成果

期刊论文数量(0)
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John R. Kelsoe其他文献

92. Synaptic Protein Expression in Bipolar Disorder Patient-Derived Glutamatergic Neurons Implicates PSD-95 as a Marker of Lithium Response
双相情感障碍患者来源的谷氨酸能神经元中的突触蛋白表达表明PSD - 95可作为锂反应的标志物
  • DOI:
    10.1016/j.biopsych.2025.02.329
  • 发表时间:
    2025-05-01
  • 期刊:
  • 影响因子:
    9.000
  • 作者:
    Johansen Amin;Kayla E. Rohr;Himanshu K. Mishra;Timothy Nakhla;John R. Kelsoe;Michael J. McCarthy
  • 通讯作者:
    Michael J. McCarthy
Circadian Rhythms in Bipolar Disorder Patient-Derived Neurons Predict Lithium Response
  • DOI:
    10.1016/j.biopsych.2021.02.193
  • 发表时间:
    2021-05-01
  • 期刊:
  • 影响因子:
  • 作者:
    Himanshu Mishra;Noelle Ying;Angelica Luis;Heather Wei;Metta Nguyen;Timothy Nakhla;John R. Kelsoe;David Welsh;Michael McCarthy
  • 通讯作者:
    Michael McCarthy
A gene for impulsivity
一个冲动的基因
  • DOI:
    10.1038/4681049a
  • 发表时间:
    2010-12-22
  • 期刊:
  • 影响因子:
    48.500
  • 作者:
    John R. Kelsoe
  • 通讯作者:
    John R. Kelsoe
Lithium-Responsiveness in Bipolar Depression Patients Attenuates Circadian Rhythm Disturbances
  • DOI:
    10.1016/j.biopsych.2021.02.834
  • 发表时间:
    2021-05-01
  • 期刊:
  • 影响因子:
  • 作者:
    Monica Federoff;Mike McCarthy;John R. Kelsoe
  • 通讯作者:
    John R. Kelsoe
Synaptotagmin-7 is a key factor for bipolar-like behavioral abnormalities in mice
  • DOI:
    doi: 10.1073/pnas.1918165117.
  • 发表时间:
    2020
  • 期刊:
  • 影响因子:
  • 作者:
    Wei Shen;Qiu-Wen Wang;Yao-Nan Liu;Maria C. Marchetto;Sara Linker;Si-Yao Lu;Yun Chen;Chuihong Liu;Chongye Guo;Zhikai Xing;Wei Shi;John R. Kelsoe;Martin Alda;Hongwei Wang;Yi Zhong;Sen-Fang Sui;Mei Zhao;Yiming Yang;Shuangli Mi;Liping Cao;Fred H. Gage;Jun Yao
  • 通讯作者:
    Jun Yao

John R. Kelsoe的其他文献

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{{ truncateString('John R. Kelsoe', 18)}}的其他基金

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
  • 财政年份:
    2010
  • 资助金额:
    --
  • 项目类别:
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:
    8196309
  • 财政年份:
    2010
  • 资助金额:
    --
  • 项目类别:
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:
    8492162
  • 财政年份:
    2010
  • 资助金额:
    --
  • 项目类别:
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:
    8307029
  • 财政年份:
    2010
  • 资助金额:
    --
  • 项目类别:
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:
    8695486
  • 财政年份:
    2010
  • 资助金额:
    --
  • 项目类别:
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:
    8391087
  • 财政年份:
    2010
  • 资助金额:
    --
  • 项目类别:
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:
    7867605
  • 财政年份:
    2010
  • 资助金额:
    --
  • 项目类别:
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:
    8139260
  • 财政年份:
    2010
  • 资助金额:
    --
  • 项目类别:
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:
    8586871
  • 财政年份:
    2010
  • 资助金额:
    --
  • 项目类别:
ROLE OF DOPAMINE METABOLISM IN ANTIDEPRESSANT EFFECT OF SLEEP DEPRIVATION
多巴胺代谢在睡眠剥夺的抗抑郁作用中的作用
  • 批准号:
    7724899
  • 财政年份:
    2007
  • 资助金额:
    --
  • 项目类别:

相似国自然基金

双极性躁郁症(Bipolar Disorder)的人诱导多能干细胞模型的建立和神经病理研究
  • 批准号:
    31471020
  • 批准年份:
    2014
  • 资助金额:
    87.0 万元
  • 项目类别:
    面上项目

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ADMIRED - Ai Driven MonItoRing Equipment for Bipolar Disorder
钦佩 - 人工智能驱动的双相情感障碍监测设备
  • 批准号:
    10089421
  • 财政年份:
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  • 资助金额:
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  • 项目类别:
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Financial Activity Data as an Objective Behavioral Marker in Bipolar Disorder: A Feasibility and Acceptance Study
金融活动数据作为双相情感障碍的客观行为标志:可行性和可接受性研究
  • 批准号:
    10575894
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Co-designing a living umbrella review platform informing guidelines and care for bipolar disorder
共同设计一个生活伞审查平台,为双相情感障碍提供指导和护理
  • 批准号:
    487901
  • 财政年份:
    2023
  • 资助金额:
    --
  • 项目类别:
    Miscellaneous Programs
A study of molecular mechanisms of bipolar disorder focused on a novel splicing variant in mitochondria
双相情感障碍的分子机制研究重点关注线粒体中的新型剪接变异
  • 批准号:
    23K07017
  • 财政年份:
    2023
  • 资助金额:
    --
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Pilot trial of time restricted eating to support an adaptive innovative clinical trial of combined chronotherapies for mania in bipolar disorder
限时饮食试点试验,以支持双相情感障碍躁狂症联合时间疗法的适应性创新临床试验
  • 批准号:
    487676
  • 财政年份:
    2023
  • 资助金额:
    --
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    Operating Grants
Narrative enhancement and cognitive therapy for self-stigma as an early intervention for bipolar disorder: A mixed-methods randomized pilot trial
自我耻辱的叙事增强和认知治疗作为双相情感障碍的早期干预:一项混合方法随机试点试验
  • 批准号:
    487719
  • 财政年份:
    2023
  • 资助金额:
    --
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Affective and Cognitive Mechanisms of Emotion-Based Impulsivity in Bipolar Disorder: Linking Neural Oscillatory Dynamics to Real-World Outcomes
双相情感障碍中基于情绪的冲动的情感和认知机制:将神经振荡动力学与现实世界的结果联系起来
  • 批准号:
    10735028
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    --
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患有躁郁症的年轻人和典型发育的年轻人未来发生酒精使用障碍的生物危险因素
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Characterizing the Neural Profiles of Bipolar Disorder with and without Auditory Hallucinations
描述有或没有幻听的双相情感障碍的神经特征
  • 批准号:
    469790
  • 财政年份:
    2022
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Dual oscillator control of rest-activity rhythms and its relevance for cyclicity in bipolar disorder
休息活动节律的双振荡器控制及其与双相情感障碍周期性的相关性
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