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

描述（由申请人提供）：该提案的总体目标是：1)准备和储存480名临床双相患者的淋巴母细胞样细胞（LCLs）和血浆，用于未来的实验；2)使用LCLs表征LCLs中的钙活性，以a)预测治疗结果；b)提供信息，帮助精神科医生选择最可能对个体双相患者有效的治疗方案；c)有助于更可靠和有效的双相情感障碍诊断。该研究将导致双相情感障碍（BD）更加个性化和全面有效的治疗和结果。为了实现这些目标，我们建议对参加双相选择试验的患者进行额外的抽血。2010年12月至2013年，双相选择网络（Bipolar CHOICE Network）开展了迄今为止最大的双相障碍前瞻性随机比较有效性研究。还将对80名健康对照受试者进行测试，以帮助区分可能与双相情感障碍诊断相关或预测治疗反应的钙测量阈值与非双相情感障碍患者自然发生的水平。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（当受到类似于人类大脑功能自然发生的化学物质刺激时进行的钙实验室测试）是否预测了双相选择研究中比较的两种情绪稳定剂（锂和喹硫平）的反应可能性。还将研究钙测试结果，以确定其作为建立双相情感障碍有效诊断和解释双相情感障碍特征的主要紊乱症状（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双相情感障碍更个性化治疗的务实目标。这项拟议的辅助钙信号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双相选择样本，该研究将提供完整的参与者和结果，确保结果将推广到实际的临床护理。只需要额外支付进行生物标志物钙信号研究的费用；AHRQ奖全额资助480名患者，随机，为期6个月的比较有效性研究。为了加强招募，减少选择和志愿者偏见，并最大限度地保留，除了随机药物，每个组将有辅助个性化治疗来管理特定的情绪状态和合并症。双相障碍是一种终身、慢性和高度复发的情绪障碍，其特征是躁狂或轻躁狂的发作以及抑郁症的发作。全谱双相情感障碍的终生患病率约为4.5%，其中一半患者报告其发病年龄为14岁，遗传率估计为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，其直接和间接费用估计为706亿美元

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.