Expansion of the Dopaminergic Dysfunction in Late-Life Depression Study (The D3 Study)

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PROJECT SUMMARY: This administrative supplement will expand scientific expertise and recruitment for the “Dopaminergic Dysfunction in Late-Life Depression” study. This proposal was originally funded as a collaborative R01 proposal between Columbia University/New York State Psychiatric Institute and Vanderbilt University Medical Center. As the Columbia site will no longer be contributing to this project, this supplement will provide support for the Vanderbilt site to: a) have the required scientific expertise to achieve study goals; b) provide budgetary support for study procedures previously covered by Columbia University; and c) expand enrollment to reach goals comparable to the funded collaborative proposal. The overall objective of the funded proposal does not change with this supplement. This supplement supports an expansion of the study that will allow us to achieve the funded study goals without Columbia University. Expansion of scientific expertise includes involvement of new personnel with expertise in biostatistics, PET imaging, MRI-based neuromelanin imaging, and peripheral inflammatory markers. It will support procedures previously supported by Columbia, specifically statistical analyses, the analyses of some neuroimaging data (Neuromelanin-MRI and [18F]-FDOPA PET) and analyses of inflammatory markers by Emory University. It will also support the expansion of recruitment beyond what was initially planned at the Vanderbilt site, expanding recruitment both at Vanderbilt and at a new subcontracted site at the University of Pittsburgh. These changes provide the scientific expertise and resources to achieve the goals of the originally funded study while maintaining statistical power. Study procedures have not substantially changed. We will enroll cumulatively 70 psychiatrically healthy elders and 100 depressed elders exhibiting likely dopaminergic dysfunction, characterized as either slowed processing speed or slowed motor speed. Participants undergo 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 are then 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. These procedures have been feasible and well tolerated with ongoing enrollment at Vanderbilt.