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，我们与通常将安慰剂视为惰性控制状态的观点分开。相反，它假设安慰剂的使用触发了一系列事件，激活了促进内环境稳定的内源性机制。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通过特定神经生物回路和机制的功能变化来解释。我们专注于对诊断为重度抑郁发作(MDE)的患者的安慰剂效果的预测，该患者在研究期间未服用药物。选择这种疾病是因为它在普通人群中的高频率和慢性化，但在对照试验中也呈现出高的安慰剂反应。一半的受试者还将被诊断为尼古丁依赖，预计这将降低安慰剂反应率，但也会影响潜在的神经生物学，增加研究结果的概括性。无问题的饮酒将被允许，并作为协变量进入分析。提出了三步法工艺。使用正电子发射断层扫描仪的研究将通过参与MDE的病理生理学和预期的影响来确定安慰剂诱导的神经递质系统的激活。功能磁共振成像将被用来确定由奖励、决策和“动机”区域的功能解释的安慰剂效应的差异比例。神经递质系统和神经回路中的个体差异将通过神经心理测试和调节这些区域网络的常见遗传多态的存在相结合来模拟。因此，这项建议解决了安慰剂效应及其潜在的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(而不是给或应用于几乎没有个人控制的患者的传统疗法)既代表了范式的转变，也是临床试验中“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的影响。

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.