The goal of this K23 Mentored Patient-Oriented Research Career Development Award is to gain the mentorship, training, and research experiences necessary to establish myself as an independent investigator focused on developing neurobiologically informed cognitive remediation interventions for geriatric depression. I am currently a research fellow at the Weill-Cornell Advanced Center for Interventions and Services Research (ACISR) for Late-Life Depression. My short-term goals are to refine the computerized cognitive remediation (CCR) intervention I developed with my mentors and to conduct a preliminary study to test its efficacy. Beyond serving as a training tool, the improved CCR methods will be critical for the next step in my career, an RCT of a streamlined version of my intervention supported by an R01 grant. These goals will be completed under the mentorship of George Alexopoulos, M.D. of the Weill-Cornell ACISR, Bruce Wexler, M.D., of Yale University School of Medicine, and a team of consultants at Weill-Cornell Medical College, Yale University School of Medicine, and Columbia University Medical Center. In geriatric depression, deficits in executive functions are common and disabling. We and others have documented that some executive dysfunctions and their underlying brain network abnormalities are associated with poor response to antidepressants. My own work suggests that a specific determinant of resistance to antidepressants is semantic strategy impairment. This impairment is evident on both verbal fluency and verbal memory tests. The identification of this specific and clinically relevant neurocognitive deficit was an essential ste in designing the proposed computerized cognitive remediation (CCR) intervention. The proposed training plan consists of formal coursework, seminars, targeted tutorials, collaborative studies, and manuscript preparation, all of which are planned with the goal of imparting knowledge and skills in the neurobiology and neural plasticity in normal aging, CCR method development, and clinical trials methodology. The process and content of the training experiences are designed in a way that it will provide the opportunity for me to benefit maximally from interaction with mentors, collaborators, and consultants, and prepare me to submit a future R01 application. In addition to the above training, I plan to conduct a research project that will function as the training ground for accomplishing my educational objectives. In my Research Plan, I propose to investigate whether computerized cognitive remediation for geriatric depression (CCR-GD) can improve the efficacy of antidepressant treatment in geriatric depression by targeting specific executive deficits and (by inference) their underlying neurobiologic abnormalities.
The first aim of the project is to pre-pilot and revise CCR-GD to achieve an optimal balance of challenge, performance, and acceptability to participants. The resultant version of CCR-GD will be piloted in my Research Plan. I hypothesize that older adults with major depression who have received therapeutic dosages of antidepressants for at least 8 weeks who receive CCR-GD will show greater reduction in depressive symptoms (MADRS), and greater increases in semantic strategy than participants on antidepressants plus a control condition over 4 weeks. Additional exploratory analyses will examine whether benefits of CCR-GD will transfer to executive functions other than those targeted by the intervention, whether verbal semantic strategy impairment at baseline moderates the advantage of CCR-GD in reducing depressive symptoms, and whether change in semantic strategy is associated with change in depression scores. Finally, the ACISR follow-up research program may offer the opportunity to examine whether benefits of CCR-GD (over the control condition) in depressive symptoms and in semantic strategy are retained 12-weeks after treatment completion.
Late-life depression is a devastating disorder often accompanied by neurocognitive deficits. In addition to increasing the severity of the illness, and disability, specific deficits in executive functions have been found to predict poor treatment response to antidepressants. We propose a training program that will prepare the applicant for a research career focused on developing cognitive remediation interventions for geriatric depression targeting network abnormalities associated with executive dysfunction and poor clinical outcomes. If successful, this line of research may enrich existing treatments with interventions relying on novel mechanisms likely to help depressed older patients who have failed first line treatments.
|Morimoto, Sarah Shizuko; Wexler, Bruce E; Liu, Jiacheng et al. (2014) Neuroplasticity-based computerized cognitive remediation for treatment-resistant geriatric depression. Nat Commun 5:4579|