Calcium Study of Lymphoblasts in Bipolar Patients to Aid Diagnosis and Treatment

双相情感障碍患者淋巴细胞的钙研究有助于诊断和治疗

• 批准号: 8462688
• 负责人: CHARLES LEE BOWDEN
• 金额: $ 21.53万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-25 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8462688
• 关键词: Adverse effects; Age of Onset; Agonist; Am 80; Award; Benefits and Risks; Biological; Biological Markers; Bipolar Disorder; Blood; Blood specimen; Brain; Calcium; Calcium Signaling; Cells; Chemicals; Chronic; Circadian Rhythms; Clinical; Controlled Study; Diagnosis; Diagnostic; Direct Costs; Disease; Disease remission; Effectiveness; Facilities and Administrative Costs; Functional disorder; Funding; Future; Goals; Health Services Research; Heritability; Human; Impulsivity; Individual; Intervention; Investigation; Laboratories; Lead; Life; Link; Lithium; Lymphocyte; Major Depressive Disorder; Manic; Measurement; Measures; Medical Technology; Medicine; Mental Depression; Mental Health; Molecular; Molecular Target; Mood Disorders; Mood stabilizers; Moods; National Institute of Mental Health; Neurons; Onset of illness; Outcome; Participant; Patients; Persons; Pharmaceutical Preparations; Pharmacogenomics; Plasma; Plasma Cells; Prevalence; Process; Psychiatrist; Randomized; Recurrence; Reporting; Research; Sampling; Sensitivity and Specificity; Signal Transduction; Single Nucleotide Polymorphism; Site; Sleep disturbances; Stress; Symptoms; Test Result; Testing; Thyroid Function Tests; Treatment Effectiveness; Treatment Efficacy; Treatment Protocols; Treatment outcome; Tremor; United States; United States Agency for Healthcare Research and Quality; United States National Institutes of Health; biobank; calcium indicator; calcium metabolism; clinical care; comparative effectiveness; cost; disability; effective therapy; effectiveness research; established cell line; evidence base; expectation; health care quality; hypomania; improved; indexing; lymphoblast; lymphoblastoid cell line; meetings; non-drug; novel; prospective; quetiapine; research study; resilience; response; treatment response; valproate; volunteer

DESCRIPTION (provided by applicant): The overall aims of this proposal are to 1) prepare and store lymphoblastoid cells (LCLs) and plasma from 480 clinically ill bipolar patients for future experiments and 2) use the LCLs to characterize calcium activity in the LCLs to a) predict treatment outcomes, b) provide information to aid psychiatrists in selecting a treatment regimen most likely to be effective for an individual bipolar patient and c) contribute to more reliable an valid diagnosis of bipolar disorder. The research will result in more personalized and overall effective treatments and outcomes of bipolar disorder (BD). To accomplish these aims, we propose an additional blood draw from patients participating in the Bipolar CHOICE Trial. The 10 site Bipolar CHOICE Network is conducting between December 2010 and 2013 the largest prospective randomized comparative effectiveness study in BD to date. Eighty healthy control subjects will also be tested to aid in differentiating the threshold values of the calcium measurements that may be diagnostically associated with bipolar disorder or predictive of treatment responses from levels that occur naturally in persons without bipolar disorder. The studies will test whether evidence based biomarkers (calcium laboratory tests conducted when stimulated by chemicals similar to ones occurring naturally in human brain function) in cell lines established from a blood sample predict the likelihood of response to the two mood stabilizers (lithium and quetiapine) being compared in the Bipolar CHOICE study. The calcium test results will also be studied to determine their utility as an additional criterion in establishing a valid diagnosis of bipolar disorder and in explaining the principal disturbed symptoms that characterize bipolar disorders (e.g., impulsivity, rapidly shifting moods, sleep disturbances). Each of these objectives serves our pragmatic goal of developing more personalized treatments for bipolar disorder. A unique strength of this proposed adjunctive calcium signaling investigation resides in using the Bipolar CHOICE sample in the NIMH Agency for Healthcare Research and Quality funded study, which will provide a full spectrum of participants and of outcomes, insuring that the results will be generalizable to actual clinical care. Only the costs o conducting the biomarker calcium signaling studies will be additionally required; the AHRQ award fully funds the 480 patient, randomized, 6 month duration comparative effectiveness study. To enhance recruitment, minimize selection and volunteer bias, and maximize retention, in addition to randomized medications, each group will have adjunctive personalized treatment to manage specific mood states and comorbid conditions. BD is a lifelong, chronic and highly recurrent mood disorder characterized by episodes of mania or hypomania as well as episodes of depression. The full spectrum of bipolar disorder has a lifetime prevalence of approximately 4.5% with half of patients reporting their onset by age 14 and heritability estimated to be 80%. This high degree of human suffering and chronic burden has placed bipolar disorder among the top 10 causes of disability worldwide, with direct and indirect costs estimated to be $70.6 billion per year in 2008 dollars in the United States. The Bipolar CHOICE study of quetiapine vs. lithium meets all pertinent criteria for testing biomarkers of treatment effectiveness. These criteria include evidence that patients can be clearly differentiated by the biomarker, an evidence base linking the biomarker both to the disease and treatment studied and prediction of benefit for one group. Understanding biological differences at the molecular level could transform our ability to use and develop medical technologies more effectively, targeting interventions at more defined groups of individuals with greater precision. This potential, sometimes referred to as personalized medicine, has strong bearing on comparative effectiveness research.

