Predicting Placebo Responses Across Disease States

预测不同疾病状态下的安慰剂反应

• 批准号: 7932818
• 负责人: Jon-Kar Zubieta
• 金额: $ 31.46万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-16 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7932818
• 关键词: Achievement; Address; Affect; Alcohol abuse; Alcohol or Other Drugs use; Area; Award; Brain; Clinical; Clinical Trials; Communities; Data; Decision Making; Diagnosis; Disease; Electronics; Environment; Event; Frequencies; Functional Magnetic Resonance Imaging; Functional disorder; Funding; General Population; Genetic Polymorphism; Grant; Guidelines; Homeostasis; Human Resources; Individual; Leadership; Logic; Major Depressive Disorder; Medicine; Methodology; Methods; Modeling; Motivation; Neurobiology; Neuropsychological Tests; Neurotransmitters; Nicotine Dependence; Noise; Outcome; Patients; Persons; Phase; Placebo Effect; Placebos; Population; Positron; Probability; Process; Program Reviews; Published Comment; Recording of previous events; Research; Research Personnel; Resources; Rewards; Role; Sampling; Source; System; Technology; Time Study; TimeLine; Training; United States National Institutes of Health; Variant; Work; base; clinical practice; control trial; design; innovation; meetings; novel; organizational structure; single episode major depressive disorder; success; tool; traditional therapy

DESCRIPTION (provided by applicant): The present proposal is concerned with the prediction of individual placebo responses in clinical samples. Here we part from the usual view of placebos as inert control states. On the contrary, it is hypothesized that placebo administration triggers a cascade of events activating endogenous mechanisms that promote homeostasis. This leads to the proposal that a substantial proportion of the variance in placebo responding in CNS trials can be explained by the functional variation of specific neurobiological circuits and mechanisms. We focus on the prediction of placebo effects in patients diagnosed with Major Depressive Episode (MDE), unmedicated at the time of the study. This illness was selected because of its high frequency and chronicity in the general population, but also one that presents with high placebo responses in controlled trials. Half of the subjects will also present with a diagnosis of nicotine dependence, which is expected to reduce placebo responses rates, but also affect the underlying neurobiology, increasing the generalizability of the findings. Non-problem alcohol use will be permitted and entered as a covariate in the analyses. A 3-step process is proposed. Studies using positron emission tomograph will determine the placebo-induced activation of neurotransmitter systems through to be involved in both the pathophysiology of MDE and the effects of expectations. Functional magnetic resonance imaging will be employed to determine the proportion of the variance in placebo effects explained by the function of reward, decision-making and "motivation" regions. Individual variations in neurotransmitter systems and circuits involved will then be modeled by a combination of neuropsychological tests and the presence of common genetic polymorphisms regulating those regional networks. This proposal therefore addresses the predictability of the placebo effect and its underlying neurobiology. The capacity to utilize internal resources to change clinical conditions (as opposed to traditional therapies that are given or applied to the patient with little individual control) represents both a shift in paradigm and a source of "noise" in clinical trials. As such, the results of the studies proposed have the potential for lasting impact in the practice of medicine at large. Placebo effects are a common occurrence in clinical trials. Recent data has shown that those may be caused by the effect that expectations have on specific brain mechanisms. Those brain mechanisms may then change the clinical state of the patients. This proposal examines these mechanisms in Major Depression with and without substance use to determine their predictability and application in clinical trials. The NIDA/NIMH/NINDS EUREKA applications were reviewed differently from more traditional NIH grant mechanisms. Specifically, the review process consisted of two phases. During the first (i.e., electronic) phase a selected panel of reviewers were given the following guidelines by which to assess the applications. They were asked to determine whether they: Strongly Agree, Moderately Agree, Neither Agree nor Disagree, Moderately Disagree, or Strongly Disagree with these descriptions. Their ratings and any additional comments are below. These initial ratings also provided the basis for the review panel to determine whether an application would be discussed during an in person meeting. Because of the very stringent review criteria and limited pool of funds set aside for this program, the review panel chose only to discuss applications that garnered the most enthusiasm. The Resume and Summary of the Discussion above summarizes opinions of the in person meeting and forms the basis of the final score. Significance: This study addresses an important problem and the outcome of the proposed studies will drive the field. The potential impact of the proposed research is exceptional, in terms of the magnitude of the impact and the size of the community affected. Innovation: The project is highly original and exceptionally innovative and seriously challenges existing paradigms or clinical practice. The project addresses a major barrier to progress in the field or it develops or employs exceptionally novel concepts, approaches, methodologies, tools, or technologies. Approach: The logic of the approach is sufficiently compelling despite the lack of experimental detail. The conceptual (or clinical) framework, design, methods, and analyses are adequately developed, well integrated and reasoned, and are appropriate for the aims of the project. The applicant acknowledges potential problem areas and considers alternative tactics. The information in the timeline inspires confidence that the PI will be able to document progress in each year of the award and either complete the project or demonstrate conclusively that it cannot be completed, despite good-faith efforts, during the term of the award. The requested duration of the award is appropriate for the proposed research. Investigators: The PD/PI(s) and other key personnel are appropriately trained and well-suited to carry out this work. Past achievements of the PI(s) suggest that the investigator(s) is/are exceptionally innovative and likely to make paradigm-shifting, high-impact discoveries. If the PI does not have a history of doing exceptionally innovative, high-impact research, the logic of the experimental plan suggests that there is at least some likelihood of success. The project is high priority for the PI(s), as indicated by the person-months of effort that the PI(s) will devote to it. For applications designating multiple PDs/PIs, the leadership plan, including the designated roles and responsibilities, governance, and organizational structure, are consistent with and justified by the aims of the project and the expertise of each of the PDs/PIs. Environment: The scientific environment(s), in which the work will be performed, contributes to the probability of success. The proposed studies benefit from unique features of the scientific environment, subject populations, or employ useful collaborative arrangements. There is evidence of institutional support.

