Evaluation of a Physiologic Marker for Schizophrenia in First-Episode Psychosis

首发精神病中精神分裂症生理标志物的评估

• 批准号: 8619703
• 负责人: JEFFREY K YAO
• 金额: $ 21.14万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-24 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8619703
• 关键词: Accounting; Antipsychotic Agents; Arachidonic Acids; Biochemical; Biological; Biological Assay; Blood; Blood flow; Blood specimen; Cell membrane; Chemicals; Classification; Control Groups; Cutaneous; DNA; DNA Repository; Data; Defect; Development; Diagnosis; Diagnostic Procedure; Disease; Early Diagnosis; Eicosanoids; Enrollment; Equilibrium; Evaluation; Exposure to; Flowmeters; Flushing; Freezing; Genetic Variation; Goals; Heterogeneity; Hospitals; Individual; Laser-Doppler Flowmetry; Lasers; Lead; Light; Link; Measures; Mediator of activation protein; Mental disorders; Methods; Modeling; N-amyl-N-methylnitrosamine; Nicotinic Acids; Onset of illness; Participant; Pathway interactions; Patients; Pharmaceutical Preparations; Phospholipids; Physiological; Plasma; Prevalence; Prostaglandins; Psychotic Disorders; Publishing; Reporting; Research; Research Design; Resources; Sampling; Schizoaffective Disorders; Schizophrenia; Signal Transduction; Site; Skin; Staging; Subgroup; Testing; Time; Whole Blood; Work; cost effective; disability; drug development; emerging adult; experience; first episode psychosis; follow-up; improved; meetings; neuropsychiatry; novel; patient population; public health relevance; response; trait

7. Project Summary/Abstract Schizophrenia (SZ) is a devastating neuropsychiatric illness with typical onset in early adulthood. Despite extensive research, its causes remain poorly understood. Our central hypothesis is that abnormalities in cell membrane phospholipids, particularly those involving arachidonic acid (AA) and related metabolites (collectively termed eicosanoids) are fundamental to at least one etiopathological pathway involved in SZ. The proposed work will test whether niacin subsensitivity can serve as a putative physiologic marker to identify a subset of individuals at onset of illness for SZ. Although niacin subsensitivity is a widely replicated physiological abnormality associated with SZ, issues of illness chronicity and exposure to antipsychotic medications confound most published data. The proposed research will effectively resolve this issue by studying a large sample of first-episode, drug-na¿ve (FEDN) patients. However, enrollment of such a unique group in the US can be challenging for a single study site. The proposed R21 project will thus be conducted exclusively at the Beijing Hui-Long-Guan Hospital. Because of its enriched resource for this unique patient population, it is not only feasible but also cost-effective to meet the recruitment goal of 300 FEDN patients. The following three specific aims are proposed: Aim 1: Estimate the prevalence of niacin subsensitivity in FEDN patients. We will use a Laser Doppler flowmeter to quantify the cutaneous blood flow response to increasing concentrations of topical ¿-methylnicotinate (AMN) in 300 FEDN psychosis patients, and 100 demographically-balanced healthy controls (HC) from Beijing site. We hypothesize that niacin sensitivity will be significantly reduced in 25% or more of FEDN-SZ subjects, but in fewer than 10% of HC and FEDN with other psychosis. Aim 2: Estimate the extent to which niacin subsensitivity is a stable marker that is predictive of SZ. We will build a classification model using initial niacin sensitivity from 300 FEDN patients (defined as the EC50 value for topical methylnicotinate to stimulate skin blood flow) to predict a diagnosis of SZ at 6-month reassessment. We hypothesize that niacin subsensitivity is a stable trait, and initial niacin sensitivity during early psychosis is predictive of a subsequent diagnosis of SZ. Aim 3: Evaluate the biochemical mechanisms underlying niacin subsensitivity. We will compare niacin sensitivity with likely chemical mediators (phospholipids, arachidonic acid and eicosanoids) from plasma and RBC samples between FEDN patients and HC groups (from Aim 1). We hypothesize that niacin subsensitivity will be associated with defects in the AA cascade. A model for prediction of EC50 values in the same enrolled FEDN and HC groups from Aim 1, will have at least one significant AA predictor after correction for multiple testing. While we do not believe that all patients have defects in AA signaling, the proposed study will establish the validity of an objective physiological marker that could help to identify a subset of SZ patients at a very early stage of illness. Elucidating its biochemical mechanism may lead to refined diagnostic methods and novel targets for drug development.

7. 项目总结/摘要 精神分裂症（SZ）是一种毁灭性的神经精神疾病，通常在成年早期发病。 尽管进行了广泛的研究，但其原因仍然知之甚少。我们的中心假设是异常 细胞膜磷脂，特别是涉及花生四烯酸 (AA) 和相关代谢物的磷脂 （统称为类二十烷酸）是 SZ 涉及的至少一种病因病理学途径的基础。这 拟议的工作将测试烟酸不敏感性是否可以作为假定的生理标志物来识别 SZ 发病时的个体子集。尽管烟酸不敏感现象已被广泛复制 与 SZ 相关的生理异常、慢性疾病问题和接触抗精神病药物 药物混淆了大多数已发表的数据。本研究将有效解决这一问题 研究大量初治未用药（FEDN）患者样本。然而，注册这样一个独特的 美国的小组对于单个研究地点来说可能具有挑战性。因此，拟议的 R21 项目将进行 仅限北京回龙观医院。因为它为这个独特的患者提供了丰富的资源 总体而言，满足 300 名 FEDN 患者的招募目标不仅可行，而且具有成本效益。 提出了以下三个具体目标： 目标 1：估计烟酸不敏感的患病率 FEDN 患者。我们将使用激光多普勒流量计来量化皮肤血流反应 在 300 名 FEDN 精神病患者和 100 名患者中增加局部 ¿-甲基烟酸酯 (AMN) 的浓度 来自北京站点的人口统计平衡健康对照（HC）。我们假设烟酸敏感性是 25% 或更多的 FEDN-SZ 受试者显着减少，但 HC 和 FEDN 与其他受试者的比例不到 10% 精神病。目标 2：估计烟酸不敏感性作为预测 SZ 的稳定标志物的程度。 我们将使用 300 名 FEDN 患者的初始烟酸敏感性（定义为 EC50 局部烟酸甲酯刺激皮肤血流的价值）可预测 6 个月时的 SZ 诊断 重新评估。我们假设烟酸不敏感是一个稳定的特征，并且在 早期精神病可预示随后诊断为精神分裂症。目标 3：评估生化机制 潜在的烟酸不敏感。我们将比较烟酸敏感性与可能的化学介质 （磷脂、花生四烯酸和类二十烷酸）来自 FEDN 患者和 HC 组（来自目标 1）。我们假设烟酸不敏感与 AA 缺陷有关 级联。用于预测目标 1 中相同登记的 FEDN 和 HC 组的 EC50 值的模型将 经过多次测试校正后，至少有一个显着的 AA 预测因子。虽然我们不相信所有 患者存在 AA 信号传导缺陷，拟议的研究将建立客观生理学的有效性 标记物可以帮助在疾病的早期阶段识别出一部分精神分裂症患者。阐明其 生化机制可能会导致精细的诊断方法和药物开发的新靶标。