描述（由申请人提供）：该提案的总体目的是1）准备和存储来自480名临床双极患者的480名临床双极患者的淋巴母细胞（LCLS）和血浆，用于将来的实验和2）使用LCLS在LCL中表征LCLS的钙活性来表征LCL的钙活性，以预测a的治疗方法，b）在精神病患者方面，b）b）在精神病患者方面，b）b）在精神病患者方面，b）在精神病患者方面有效地提高了精神病患者的范围​​，以促进精神病患者的范围​​。有助于更可靠的对躁郁症的有效诊断。这项研究将导致躁郁症（BD）更具个性化和整体的有效疗法和结果。为了实现这些目标，我们提出了参加双极选择试验的患者的额外抽血。 2010年12月至2013年12月至迄今为止，在2010年12月至2013年12月至2013年之间进行了10个现场双极选择网络。还将对80名健康对照受试者进行测试，以帮助区分钙测量值的阈值，这些钙测量值可能与双相情感障碍诊断有关，或者可以预测自然存在于没有双相情感障碍的人的水平上的治疗反应。该研究将测试在双极选择研究中比较从血液样本确定的细胞系中基于证据的生物标志物（钙实验室测试，当时是通过血液样本确定的细胞系中的化学物质进行刺激时进行的，类似于人脑功能中的化学物质类似于人类脑功能中发生的化学物质（类似于人类脑功能中发生的化学物质）的细胞系（liThium and quetiapine）的可能性。还将研究钙测试结果，以确定它们的效用，作为建立有效诊断躁郁症的其他标准，并解释了表征双相情感障碍（例如冲动性，迅速转移的情绪，睡眠障碍）的主要干扰症状时。这些目标中的每一个都实现了我们的务实目标，即开发更多个性化的双相情感障碍治疗方法。 这项提出的辅助钙信号调查的独特强度在于使用NIMH医疗研究和质量资助的研究中使用双极选择样品，该样本将提供全部参与者和结果，确保结果可以推广到实际临床护理。仅需要进行生物标志物钙信号研究的成本o； AHRQ奖为480名患者，随机，6个月的比较有效性研究提供了全额资金。为了增强招聘，最大程度地减少选择和志愿者偏见并最大化保留率，除了随机药物外，每组还将进行辅助的个性化治疗方法，以管理特定的情绪状态和合并症。 BD是一种终生，慢性和高度复发的情绪障碍，其特征是躁狂或躁狂症发作以及抑郁症发作。躁郁症的全频率大约为4.5％，一半的患者报告了14岁的发作，遗传力估计为80％。这种高度的人类痛苦和慢性负担使躁郁症置于全球残疾的十大原因之列，直接和间接费用估计为706亿美元 2008年每年在美国。 喹硫平与锂的双极选择研究符合所有相关标准，用于测试治疗有效性的生物标志物。这些标准包括证据表明，可以通过生物标志物明确区分患者，这是将生物标志物与疾病和研究的治疗联系在一起的证据基础，并预测了一组的利益。理解分子水平的生物学差异可以改变我们更有效地使用和开发医疗技术的能力，以更精确的个人为目标。这种潜力有时被称为个性化医学，对比较有效性研究有很大的影响。

项目成果

Distinct lithium-induced gene expression effects in lymphoblastoid cell lines from patients with bipolar disorder.

• DOI: 10.1016/j.euroneuro.2017.09.003
• 发表时间: 2017-11
• 期刊: European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology
• 作者: Fries GR;Colpo GD;Monroy-Jaramillo N;Zhao J;Zhao Z;Arnold JG;Bowden CL;Walss-Bass C
• 通讯作者: Walss-Bass C