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，我们回应了IRG的每一项关切，将生物行为的僵化作为确定青少年起病抑郁(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更明确的表述；b)解决可能的环境调节因素；c)介绍新的先导性研究的结果，这些研究表明我们有能力诱导和补救匈牙利受试者的烦躁情绪，并支持在年轻人中使用体细胞探头来控制心脏迷走神经。在这一应用中，我们建议研究当前和未来的JOD风险与两个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。为了描述CVC缺乏灵活性的特征，我们将评估CVC在不同实验挑战(躯体和心理)、一种类型挑战的不同版本(例如，替代心理任务)以及CVC的不同方面(休息与CVC反应和恢复)之间的功能。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(积极的自传性回忆和分心)以及不同的情绪修复机会(实验控制的和非结构化的)来评估受试者在消极情绪挑战后缓解烦躁情绪的能力。我们的样本(入选时年龄在11-18岁)将包括200名患有JOD的先证者，200名尚未受到JOD影响的高危兄弟姐妹，以及100名从未患病的对照组。先证者(和兄弟姐妹)将从精心诊断和特征良好的700多名JOD年轻患者(每个患者至少有一个兄弟姐妹)样本中招募，这些患者代表匈牙利的一个全国性临床样本，他们参加了最近的一项计划项目。该设计包括CVC的横断面评估、情绪修复、精神状态和心理社会功能，以及纵向临床随访。我们认为：(1)生理缺乏灵活性(作为CVC受损的指数)和行为缺乏(作为情绪修复受损的指数)及其组合(全球生物行为缺乏指数)将横断面区分先证者、高危兄弟姐妹和对照同龄人，(2)全球生物行为缺乏指数将前瞻性地预测临床病程(抑郁症状增加，JOD先证者反复抑郁发作，先前未受影响的兄弟姐妹首次抑郁发作)。我们还将在环境主持人在场的情况下测试我们的全球僵化模型的要素。我们的研究意义重大，因为抑郁症是世界范围内导致残疾的主要原因。此外，JOD是一种严重的反复发作的抑郁症，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)整合了与抑郁相关的生物学和行为指标，这些指标具有现成的翻译潜力；(B)使用多种刺激条件下CVC和情绪修复的交替探针，以获得对这些结构的更丰富的表征；(C)其生物行为目标可以为改进检测、预防和治疗抑郁症的努力提供信息。公共卫生相关性：在这项应用中，我们将抑郁症概念化为生物行为不灵活的状况，并将这一框架应用于青少年起病抑郁症(JOD)--一种特别严重的情绪障碍形式。通过比较抑郁的青少年、非抑郁的兄弟姐妹和从不抑郁的同龄人，我们将确定缺乏灵活性的生物和行为方面会增加青少年患JOD的风险，并阻碍他们从这种情况中恢复。该项目的公共卫生意义来自这样一个事实，即它将产生能够改进发现、预防和治疗JOD的努力的知识。

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.