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。与促进大脑和行为科学发现的NIH目标相一致，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，何地以及如何进行干预，关键的公共卫生优先事项是开发用于识别和改变增加个体易患抑郁症的因素和机制的方法。抑郁父母的后代患抑郁症的风险较高;因此，评估这些儿童一直是阐明与精神疾病风险增加相关因素的重要策略。然而，迄今为止，很少有研究超越记录这种风险的程度，以检查可能是抑郁症风险代际传递的具体机制。在过去的四年里，我们努力招募和测试了一个大的，仔细诊断的，10到14岁的从未有过抑郁症的女孩样本，这些女孩的抑郁症家族风险很高或很低。每个女孩都有一个亲生母亲，她要么在女儿的一生中经历过反复发作的重度抑郁症（MDD）（高风险），要么从未经历过任何Axis-I障碍（低风险）。尽管高危女孩没有症状，但我们发现她们已经表现出MDD的特征，包括对悲伤面孔的选择性注意，对实验室压力源的反应中更高和更长的皮质醇分泌，更高水平的唤醒皮质醇，更小的神经活动，以及对奖励和惩罚的反应以及在经历和调节悲伤情绪时的异常神经功能。因为我们在四年前才开始招募这个年轻的女孩参加这项研究，我们还不能完全检查这些困难是否预测了MDD首次发作的后续发作。因此，我们建议对该样本进行为期54个月的随访诊断，并增加第二次fMRI扫描，以评估患有MDD的高危女孩与不患有MDD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新的样本的高风险的女儿，教他们通过注意力偏差训练或通过实时神经反馈训练，以改变机制，我们认为是MDD的发展，并评估调节这些机制的短期和长期影响。我们建议检查即时变化的压力反应，认知偏差，奖励处理作为一个功能的培训。我们还建议进行18个月的随访评估，以检查培训对特定临床结构的长期影响，如抑郁症状水平，应对策略和MDD的发作。该项目将产生关于MDD的心理和生物风险因素的新见解，并将提供可用于开发预防抑郁症的创新和有效方法的重要信息。 公共卫生相关性：该项目有望提高我们对增加抑郁症风险的心理和生物机制的理解，抑郁症是一种影响世界四分之一人口的毁灭性精神疾病，在生命早期开始，经常成为慢性和无情的。了解这些机制将有助于我们开发更有效的方法来预防临床抑郁症。

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.