Treatment Development Targeting Positive Affect Function in Adolescent Depression

描述(申请人提供)：青春期抑郁症发病率急剧上升，成为导致终生残疾的主要原因，复发率和慢性损伤发生率较高。尽管在有效治疗方面取得了进展，但只有50%的接受治疗的青少年获得了持续的缓解。来自发展情感神经科学的最新见解表明，在青春期可能存在大脑可塑性的窗口，此时可能最好地获得某些有效管理情感(情绪和动机)的技能。为此，候选人的长期职业目标是通过利用发展情感神经科学框架来指导这一努力，开发更有效的青少年情感障碍治疗方法。候选人的当务之急是瞄准患有抑郁症的青少年的积极情感功能，并调查越来越多的证据表明，青春期可能是干预的时机成熟时期。青春期积极情感和奖励系统的关键神经底物的标准化重构在青春期抑郁症的发展中起着作用。这些变化可能预示着一个相对敏感的时期(青春期成熟前后)，此时练习管理积极情绪的关键技能可能会对抑郁症的大脑行为机制产生持久的影响。目前的以患者为导向的指导职业发展奖将使候选人在推进这一议程方面发挥独特的作用。她的背景包括儿童临床心理学的专门培训，青少年抑郁症的治疗发展，情感功能的心理社会方法，基本的多变量统计，以及广泛接触发展情感神经科学的基础知识。为了最有效地将发展中的情感神经科学与治疗创新联系起来，她试图深化和扩展她的培训，以包括：1)更复杂地理解积极情感功能的大脑行为理论，特别是当它们与抑郁症的发展有关时；2)在儿科治疗试验的背景下检验大脑行为机制的高级统计数据和方法；以及3)将这些大脑行为理论和方法转化为临床实践的治疗发展战略。匹兹堡大学是一个出色的环境，可以参与实现这些培训目标所需的跨学科培训。这位候选人的导师-大卫·布伦特、罗纳德·达尔和格雷格·西格尔-拥有青少年抑郁症和治疗开发、情感障碍的神经发育途径以及衡量治疗反应的大脑行为机制的多种方法方面的专业知识。除了他们个人的生产力和强大的指导历史外，这支调查团队还在大型跨学科项目上进行合作，以促进年轻人对情感障碍的科学理解和治疗。拟议的项目利用这一培训和专门知识开发一个治疗单元(6期)，以改善青少年抑郁症患者的积极情感功能特征。积极情感刺激和维持[PASS]模块教授维持积极情感状态的策略，目的是在这一发育可塑性时期加强关键神经回路。积极情感功能的相对缺陷是抑郁症发展和临床病程的核心；然而，很少有针对这些缺陷的治疗方法。行为激活增加了与愉快事件相关的暴露和强化，但新出现的证据表明，在经历了积极的经历后，抑郁的人的情感状态会迅速消退。因此，PASS可以通过延长情感体验来增强行为激活。候选人先前的研究支持PASS的可行性，以及主观积极情绪和抑郁症状的变化。目前的研究建议通过随机对照试验(RCT)来扩展这项工作，在该试验中，患有抑郁症的青少年(n=60；年龄12-17岁)将被随机分为PASS或认知疗法(一种不针对积极情感功能的对照疗法)，为期6周。参与者将完成对目标机制和症状的自我报告和行为评估，34名参与者将完成旨在引发积极情绪和激活潜在神经回路(例如额叶-中脑边缘回路)的神经成像任务。目前试验的主要目标包括：1)建立PASS的可行性和可接受性，2)采用多种方法来测量靶机制中PASS相关的变化，以及3)探索PASS相关的可持续性变化和额中边缘网络内关键回路的连通性。所有这些目标将为手册的迭代改进提供信息，并将为未来的大规模随机对照试验产生更具体的假设和方法。基于这项工作的结果，未来的试验可能，例如，包括一项增强设计，以确定PASS是否在行为激活之上和之外增加价值，并可能测试关于治疗方法的适当发育窗口(例如青春期早期和青春期中期)的假设。

DESCRIPTION (provided by applicant): Rates of depression rise sharply during adolescence, becoming a leading cause of lifetime disability with high rates of recurrence and chronic impairment. Despite progress in efficacious treatments, only 50% of treated adolescents attain sustained remission. Recent insights from developmental affective neuroscience suggest that there may be windows of brain plasticity during adolescence when certain skills for effectively managing affect (emotions and motivations) may best be acquired. To this end, the candidate's long term career objective is to develop more effective treatments for affective disorders among youth by utilizing a developmental affective neuroscience framework to guide this effort. The candidate's immediate focus is to target positive affective functioning among adolescents with depression, and to investigate growing evidence that adolescence may be an opportune maturational period for intervention. Normative remodeling of key neural substrates of positive affect and reward systems at puberty plays a role in the development of depression during adolescence. These changes may signal a relatively sensitive period (surrounding pubertal maturation) when practicing key skills for managing positive affect may have an enduring impact on brain-behavior mechanisms of depression. The current Mentored Patient Oriented Career Development Award will uniquely position the candidate to advance this agenda. Her background includes specialized training in child clinical psychology, treatment development for adolescent depression, psychosocial approaches to affective functioning, basic multivariate statistics, and a broad exposure to the basics of developmental affective neuroscience. To most effectively bridge developmental affective neuroscience with treatment innovation she seeks to deepen and extend her training