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: 8283631
• 负责人: CHARLES LEE BOWDEN
• 金额: $ 18.64万
• 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 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8283631
• 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. PUBLIC HEALTH RELEVANCE: The goals of this calcium biomarker study conducted as part of a comparative effectiveness study of over 400 clinically ill bipolar patients are to improve prediction of treatment outcomes, aid psychiatrists in selecting a treatment regimen most likely to be effective for an individual bipolar patient and improve the validity of diagnosis of bipolar disorder. The research will result in more personalized and overall effective treatments and outcomes of bipolar disorder.

描述（由申请人提供）：本提案的总体目标是 1) 制备和储存来自 480 名临床双相情感障碍患者的类淋巴母细胞 (LCL) 和血浆，用于未来的实验；2) 使用 LCL 来表征 LCL 中的钙活性， a) 预测治疗结果，b) 提供信息帮助精神科医生选择最有可能对个体双相情感障碍患者有效的治疗方案，以及 c) 有助于更可靠地对双相情感障碍进行有效诊断紊乱。该研究将为双相情感障碍（BD）带来更加个性化和全面有效的治疗和结果。为了实现这些目标，我们建议从参与双极 CHOICE 试验的患者中额外抽取血液。 2010 年 12 月至 2013 年期间，拥有 10 个站点的双极 CHOICE 网络正在进行 BD 迄今为止规模最大的前瞻性随机比较有效性研究。还将对八十名健康对照受试者进行测试，以帮助区分钙测量的阈值，这些阈值可能与双相情感障碍诊断相关，或与无双相情感障碍的人自然发生的水平预测治疗反应。这些研究将测试从血液样本中建立的细胞系中基于证据的生物标志物（在类似于人脑功能中自然存在的化学物质刺激时进行的钙实验室测试）是否可以预测对两种情绪稳定剂（锂和喹硫平）产生反应的可能性在双相选择研究中进行比较。还将研究钙测试结果，以确定其作为建立双相情感障碍的有效诊断和解释双相情感障碍的主要紊乱症状（例如冲动、情绪快速变化、睡眠障碍）的附加标准的效用。这些目标中的每一个都服务于我们开发更加个性化的双相情感障碍治疗方法的务实目标。 这项拟议的辅助钙信号传导研究的独特优势在于使用 NIMH 医疗保健研究和质量机构资助的研究中的双极 CHOICE 样本，该样本将提供全方位的参与者和结果，确保结果可推广到实际情况临床护理。仅额外需要进行生物标志物钙信号传导研究的费用； AHRQ 奖项全额资助了 480 名患者、随机、为期 6 个月的有效性比较研究。为了加强招募，最大限度地减少选择和志愿者偏见，并最大限度地提高保留率，除了随机药物外，每个小组还将接受辅助个性化治疗，以管理特定的情绪状态和共病。 BD 是一种终生、慢性且高度复发的情绪障碍，其特征是躁狂或轻躁狂发作以及抑郁发作。全谱双相情感障碍的终生患病率约为 4.5%，一半患者报告其在 14 岁时发病，遗传性估计为 80%。这种高度的人类痛苦和慢性负担使双相情感障碍成为全球十大致残原因之一，直接和间接损失估计达 706 亿美元 2008 年美国每年。 喹硫平与锂的双极 CHOICE 研究符合测试治疗效果生物标志物的所有相关标准。这些标准包括可以通过生物标志物清楚区分患者的证据、将生物标志物与所研究的疾病和治疗方法联系起来的证据基础以及对一组的益处的预测。了解分子水平上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，从而更精确地针对更明确的个体群体进行干预。这种潜力有时被称为个性化医疗，对比较有效性研究有很大影响。 公共健康相关性：这项钙生物标志物研究是对 400 多名临床双相情感障碍患者进行的比较有效性研究的一部分，目的是改善对治疗结果的预测，帮助精神科医生选择最有可能对个体双相情感障碍有效的治疗方案患者并提高双相情感障碍诊断的有效性。该研究将为双相情感障碍带来更加个性化和全面有效的治疗和结果。