Biobehavioral inflexibility and risk for juvenile-onset depression

描述（由申请人提供）：在这份修订后的申请中，我们对IRG的每一个问题都做出了回应，该申请侧重于将生物行为不灵活性作为识别青少年抑郁症（JOD）风险因素的框架。特别是，我们：a)对我们的模型、假设和统计方法提供了更明确的表述，b)解决了可能的环境调节因素，c)提出了新的试点研究的结果，这些研究表明我们有能力诱导和纠正匈牙利受试者的烦躁情绪，并支持在年轻人中使用心脏迷走神经控制的躯体探针。在这项应用中，我们建议研究当前和未来JOD风险与两个功能重要的生物行为系统：心脏迷走神经控制（CVC）和情绪修复之间的关系。为了表征CVC的不灵活性，我们将评估CVC在不同实验挑战下的功能（躯体与心理）；在一种挑战的不同版本中（例如，替代性心理任务）；以及CVC的不同方面（休息vs. CVC反应性和恢复）。为了描述不灵活的情绪修复，我们将通过实施两种不同的情绪修复策略（积极的自传体回忆vs分心）和不同的情绪修复机会（实验控制vs非结构化）来评估受试者在负面情绪挑战后减轻烦躁情绪的能力。我们的样本（11-18岁）将包括200名患有JOD的先证者，200名未患JOD的有风险的兄弟姐妹，以及100名从未患病的对照。先证（和兄弟姐妹）将从仔细诊断和特征明确的700多名年轻JOD患者（每个患者至少有一个兄弟姐妹）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项目。设计包括CVC、情绪修复、精神状态和社会心理功能的横断面评估，以及纵向临床随访。我们建议：(1)生理不灵活性（作为CVC受损的指标）和行为不灵活性（作为情绪修复受损的指标）及其组合（整体生物-行为不灵活性指标）将在横断面上区分先证者、有风险的兄弟姐妹和对照组同伴；(2)整体生物行为不灵活性指标将前瞻性地预测临床病程（抑郁症状升高、抑郁复发）；在先前未受影响的兄弟姐妹中首次出现抑郁发作)。我们还将在环境调节者在场的情况下测试我们的全球不灵活性模型的要素。我们的研究意义重大，因为抑郁症是全球致残的主要原因。此外，JOD是一种严重且反复发作的抑郁症，约占年轻人抑郁症病例的50%。我们的研究具有创新性，因为它：(a)整合了与抑郁症相关的生物学和行为指标，这些指标具有转化潜力；(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特征；(c)其生物行为靶点可以为改进检测、预防和治疗抑郁症的努力提供信息。公共卫生相关性：在本应用中，我们将抑郁症概念化为一种生物行为缺乏灵活性的状况，并将此框架应用于青少年性抑郁症（JOD）——一种特别严重的情绪障碍。通过比较患有抑郁症的青少年、未患抑郁症的兄弟姐妹和从未患抑郁症的同龄人，我们将确定缺乏灵活性的生理和行为方面的因素，这些因素会增加青少年患JOD的风险，并阻碍从这种情况中康复。该项目的公共卫生意义在于，它将产生能够改进检测、预防和治疗JOD工作的知识。

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.