Dopamine Availability and Developmental Pathways of Adolescent Depression and Anhedonia

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Project Summary/Abstract Depression is a common, serious form of psychopathology that is associated with suffering, disability, and suicide. Depression is characterized by disrupted reward function and typically begins during adolescence, a key developmental period for change in neurobehavioral systems supporting reward-driven behavior. The dopamine neuromodulatory system is consistently associated with depression and thought to be specifically reflected in anhedonia, a cardinal symptom of depression that involves difficulty with motivation for or enjoyment of pleasant experiences. Furthermore, dopamine function is postulated to mediate the influence of neuroinflammation on depression. Developmentally, understanding the role of dopamine in depression requires examining changes in reward function over time and across domains, including frontostriatal reward circuitry, dopamine availability in the striatum, reward-driven behavior, and reward-focused experiences in real-life settings. The proposed study uses a developmental psychopathology and clinical neuroscience approach. It situates changes in depression, dopamine, and their association against a backdrop of typical development and captures key constructs across methods and domains. Its translational strategy emphasizes measures of dopamine function inspired by basic neuroscience. The study will examine developmental pathways of dopamine in adolescent depression, using an accelerated longitudinal design with assessments at 0, 12, and 24 months in 150 adolescents (age 16-22), 75 with depression and 75 who are psychiatrically healthy. Adolescents will complete a magnetic resonance imaging (MRI) session to assess dopamine function; functional MRI of frontostriatal response during a reward paradigm and at rest; ecological momentary assessment (EMA) of reward anticipation and reward-seeking behavior; smartphone-based passive sensing of motor activity and phone/text activity; behavioral tasks of reward motivation; self-report of depression, anhedonia, and reward function; and measurement of circulating inflammatory markers (e.g., CRP, IL-6). Dopamine function will be measured safely and noninvasively through MRI. The primary focus will be dopamine availability via R2’, a measure of tissue iron, which is concentrated in the basal ganglia, co-localizes with pre-synaptic dopamine vesicles, and is necessary for dopamine synthesis. The study will elucidate the relation of depression and dopamine availability, their possible co-fluctuation across adolescence, and the potential association of inflammatory markers with depression through dopamine availability. Findings will have relevance to the pathophysiology, course, and treatment of depression.