2/2-Dopaminergic Dysfunction in Late-Life Depression (The D3 Study)

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PROJECT SUMMARY: Growing evidence suggests that dopamine contributes to key functions in multiple RDoC domains, specifically Positive Valence Systems, Cognitive Systems, and Sensorimotor Systems. In Late-Life Depression (LLD), dysfunction in all these systems is common, portends poor outcomes, and manifests as deficits in motivation and effort, executive dysfunction, and gait impairment. While studies of dopamine function in early and midlife depression primarily focus on reward processing, they often exclude the cognitive and sensorimotor domains relevant for older adults despite a recognized decline in dopamine function with normal aging. The objectives of this collaborative R01 proposal between Columbia University/New York State Psychiatric Institute and Vanderbilt University Medical Center are to: 1) characterize dopaminergic dysfunction in LLD across multiple RDoC domains (Positive Valence Systems, Cognitive Systems, and Sensorimotor Systems) at several levels of analysis (cellular [PET], circuit [MRI], and behavioral / self-report); and 2) examine the responsivity of dopamine-related circuits and behavior to stimulation with levodopa (L-DOPA). Supported by pilot data, this project builds on our past work demonstrating that dopamine function declines with aging, that dopaminergic dysfunction contributes to deficits in behavioral measures of the Positive Valence Systems, Cognitive Systems, and Sensorimotor Systems, and that L-DOPA administration improves performance in these systems. The long-term goal of this line of research is to determine how dopaminergic dysfunction contributes to clinical presentations of LLD, how responsive behavioral symptoms are to modulation of dopamine function, and to identify novel targets for future interventions. Our approach is to enroll 60 psychiatrically healthy elders (30 per site) and 120 depressed elders (60 per site) exhibiting likely dopaminergic dysfunction, characterized as either slowed processing speed or slowed gait speed. Participants will undergo thorough clinical characterization and complete PET imaging measuring dopamine synthesis and dopamine receptor availability, neuromelanin-sensitive MRI measurement of long-term nigrostriatal dopamine transmission, task positive MRI focused on effort-based decision making and reward processing, a comprehensive neurocognitive evaluation, a physical performance evaluation, and measurement of inflammatory markers. To assess responsivity of the dopamine system to modulation, depressed subjects then will be randomized to L-DOPA or placebo for 3 weeks, followed by repeat multimodal MRI and cognitive/behavioral assessments. Using a cross-over design, participants will receive the opposite intervention for an additional 3 weeks followed by clinical and cognitive assessments only. This proposal is significant and innovative, as no prior published study has comprehensively examined dopamine-dependent behaviors in LLD. This will inform treatment approaches focusing on facilitating cognition and movement, reducing the effort cost of voluntary behavior, and promoting behavioral activation.