A Targeted Intervention of a Putative Striatal Subtype of Pharmacoresistant Depression

项目总结

PROJECT SUMMARY Major depression is the leading cause of disability worldwide, affecting over 300 million people. Individuals with treatment-resistant depression (TRD) experience the greatest toll, with double the risk of suicide, particularly prolonged suffering, and greater use of resources. Anhedonia, the inability to feel pleasure, is among the most important risk factors for the development of TRD. Because anhedonia implicates dysfunction in key regions of the brain’s reward circuits, these regions are viable mechanistic biomarkers for testing engagement of novel interventions for depressed people who do not respond to currently available antidepressants. In this K23 proposal, I will deploy a novel target-engagement design to evaluate a biomarker and alternative intervention approach for anhedonia in TRD. I target D3 receptor agonism with pramipexole and evaluate the effects on a reward circuit biomarker of interest, the ventral striatum (VS), as well as clinical, functional, and suicidality outcomes in TRD patients with prominent anhedonia. First, I will determine whether reward task-evoked VS activation changes in a group of TRD subjects as a result of treatment with pramipexole after 8 weeks; second, evaluate whether anhedonia measures, function, and suicidality change in the same group after 8 weeks of treatment with pramipexole; and third, assess whether baseline ventral striatal activation is associated with change in VS activation and clinical outcomes. This K23 proposal and accompanying training plan would enable me to receive advanced training in three key areas: the analysis and interpretation of functional neuroimaging data, traditional and biomarker-guided clinical trials, and biomarkers across multiple domains. Furthermore, I have assembled an interdisciplinary mentorship team ideally suited to guiding me through this project, consisting of leaders in functional neuroimaging (Dr. Leanne Williams, Primary Mentor), biomarkers in depression (Dr. Andrew Krystal, Collaborator), depressive disorders and traditional clinical trials (Dr. Alan Schatzberg, Co-Mentor), statistics and innovative clinical trial design (Dr. Philip Lavori, Collaborator), reward processing (Dr. Michael Treadway, Collaborator), and neuroimaging-guided trials in major depressive disorder (Dr. Boadie Dunlop, Collaborator). Furthermore, as part of my training, I intend to continue clinical work during the period of my Career Development Award, launching my own consultation clinic for patients with treatment-resistant mood disorders facilitated under the umbrella of the Mood Disorders Center at Stanford during the latter years of the Award. Conducting clinical work together with research will ideally position me to ask scientific questions and implement study designs that explicitly translate key discoveries from basic science into guidance for clinical decision-making. This proposal will be carried out at Stanford University, a world renowned hub of neuroscience and psychiatry research and at Stanford’s Center for Cognitive and Neurobiological Imaging, a state-of-the-art neuroimaging facility.