Predicting Placebo Responses Across Disease States

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，我们与通常认为安慰剂是惰性控制状态的观点分道扬镳。相反，有假说认为安慰剂会引发一系列事件，激活促进体内平衡的内源性机制。这导致了一种建议，即在中枢神经系统试验中，安慰剂反应的很大一部分差异可以用特定神经生物学回路和机制的功能变化来解释。我们关注的是在研究时未用药的重度抑郁发作（MDE）患者中安慰剂效应的预测。选择这种疾病是因为它在一般人群中的高频率和慢性，但在对照试验中也表现出很高的安慰剂反应。一半的受试者还将被诊断为尼古丁依赖，这有望降低安慰剂的反应率，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。允许无问题的酒精使用，并将其作为协变量输入分析。提出了一个三步法。使用正电子发射断层扫描的研究将通过参与MDE的病理生理和预期的影响来确定安慰剂诱导的神经递质系统的激活。将使用功能性磁共振成像来确定由奖励、决策和“动机”区域的功能解释的安慰剂效应方差的比例。神经递质系统和相关回路的个体差异将通过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结合来建模。因此，该建议解决了安慰剂效应的可预测性及其潜在的神经生物学问题。利用内部资源来改变临床条件的能力（相对于传统的治疗方法，给予或应用于很少有个体控制的患者）既代表了范式的转变，也是临床试验中的“噪音”来源。因此，提出的研究结果有可能对整个医学实践产生持久的影响。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。本提案研究了这些机制在有和没有药物使用的重度抑郁症中，以确定其可预测性和在临床试验中的应用。

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.