描述（由申请人提供）：本提案涉及临床样本中个体安慰剂反应的预测。在这里，我们不同于将安慰剂视为惰性对照状态的通常观点。相反，据推测，服用安慰剂会引发一系列激活内源性机制的事件，从而促进体内平衡。这导致有人提出中枢神经系统试验中安慰剂反应的很大一部分差异可以通过特定神经生物学回路和机制的功能变化来解释。我们重点关注在研究时未接受药物治疗的诊断为重度抑郁发作 (MDE) 的患者中预测安慰剂效应。选择这种疾病是因为它在普通人群中发病率高且长期存在，而且在对照试验中安慰剂反应也较高。一半的受试者还将诊断出尼古丁依赖，这预计会降低安慰剂反应率，但也会影响潜在的神经生物学，从而增加研究结果的普遍性。无问题的饮酒将被允许并作为协变量输入分析中。建议分三步进行。使用正电子发射断层扫描仪的研究将确定安慰剂诱导的神经递质系统激活，从而参与 MDE 的病理生理学和期望的影响。功能性磁共振成像将用于确定安慰剂效应的方差比例，该方差由奖励、决策和“动机”区域的功能来解释。然后，通过结合神经心理学测试和调节这些区域网络的常见遗传多态性的存在，对所涉及的神经递质系统和回路的个体差异进行建模。因此，该提案解决了安慰剂效应及其潜在神经生物学的可预测性。利用内部资源改变临床状况的能力（与在几乎没有个人控制的情况下给予或应用于患者的传统疗法相反）既代表了范式的转变，也代表了临床试验中“噪音”的来源。因此，所提出的研究结果有可能对整个医学实践产生持久影响。安慰剂效应在临床试验中很常见。最近的数据表明，这些可能是由预期对特定大脑机制的影响引起的。这些大脑机制可能会改变患者的临床状态。该提案研究了有或没有物质使用的重度抑郁症的这些机制，以确定它们在临床试验中的可预测性和应用。 NIDA/NIMH/NINDS EUREKA 申请的审查方式与传统的 NIH 拨款机制不同。具体来说，审查过程分为两个阶段。在第一阶段（即电子阶段），选定的评审小组将获得以下指导方针来评估申请。他们被要求确定他们是否：强烈同意、一般同意、既不同意也不反对、一般不同意或强烈不同意这些描述。他们的评级和任何其他评论如下。这些初步评级还为审查小组确定是否在面对面会议期间讨论申请提供了基础。由于该计划的审查标准非常严格，而且预留的资金有限，审查小组选择只讨论最受关注的申请。上述讨论的简历和摘要总结了现场会议的意见，并构成了最终得分的基础。 意义：这项研究解决了一个重要问题，拟议研究的结果将推动该领域的发展。就影响的程度和受影响社区的规模而言，拟议研究的潜在影响是非凡的。 创新：该项目具有高度原创性和非凡的创新性，严重挑战现有的范式或临床实践。该项目解决了该领域进步的主要障碍，或者开发或采用了异常新颖的概念、方法、方法、工具或技术。 方法：尽管缺乏实验细节，但该方法的逻辑足够引人注目。概念（或临床）框架、设计、方法和分析得到充分开发、充分整合和推理，并且适合项目的目标。申请人承认潜在的问题领域并考虑替代策略。时间表中的信息激发了人们的信心，即 PI 将能够记录奖项每年的进展情况，并完成项目或最终证明，尽管在奖项期限内做出了善意的努力，项目仍无法完成。所要求的奖励期限适合拟议的研究。 调查人员：PD/PI 和其他关键人员经过适当的培训并且非常适合开展这项工作。 PI 过去的成就表明，研究者具有非凡的创新性，并且可能做出范式转变、高影响力的发现。如果 PI 没有做过特别创新、高影响力的研究的历史，那么实验计划的逻辑表明至少有一定的成功可能性。该项目对于 PI 来说是高度优先的，正如 PI 为该项目投入的人月努力所表明的那样。对于指定多个 PD/PI 的应用程序，领导力计划（包括指定的角色和职责、治理和组织结构）与项目目标以及每个 PD/PI 的专业知识一致并得到证明。 环境：开展工作的科学环境有助于提高成功的可能性。拟议的研究受益于科学环境、受试者群体的独特特征，或采用有用的合作安排。有证据表明有机构支持。