Neurobehavioral Trajectories of Pediatric Depression and Insulin Sensitivity

 描述（由申请人提供）：抑郁症和肥胖症在当今的美国青年中达到流行病的比例，当它们同时发生时，它们可能具有复合有害影响，包括胰岛素敏感性受损向胰岛素抵抗的发展（糖尿病的前兆，其中细胞不能对激素胰岛素的正常作用做出反应）。传统上，抑郁症和胰岛素敏感性受损被划分为单独的情绪和身体健康综合征。然而，最近的证据表明，这些综合征之间的相互作用和共同的神经行为途径可能导致抑郁症状恶化。到目前为止，还没有研究调查抑郁症和胰岛素敏感性受损青年抑郁症状恶化的潜在机制或风险因素。 临床上迫切需要更好地确定哪些患有抑郁症和胰岛素敏感性受损的青年最有可能发展为抑郁症状恶化，因为目前用于克服终身抑郁症和肥胖症的新兴威胁的药理学和饮食/生活方式策略的疗效有限，具有不良副作用，并且在大多数情况下无法治愈。令人信服的最新数据表明，抑郁的年轻人，独立于体重的变化，有早期中断的神经生物学系统的反应和调节的奖励，最显着的是在神经核，前扣带皮层，杏仁核和杏仁核神经奖励电路的关键。本研究涉及NIMH研究领域标准（RDoC）积极效价系统的方法动机结构的参与，该系统描述了抑郁症青年参与不健康的生活方式行为（例如暴饮暴食）时奖励功能障碍的基本方面，这些行为使他们处于抑郁症状逐渐恶化的高风险中。 该提案旨在在第一项前瞻性研究中使用RDoC框架，以调查抑郁症状恶化的机制和风险因素，这些机制和风险因素与抑郁症和胰岛素敏感性受损的青少年的功能障碍性接近动机相关。为了实现这些目标，120名超重女孩和男孩（9-15岁）寻求治疗中度至重度抑郁症状，将在基线、6个月和24个月时评估接近动机的认知和行为标志物、胰岛素敏感性的血清标志物和抑郁症的临床标志物。青年将成为 在基线和6个月时用多模态MRI扫描。我们的目的是确定是否恶化的抑郁症和胰岛素敏感性受损的青年抑郁症状是由神经奖赏回路的变化介导的，并确定临床，人口统计学和家庭的危险因素，发展这些青年抑郁症恶化。这方面的知识将是至关重要的精神卫生和初级保健专业人员谁拥有有限的经验证据，他们的做法。它也有可能告知其他疾病的病理生理学与功能失调的方法动机和发展新的经验目标，以治疗这些复杂的问题，在青年。

 DESCRIPTION (provided by applicant): Depression and obesity are reaching epidemic proportions in American youth today, and when they co-occur, they may have compounding deleterious effects, including the development of impaired insulin sensitivity toward insulin resistance (a precursor to diabetes in which cells fail to respond to the normal actions of the hormone insulin). Traditionally, depression and impaired insulin sensitivity have been compartmentalized as separate emotional and physical health syndromes. However, recent evidence suggests interactions and common neurobehavioral pathways between these syndromes that can lead to worsening depressive symptoms. To date, no study has investigated the underlying mechanisms or risk factors for developing worsening of depressive symptoms in youth with depression and impaired insulin sensitivity. There is a pressing clinical need to better identify which youth with depression and impaired insulin sensitivity are most likely to develop worsening depressive symptoms, as current pharmacological and dietary/lifestyle strategies to overcome the burgeoning threat of lifelong depression and obesity are of limited efficacy, have adverse side effects, and in most cases are not curative. Compelling recent data have shown that depressed youth, independent of changes in weight, have early disruptions of neurobiological systems critical for the response and regulation of reward, most notably in the nucleus accumbens, anterior cingulate cortex, insula, and amygdala neural reward circuit. This Research has implicated involvement of the Approach Motivation construct of the NIMH Research Domain Criteria (RDoC) Positive Valence Systems, which describes fundamental aspects of reward dysfunction when youth with depression engage in unhealthy lifestyle behaviors (e.g. overeating) that place them at high risk for progressively worsening depressive symptoms. This proposal aims to use an RDoC framework in the first prospective study to investigate the mechanisms and risk factors for worsening depressive symptoms that are associated with dysfunctional Approach Motivation in youth with depression and impaired insulin sensitivity. To accomplish these aims, 120 overweight girls and boys (ages 9-15 years) seeking treatment for moderate to severe depressive symptoms, will be assessed at baseline, 6 months, and 24 months with cognitive and behavioral markers of Approach Motivation, serum markers of insulin sensitivity, and clinical markers of depression. Youth will be scanned with multimodal MRI at baseline and at 6 months. We aim to determine whether worsening depressive symptoms in youth with depression and impaired insulin sensitivity is mediated by changes in neural reward circuitry, and to identify clinical, demographic, and familial risk factors for developing worsening depression in these youth. This knowledge will be vitally important to mental health and primary care professionals who have limited empirical evidence on which to base their practice. It also has potential to inform the pathophysiology of other disorders associated with dysfunctional approach motivation and the development of novel empirical targets for treating these complex problems in youth.