to include: 1) a more intricate understanding of brain-behavior theories of positive affective functioning, particularly as they relate to the development of depression, 2) advanced statistics and methods for examining brain-behavior mechanisms in the context of pediatric treatment trials, and 3) strategies for treatment development that translate these brain-behavior theories and methods to clinical practice. The University of Pittsburgh is an outstanding environment in which to engage in the interdisciplinary training required to achieve these training goals. The candidate's mentors-David Brent, Ronald Dahl and Greg Siegle-have combined expertise in adolescent depression and treatment development, neuro-developmental pathways to affective disorders, and multi-method approaches to measuring brain-behavior mechanisms of treatment response. In addition to their individual productivity and strong mentoring histories, this team of investigators has collaborated on large-scale, interdisciplinary projects to advance the scientific understanding and treatment of affective disorders among youth. The proposed project draws on this training and expertise to develop a treatment module (6 sessions) for improving features of positive affective functioning among adolescents with depression. The Positive Affect Stimulation and Sustainment [PASS] module teaches strategies for sustaining positive affective states, with the goal of strengthening key neural circuitry during this period of developmental plasticity. Relative deficits in features of positive affective functioning are central to the development and clinical course of depression; yet, few treatments target these deficits. Behavioral activation increases exposure and reinforcement related to pleasant events, but emerging evidence suggests that affective states quickly fade for depressed individuals following positive experiences. As such, PASS may augment behavioral activation by extending affective experiences. The candidate's prior research supports the feasibility of PASS, as well as changes in subjective positive emotion and depressive symptoms. The current study proposes to extend this work with a randomized controlled trial (RCT) in which adolescents with depression (n=60; ages 12-17) will be randomized to PASS or Cognitive Therapy (a comparison treatment that does not target positive affective functioning) for 6 weeks. Participants will complete self report and behavioral assessments of targeted mechanisms and symptoms, and 34 participants will complete neuroimaging tasks designed to elicit positive affect and activate underlying neural circuitry (e.g. fronto-mesolimbic circuits). The primary goals of the current trial include: 1) establish feasibility and acceptability of PASS, 2) employ a multi-method approach to measure PASS related change in targeted mechanisms, and 3) explore PASS-related changes in sustainability and connectivity in key circuits within the fronto-mesolimbic network. All of these goals will inform iterative refinements of the manual, and will generate more specific hypotheses and methods for a future, large-scale RCT. Based on the results of this work, future trials may, e.g., include an augmentation design to determine if PASS adds value above and beyond behavioral activation, and may test hypotheses regarding opportune developmental windows (e.g. early vs. mid puberty) for the treatment approach.