Investigating Neural and Psychotherapeutic Mediators of Placebo Response in MDD

描述（由申请方提供）：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研究中，临床抑郁症患者经历的症状改善中约有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，国家卫生研究所呼吁加强这一领域的研究（RFA-DA-12- 003，RFA-DA-12-004）。更好地了解抑郁症患者在治疗中如何以及为什么会改善，最终可能会导致开发更有效和更高效的治疗方法来治疗这种复发性和高度衰弱的疾病。一个F32博士后奖学金将允许申请人调查几个有前途的神经和心理治疗中介的安慰剂反应在青少年MDD的心理治疗。更具体地说，考虑到它们在奖励机制（包括奖励的期望）中的作用，多巴胺和前扣带皮层（ACC）可能在介导MDD治疗中的安慰剂反应中发挥重要作用。事实上，安慰剂的施用可以被概念化为引发对特定类型的奖励的期望（即，症状改善）。基于这个框架，目前的建议集中在反馈相关的负性（FRN）和反馈相关的正性（FRP），两个成熟的多巴胺介导的强化学习过程的电生理指标，这被假设为起源于背侧ACC和纹状体区域。与拟议的研究直接相关，FRN和FRP功能障碍都出现在MDD中。具体而言，相对于控制，抑郁症的成年人的特点是较大的FRN振幅负反馈和钝化FRP振幅响应于预期的奖励和奖励结果。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，以评估MDD治疗临床试验背景下的这些神经变量。此外，关于可能构成安慰剂反应的心理治疗机制，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。John Weisz博士（二级导师）将在适当开展MDD心理治疗临床试验方面提供关键指导。总体而言，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，这将补充目前心理治疗研究的专业知识。 公共卫生相关性：尽管越来越多的研究支持心理治疗对青少年临床抑郁症的疗效，但很少有人知道心理治疗为什么以及如何起作用。该项目的目标是调查有前途的神经生物学和心理治疗过程，这可能有助于解释为什么以及如何抑郁的青少年在治疗中改善。了解抑郁症治疗中的“活性成分”和症状改善机制至关重要，因为它可能最终导致开发更有效和更高效的青年抑郁症干预措施。

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. PUBLIC HEALTH RELEVANCE: Despite the growing body of research supporting the efficacy of psychotherapy for the treatment of clinical depression in adolescents, very little is known regarding why and how psychotherapy works. The goal of the project is to investigate promising neurobiological and psychotherapeutic processes that may help explain why and how depressed adolescents improve in therapy. An understanding of the "active ingredients" and mechanisms of symptom improvement in depression treatment is critical, as it may ultimately lead to the development of more effective and efficient interventions for depression in youth.