Investigating Neural and Psychotherapeutic Mediators of Placebo Response in MDD

描述（由申请人提供）：安慰剂效应在成人和青少年重度抑郁症（MDD）治疗文献中受到越来越多的关注。在抗抑郁药或心理治疗的研究中，临床抑郁症患者所经历的症状改善中约有60%可归因于安慰剂效应的潜在因素（例如，患者对症状改善的期望）。然而，安慰剂效应导致抑郁症状改善的机制仍然知之甚少。事实上，国家卫生研究所已呼吁加强这一领域的研究（RFA-DA-12- 003, RFA-DA-12-004）。对抑郁症患者如何以及为什么在治疗中得到改善的更准确的理解，可能最终导致对这种复发性和高度衰弱性疾病更有效和高效的治疗方法的发展。F32博士后奖学金将允许申请人研究青少年重度抑郁症心理治疗中安慰剂反应的几种有前途的神经和心理治疗介质。更具体地说，考虑到多巴胺和前扣带皮层（ACC）在奖励机制（包括奖励预期）中的作用，它们可能在重度抑郁症治疗中介导安慰剂反应中发挥重要作用。事实上，安慰剂的使用可以被概念化为引起对特定类型奖励的期望（即症状改善）。基于这一框架，目前的研究重点是反馈相关负性（FRN）和反馈相关正性（FRP），这是多巴胺介导的强化学习过程的两个公认的电生理指标，假设它们起源于背侧ACC和纹状体区域。与本研究直接相关的是，在MDD中出现了FRN和FRP功能障碍。具体而言，与对照组相比，抑郁症成年人的特征是负反馈后FRN幅度更大，而对奖励和奖励结果的预期反应中FRP幅度变钝。在抑郁症神经生物学基础研究的领导者Diego Pizzagalli博士（主要导师）的专家指导下，申请人将接受高密度事件相关电位（ERP）数据的收集，处理和分析的关键培训，以评估这些神经变量在MDD治疗的临床试验背景下。此外，关于安慰剂反应的心理治疗机制，本研究将探讨(1)治疗师和患者之间的治疗联盟的中介作用，以及(2)患者获得和利用现代心理治疗中鼓励的核心认知、行为和人际交往技能的程度。Dr. John Weisz（二级导师）将为抑郁症心理治疗临床试验的正确实施提供关键的指导。总的来说，拟议的量身定制的研究培训计划将使申请人获得抑郁症神经科学方法的新技能和知识，这将补充目前在心理治疗研究方面的专业知识。

DESCRIPTION (provided by applicant): The placebo effect has received increased attention in both the adult and youth Major Depressive Disorder (MDD) treatment literatures. Approximately 60% of the symptom improvement experienced by clinically depressed patients in studies of antidepressants or psychotherapy may be attributable to factors underlying the placebo effect (e.g., patients' expectations of symptom improvement). However, the mechanisms through which the placebo effect results in depressive symptom improvement remain poorly understood. Indeed, the National Institute of Health has called for increased research in this area (RFA-DA-12- 003, RFA-DA-12-004). A greater understanding of precisely how and why depressed patients improve in treatment could ultimately lead to the development of more effective and efficient treatments for this recurrent and highly debilitating disorder. An F32 postdoctoral fellowship would allow the applicant to investigate several promising neural and psychotherapeutic mediators of placebo response in psychotherapy for adolescent MDD. More specifically, given their role in reward mechanisms (including the expectation of reward), dopamine and the anterior cingulate cortex (ACC) may play important roles in mediating placebo response in MDD treatment. Indeed, the administration of a placebo may be conceptualized as eliciting the expectation of a particular type of reward (i.e., symptom improvement). Based on this framework, the current proposal focuses on the feedback-related negativity (FRN) and feedback-related positivity (FRP), two well-established electrophysiological indices of dopamine-mediated reinforcement learning processes, which are hypothesized to originate from dorsal ACC and striatal regions. Directly relevant to the proposed research, both FRN and FRP dysfunctions have emerged in MDD. Specifically, relative to controls, depressed adults have been characterized by larger FRN amplitude following negative feedback and blunted FRP amplitude in response to the expectation of a reward and reward outcome. Under the expert guidance of Dr. Diego Pizzagalli (primary mentor), a leader in the study of the neurobiological underpinnings of depression, the applicant will receive critical training in collecting, processing and analyzing high-density event-related potentials (ERP) data to assess these neural variables within the context of a clinical trial of MDD treatment. In addition, with regards to psychotherapeutic mechanisms that may underlie placebo response, the current study will investigate the mediating role of (1) the therapeutic alliance between therapists and patients, as well as (2) the extent to which patients acquire and utilize the central cognitive, behavioral and interpersonal skills encouraged in modern psychotherapy. Dr. John Weisz (secondary mentor) will provide key mentorship in the proper conduct of clinical trials of psychotherapy for MDD. Collectively, the proposed tailored research training plan will allow the applicant to acquire new skills and knowledge in neuroscientific approaches to depression, which will complement current expertise in psychotherapy research.