Biobehavioral inflexibility and risk for juvenile-onset depression

描述（由申请人提供）：在此修订后的申请中，重点是生物行为可识别性作为识别青少年发作性抑郁症（JOD）风险因素的框架，我们对IRG的每一个问题都做出了回应。我们尤其：a）提供我们的模型，假设和统计方法的更明确的公式，B）地址可能的环境调节器，和c）提出新的试点研究的结果，这表明我们有能力诱导和补救烦躁情绪在匈牙利的主题，并支持使用身体探针的心脏迷走神经控制的青年。在这个应用程序中，我们建议研究当前和未来的JOD风险和两个功能重要的生物行为系统之间的关系：心脏迷走神经控制（CVC）和情绪修复。为了表征CVC的适应性，我们将评估CVC在不同实验挑战（躯体与心理）中的功能;在一种类型的挑战的版本（例如，替代心理任务）;以及CVC的不同方面（休息与CVC反应性和恢复）。为了表征不灵活的情绪修复，我们将通过实施2种不同的情绪修复策略（积极自传体回忆与分心）和不同的情绪修复机会（实验控制与非结构化）来评估受试者在消极情绪挑战后减弱烦躁情绪的能力。我们的样本（入组时11-18岁）将包括200名JOD先证者，200名尚未受JOD影响的高危兄弟姐妹和100名从未患病的对照。先证者（和兄弟姐妹）将从700多名JOD年轻患者（每个人至少有一个兄弟姐妹）的仔细诊断和良好表征的样本中招募，代表匈牙利的国家临床样本，他们参加了最近的一个计划项目。该设计包括CVC，情绪修复，精神状态和心理社会功能的横断面评估，以及纵向临床随访。我们建议：（1）生理适应性（可操作为受损CVC的指标）和行为能力（可操作为受损情绪修复的指标），以及它们的组合（全球生物行为能力指数），将横截面区分先证者，在风险的兄弟姐妹，并控制同行和（2）全球生物行为能力指数将前瞻性预测临床过程（抑郁症状升高，JOD先证者的复发性抑郁发作，先前未受影响的兄弟姐妹首次抑郁发作）。我们还将在环境调节剂存在的情况下测试我们的全球可接受性模型的元素。我们的研究意义重大，因为抑郁症是全球残疾的主要原因。此外，JOD是一种严重且复发的抑郁症，约占年轻人抑郁症病例的50%。我们的研究是创新的，因为它：（a）整合了与抑郁症相关的生物和行为指标，这些指标具有现成的翻译潜力，（B）在多种刺激条件下使用CVC和情绪修复的替代探针，以获得这些结构的更丰富的表征，以及（c）其生物行为目标可以为检测，预防和治疗抑郁症的改进工作提供信息。公共卫生相关性：在这个应用程序中，我们将抑郁症概念化为生物行为可持续性的一种条件，并将此框架应用于青少年发作的抑郁症（JOD）-一种特别严重的情绪障碍。通过比较抑郁的青少年，非抑郁的兄弟姐妹和从未抑郁的同龄人，我们将确定生物和行为方面的可持续性，增加青少年发展JOD的风险，并阻碍从这种情况下恢复。该项目的公共卫生意义来自于这样一个事实，即它将产生知识，可以改善检测，预防和治疗JOD的努力。

DESCRIPTION (provided by applicant): In this revised application, which focuses on bio-behavioral inflexibility as a framework to identify risk factors for juvenile-onset depression (JOD), we responded to each of the IRG's concerns. In particular, we: a) offer more explicit formulations of our model, hypotheses, and statistical approaches, b) address possible environmental moderators, and c) present the results of new pilot studies, which show our ability to induce and remediate dysphoric mood in Hungarian subjects and support the use of somatic probes of cardiac vagal control in youths. In this application, we propose to study the relation between current and prospective JOD risk and two functionally important bio-behavioral systems: cardiac vagal control (CVC) and mood repair. To characterize CVC inflexibility, we will assess CVC functioning across different experimental challenges (somatic vs. psychological); within versions of one type of challenge (e.g., alternative psychological tasks); and across different facets of CVC (resting vs. CVC reactivity and recovery). To characterize inflexible mood repair, we will assess subjects' ability to attenuate dysphoric mood subsequent to negative mood challenges by implementing 2 different mood repair strategies (positive autobiographical recall vs. distraction) and across different mood repair opportunities (experimentally controlled vs. unstructured). Our sample (11-18 years old at entry) will include 200 probands with JOD, 200 of their at-risk siblings not yet affected by JOD, and 100 never-ill controls. Probands (and siblings) will be recruited from a carefully diagnosed and well-characterized sample of 700+ young patients with JOD (each with at least one sibling), representing a national, clinical sample in Hungary, who participated in a recent Program Project. The design includes cross-sectional assessment of CVC, mood repair, psychiatric status, and psychosocial functioning, and longitudinal clinical follow-up. We propose that: (1) physiological inflexibility (operationalized as indices of impaired CVC) and behavioral inflexibility (operationalized as indices of impaired mood repair), and their combinations (global bio- behavioral inflexibility indices), will cross-sectionally distinguish probands, at-risk siblings, and control peers and that (2) global bio-behavioral inflexibility indices will prospectively predict clinical course (elevated depressive symptoms, recurrent depressive episodes in JOD probands, onset of first depressive episode in previously unaffected siblings). We also will test elements of our global inflexibility models in the presence of environmental moderators. Our study is significant because depression is a leading cause of disability worldwide. Moreover, JOD is a severe and recurrent form of depression that accounts for about 50% of the cases of depression in young adults. Our study is innovative because it: (a) integrates biological and behavioral indices relevant to depression that have ready translational potential, (b) uses alternate probes of CVC and mood repair across multiple stimulus conditions to obtain a richer characterization of these constructs, and (c) its bio-behavioral targets can inform improved efforts to detect, prevent, and treat depression. PUBLIC HEALTH RELEVANCE: In this application, we conceptualize depression as a condition of bio-behavioral inflexibility and apply this framework to juvenile-onset depression (JOD)--a particularly serious form of mood disorder. By comparing depressed youths, non-depressed siblings, and never-depressed peers, we will identify biological and behavioral aspects of inflexibility that increase a youngsters' risk of developing JOD and hinder recovery from this condition. The public health significance of this project derives from the fact that it will yield knowledge that can improve efforts to detect, prevent, and treat JOD.