Neurobehavioral Trajectories of Pediatric Depression and Insulin Sensitivity

 描述(申请人提供)：抑郁症和肥胖症在今天的美国年轻人中正达到流行的比例，当它们同时出现时，它们可能会产生复合的有害影响，包括对胰岛素抵抗(糖尿病的前驱症状，细胞对胰岛素的正常作用不起作用)的胰岛素敏感性受损。传统上，抑郁和胰岛素敏感性受损被划分为不同的情绪和身体健康症状。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路径可能导致抑郁症状恶化。到目前为止，还没有研究调查患有抑郁症和胰岛素敏感性受损的青年抑郁症状恶化的潜在机制或危险因素。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出现恶化的抑郁症状，因为目前克服终身抑郁和肥胖威胁的现有药物和饮食/生活方式策略效果有限，有不良副作用，而且在大多数情况下无法治愈。令人信服的最新数据表明，与体重变化无关的抑郁青年，早期会出现对奖赏反应和调节至关重要的神经生物学系统的紊乱，最明显的是伏隔核、扣带前皮质、脑岛和杏仁核神经奖赏回路。这项研究涉及NIMH研究领域标准(RDoC)积极价值系统的方法动机结构，该系统描述了当患有抑郁症的青少年从事不健康的生活方式行为(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逐渐恶化抑郁症状的高风险中。这项建议的目的是在第一项前瞻性研究中使用RDoC框架来调查抑郁症状恶化的机制和危险因素，这些抑郁症状与患有抑郁症和胰岛素敏感性受损的青年的方法动机障碍有关。为了实现这些目标，120名寻求治疗中重度抑郁症状的超重女孩和男孩(9-15岁)将在基线、6个月和24个月接受认知和行为标记物的评估，包括接近动机的认知和行为标记物、血清胰岛素敏感性标记物和抑郁症的临床标记物。青春将会是 分别于基线和6个月行多模式MRI扫描。我们的目的是确定患有抑郁症和胰岛素敏感性受损的年轻人抑郁症状的恶化是否由神经奖赏回路的变化所介导，并确定这些年轻人发展恶化抑郁症的临床、人口和家庭危险因素。这一知识对心理健康和初级保健专业人员至关重要，因为他们的实践所依据的经验证据有限。它还有可能为其他与功能失调的方法动机相关的疾病的病理生理学提供信息，并为治疗青年中的这些复杂问题开发新的经验目标。

 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.