HPA & Neural Response to Peer Rejection: Biomarkers of Adolescent Depression Risk

描述（由申请人提供）：青少年重度抑郁症（MDD）很常见，与成人MDD具有连续性，并与许多不良结局相关。然而，青少年抑郁症风险的生物标志物仍然难以捉摸，尽管建立因果通路，开发治疗靶点，并最终先发制人的青少年MDD的影响。聚合线的研究表明，同伴拒绝作为一个突出的触发青少年抑郁症和神经生物学反应的同伴拒绝重叠的神经生物学缺陷的抑郁症。我们的研究小组显示，在患有抑郁症和抑郁症高危的青少年中，神经内分泌和额杏仁核对同伴拒绝挑战的反应增加。由于抑郁症的发病率增加，神经生物学敏感性增加，在女孩的同伴拒绝，我们建议提高神经内分泌和额杏仁核神经反应的同伴拒绝作为一种新的生物行为标记物的抑郁症的风险在青春期女孩。在这个修订后的应用程序中，我们调查了三组青春期女孩对生态有效的同伴拒绝挑战的神经内分泌和神经反应：1）目前患有MDD的女孩，2）MDD高风险的女孩（基于父母的历史），3）低风险对照女孩。中心方法将包括评估，以确定在功能性磁共振成像（fMRI）同伴拒绝任务期间的区域大脑激活（聊天室）和神经内分泌反应的实验室同伴拒绝任务（耶鲁人际压力-儿童版），“现实世界”的日常日记社会经验的措施，和家庭功能的评估青春期成熟，随后进行6个月和12个月的精神病学评估，以确定抑郁症状的增长和MDD的发作/缓解。目标是：1）表征患有MDD和相对于低风险女孩的高MDD风险女孩对同伴拒绝的神经内分泌反应，2）表征患有MDD和相对于低风险女孩的高MDD风险女孩对同伴拒绝的额杏仁核神经反应，3）表征神经内分泌和对同伴拒绝的神经反应之间的关联，并探索与“现实世界”社会经验、家庭功能、和青春期成熟，和4）以确定是否综合神经生物学反应同伴排斥区分女孩与MDD和高风险的MDD低风险的女孩，并预测抑郁症状/MDD的增长/缓解。修订后的研究是第一个评估神经生物学基板的同伴拒绝在青少年中选择的MDD和MDD风险的纵向设计。我们的研究的特点是定义生物标志物在上下文相关的挑战方面的概念转变，使用我们小组开创的创新，生态有效的方法，以及抑郁症和上下文因素的全面，前瞻性的措施。结果将阐明关键的和潜在的修改过程沿着的路径，以确定目标和早期干预工作的最佳发展时机的影响，并开发新的评估，以量化的变化，同伴拒绝敏感性，以评估治疗反应和个性化治疗。 公共卫生相关性：该应用程序提供了一种创新的方法来了解青少年过渡期抑郁症的原因，这是抑郁症风险增加的关键时期，特别是在女孩中。这项拟议的研究将调查大脑和荷尔蒙对同伴拒绝的反应，作为青春期女孩抑郁风险增加的一种新机制。研究结果将加深我们对抑郁症发病过程沿着关键和潜在可改变过程的理解，这些过程可能：a）提高我们预测和理解青少年抑郁症的能力，B）指出新的评估，以量化风险和治疗反应的进展，c）导致新的药物和预防/干预计划的内容的改进，以及d）最终预防青少年抑郁症，因此，改善处境危险女孩的生活轨迹。

DESCRIPTION (provided by applicant): Adolescent major depressive disorder (MDD) is common, shows continuity with adult MDD and is associated with numerous adverse outcomes. However, biomarkers of risk for adolescent depression have remained elusive despite implications for establishing causal pathways, developing therapeutic targets, and ultimately, pre-empting adolescent MDD. Converging lines of research reveal peer rejection as a prominent trigger for adolescent MDD and neurobiological response to peer rejection as overlapping with neurobiologic deficits in MDD. Our group has shown increased neuroendocrine and fronto-amygdala response to peer rejection challenge in adolescents with MDD and at high-risk for MDD. Given increased rates of MDD and increased neurobiologic sensitivity to peer rejection in girls, we propose heightened neuroendocrine and fronto-amygdala neural response to peer rejection as a novel biobehavioral marker of MDD risk in adolescent girls. In this revised application, we investigate neuroendocrine and neural response to ecologically-valid peer rejection challenges in three groups of adolescent girls: 1) girls with current MDD, 2) girls at high risk for MDD (based on parental history), and 3) low risk control girls. The central methodology will include assessments to determine regional brain activation during a functional magnetic resonance imaging (fMRI) peer rejection task (Chatroom), and neuroendocrine response to a laboratory peer rejection task (Yale Interpersonal Stressor-Child version), "real-world" daily diary measures of social experience, and assessment of family function pubertal maturation, followed by 6 and 12-month psychiatric assessments to determine growth of depressive symptoms and onset/remission of MDD. Aims are: 1) to characterize neuroendocrine response to peer rejection in girls with MDD and at high MDD risk relative to low risk girls, 2) to characterize fronto-amygdala neural response to peer rejection in girls with MDD and at high MDD risk relative to low risk girls, 3) to characterize associations between neuroendocrine and neural response to peer rejection and explore links to "real-world" social experience, family function, and pubertal maturation, and 4) to determine if integrated neurobiological response to peer rejection distinguishes girls with MDD and at high MDD risk from low risk girls and predicts growth/remission of depressive symptoms/MDD. The revised study is the first to evaluate the neurobiological substrates of peer rejection in adolescents selected for MDD and MDD risk in a longitudinal design. Our study is distinguished by a conceptual shift of defining biomarkers in terms of contextually relevant challenges, the use of innovative, ecologically-valid methods pioneered by our group, and comprehensive, prospective measures of depression and contextual factors. Results will elucidate key and potentially modifiable processes along the pathway to MDD with implications for identifying targets and optimal developmental timing of early intervention efforts, and for developing new assessments to quantify changes in peer rejection sensitivity to evaluate treatment response and personalize treatment. PUBLIC HEALTH RELEVANCE: This application offers an innovative approach to understanding causes of depression over the adolescent transition, a key period of increased risk for depression, especially in girls. The proposed study will investigate brain and hormonal response to peer rejection as a novel mechanism underlying increased risk for depression in adolescent girls. Results will deepen our understanding of key and potentially modifiable processes along the pathway to depression that may: a) improve our ability to predict and understand adolescent depression, b) point to new assessments to quantify progression of risk and treatment response, c) lead to new medications and refinements to the content of prevention/intervention programs, and d) ultimately pre-empt adolescent depression and thus, improve life trajectories for at-risk girls.