Depression is a leading cause of worldwide disability that increases markedly during adolescence. The period surrounding pubertal maturation may represent a sensitive period for the development and prevention of depression, and also provides a valuable window of opportunity to better understand how depression develops. Having an anxiety disorder before reaching puberty seems to put youth at increased risk of developing depression during adolescence. Our goal is to better understand why so many anxious children become depressed as adolescents, and whether treatment of anxiety in early adolescence can prevent these children from becoming depressed. From an affective neuroscience perspective, we focus on problems in neural response to potential social evaluation and potential reward as two vulnerabilities that may link child anxiety to adolescent depression. These vulnerabilities (a) have been associated with depression (b) are likely to be problematic in many but not all anxious youth, (c) may be exacerbated by maturational processes that occur around pubertal development in ways that could create a negative spiral into a depressive disorder, and (d) if targeted through early intervention could alter the trajectory toward depression. We will build upon an existing Center for Intervention Development and Applied Research that provides cognitive behavioral therapy and supportive psychotherapy to 9-13 year old youth with generalized anxiety disorder, separation anxiety disorder, and social phobia. We will conduct annual psychiatric follow-up interviews and biannual assessments of depressive symptomatology for approximately 180 of these treated youth through mid-to-late adolescence (4 years after treatment; ages 13 to 17). Two years following treatment, youth will complete a battery of socially relevant laboratory tasks, such as a virtual peer interaction and a parental criticism and praise task, during functional neuroimaging of brain activity with concurrent assessment of pupil dilation. We will also assess social threat and reward-related behaviors and emotions in the home environment using an ecological momentary assessment battery administered via cell phone interviews with the youth. These assessments will allow us to track how treatment and threat- and reward-related vulnerabilities contribute to the onset of depression and growth in depressive symptoms throughout this high-risk period and to track changes in these vulnerabilities with pubertal maturation. Specifically, we will examine (1) whether successful early treatment of anxiety prevents depression in adolescence, (2) whether it does so by normalizing response to social threat and reward, and (3) whether residual vulnerabilities in response to social threat and reward immediately following treatment predict which youth develop depression in adolescence. We will also explore (4) whether these vulnerabilities increase as the youth advance in pubertal maturation, (5) whether this exacerbation is attenuated by successful treatment during pre-to-early puberty; and (6) whether the timing of the intervention relative to pubertal development influences later risk for depression and its neural underpinnings. PUBLIC HEALTH RELEVANCE: Adolescent depression is associated with serious disruptions in emotional, social and occupational functioning into adulthood, high rates of recurrence, and high rates of morbidity and lifetime disability. This proposal seeks to address this enormous public health problem by identifying modifiable developmental precursors of depressive disorders during this key period of development. Results of this investigation could support better screening for early anxiety, better availability of prevention/intervention programs targeting anxiety in early adolescence, improved understanding of the mechanisms through which anxiety and its treatment influence risk for later depression, refinements to the content of anxiety treatment and/or depression prevention programs, and recommendations about the optimal timing of treatment relative to pubertal development.