Risk for Depression:Identifying and Altering Psychobiological Mechanisms

描述（由申请人提供）：抑郁症是所有精神疾病中最普遍的。美国国立卫生研究院的目标是促进大脑和行为科学的发现，以推动对精神障碍原因的研究，并绘制精神疾病轨迹，以确定何时、何地以及如何干预，这与NIH的目标相一致，关键的公共卫生优先事项是开发识别和改变增加个人易患抑郁症的因素和机制的方法。众所周知，患有抑郁症的父母的后代患抑郁症的风险较高；因此，评估这些儿童已成为阐明与精神障碍风险增加相关因素的重要策略。然而，迄今为止，很少有研究超越了记录这种风险的程度，以检查可能导致抑郁症风险代际传递的具体机制。在过去的四年里，我们一直在努力招募和测试一个庞大的、经过仔细诊断的样本，这些样本来自10到14岁的、从未患过抑郁症的女孩，她们有高或低的家族性抑郁症风险。每个女孩的生母要么在女儿的一生中经历过重度抑郁症（MDD）的反复发作（高风险），要么从未经历过任何轴- 1障碍的发作（低风险）。虽然高危女孩没有症状，但我们发现她们已经表现出重度抑郁症的特征，包括选择性地注意悲伤的脸，对实验室压力源的皮质醇分泌更高且更长时间，唤醒皮质醇水平更高，海马体较小，在对奖励和惩罚的反应中以及在经历和调节悲伤情绪时出现异常的神经功能。因为我们在四年前才开始招募这么小的女孩参加这项研究，我们还不能完全检查这些困难是否能预测随后的MDD首发发作。因此，我们建议对该样本进行54个月的随访诊断，并增加第二次功能磁共振成像扫描，以评估患重度抑郁症和未患重度抑郁症的高危女孩之间神经结构和功能稳定性的差异。我们还建议招募一个高风险女儿的新样本，通过注意偏差训练或实时神经反馈训练来教她们改变我们假设的MDD发展背后的机制，并评估调节这些机制的短期和长期影响。我们建议检查应激反应、认知偏差和奖励处理的即时变化作为训练的功能。我们还建议进行为期18个月的随访评估，以检查培训对特定临床结构（如抑郁症状水平、应对策略和重度抑郁症发病）的长期影响。该项目将产生关于重度抑郁症的心理和生物学风险因素的新见解，并将提供重要信息，可用于开发创新和有效的方法来预防抑郁症。

DESCRIPTION (provided by applicant): Depression is among the most prevalent of all psychiatric disorders. Consistent with the NIH objectives of promoting discovery in the brain and behavioral sciences to fuel research on the causes of mental disorders and charting mental illness trajectories to determine when, where, and how to intervene, a critical public health priority is the development of methods for identifying and altering factors and mechanisms that increase individuals' vulnerability to depression. Offspring of depressed parents are known to be at elevated risk for developing depression; consequently, assessing these children has been an important strategy for elucidating factors associated with the increased risk for psychiatric disorder. To date, however, few studies have gone beyond documenting the magnitude of this risk to examine specific mechanisms that might underlie the intergenerational transmission of risk for depression. Over the last four years we have worked hard to recruit and test a large, carefully diagnosed, sample of 10- to 14-year-old never-disordered girls at either high or low familial risk for depression. Each girl has a biological mother who either has experienced recurrent episodes of Major Depressive Disorder (MDD) during her daughter's lifetime (high risk) or has never experienced an episode of any Axis-I disorder (low risk). Although the high-risk girls are asymptomatic, we have found that they nevertheless already exhibit characteristics of MDD, including selective attention to sad faces, higher and more prolonged cortisol secretion in response to a laboratory stressor, higher levels of awakening cortisol, smaller hippocampi, and anomalous neural functioning both in response to reward and punishment and while experiencing and regulating a sad mood. Because we began recruiting the girls in this study at this young age only four years ago, we have not yet been able to examine fully whether these difficulties predict the subsequent onset of a first episode of MDD. Therefore, we propose to conduct a 54-month follow-up diagnostic session with this sample and to add a second fMRI scan to assess differences in the stability of neural structure and function between high-risk girls who do, and who do not, develop MDD. We also propose to recruit a new sample of high-risk daughters, to teach them either through attentional bias training or through real-time neurofeedback training to alter mechanisms that we posit underlie the development of MDD, and to assess both short- and long-term effects of modulating these mechanisms. We propose to examine immediate changes in stress reactivity, cognitive biases, and reward processing as a function of training. We also propose to conduct an 18-month follow-up assessment to examine longer-term effects of training on specific clinical constructs, such as levels of depressive symptoms, coping strategies, and the onset of MDD. This project will yield new insights concerning psychological and biological risk factors for MDD, and will provide important information that can be used to develop innovative and effective approaches to the prevention of depression. PUBLIC HEALTH RELEVANCE: This project promises to improve our understanding of psychological and biological mechanisms that increase risk for depression, a devastating psychiatric condition that affects one-quarter of the world's population, that starts early in life and frequently becomes chronic and unrelenting. Understanding these mechanisms will help us to develop more effective approaches to the prevention of clinical depression.