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严重抑郁障碍(MDD)治疗文献中受到越来越多的关注。在抗抑郁药物或心理治疗的研究中，临床抑郁症患者经历的症状改善约有60%可能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，安慰剂效应改善抑郁症状的机制仍然知之甚少。事实上，国家卫生研究所呼吁增加这一领域的研究(RFA-DA-12-003、RFA-DA-12-004)。更好地了解抑郁症患者如何以及为什么在治疗中有所改善，最终可能导致开发出更有效和更有效的治疗这种反复发作和高度虚弱的疾病的方法。F32博士后奖学金将允许申请者研究在青少年MDD心理治疗中安慰剂反应的几种有前途的神经和心理治疗媒介。更具体地说，鉴于它们在奖赏机制(包括奖赏预期)中的作用，多巴胺和前扣带回(ACC)可能在MDD治疗中发挥重要作用。事实上，安慰剂的服用可能被概念化为引发对特定类型奖励的期望(即症状改善)。基于这一框架，目前的研究集中在反馈相关负性(FRN)和反馈相关正性(FRP)这两个公认的多巴胺介导的强化学习过程的电生理学指标上，假设它们起源于背侧ACC和纹状体区域。与拟议的研究直接相关的是，MDD中出现了FRN和FRP功能障碍。具体地说，与对照组相比，抑郁症成人的特征是负反馈后FRN幅度更大，以及对奖励和奖励结果的预期做出反应时FRP幅度变钝。在抑郁症神经生物学基础研究领域的领导者Diego Pizzagalli博士(首席导师)的专家指导下，申请者将接受收集、处理和分析高密度事件相关电位(ERP)数据的关键培训，以在MDD治疗的临床试验的背景下评估这些神经变量。此外，关于安慰剂反应背后的心理治疗机制，本研究将调查(1)治疗师和患者之间的治疗联盟，以及(2)患者获得和利用现代心理治疗中鼓励的中央认知、行为和人际交往技能的程度。John Weisz博士(二级导师)将在适当进行MDD心理疗法临床试验方面提供关键指导。总的来说，拟议的量身定做的研究培训计划将允许申请者获得治疗抑郁症的神经科学方法方面的新技能和知识，这将补充目前心理治疗研究的专业知识。

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.