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.

PUBLIC HEALTH RELEVANCE: Depression and obesity are affecting a growing number of youth worldwide and, together, may lead to progressive lifelong depressive symptoms and medical morbidities such as diabetes and cardiovascular disease. The proposed research will help to identify early neurobehavioral mechanisms and risk factors for developing worsening symptoms of depression in overweight youth with depression and impaired insulin sensitivity that could prevent the development of adverse long-term health outcomes.