Project Summary/Abstract The goal of the proposed K23 Mentored Patient-Oriented Research Career Development Award is to provide the PI with the mentorship, theoretical knowledge, and research skills to develop into a fully independent psychophysiological researcher studying biomarkers of depression that can be used as targets for novel interventions. In consultation with her mentors, the PI has recruited a team of expert consultants to guide her in executing a research project and training plan that will provide experience essential to her goals. The proposed study will be conducted at the ALACRITY Center of the Weill Cornell Institute of Geriatric Psychiatry. The study focuses on late-life depression because it is prevalent and has negative outcomes. Existing treatments have low response rates and are rarely used correctly in the community due to their complexity. The project is based on the premise that focused treatments targeting biosignatures of specific neural abnormalities will have the greatest impact on clinical outcomes in late-life depression. It concentrates on positive valence systems, which are vulnerable to aging and often impaired in depression. The project will investigate positive valence systems in older adults with major depression receiving Engage, a psychotherapy designed to reactivate reward system functions. Engage has been found efficacious in late-life depression and easy to learn by community-based therapists. Consistent with RDoC methods, the proposed study will examine target engagement of Engage in 35 depressed older adults (age ≥ 60) during a 9-week course of Engage therapy, using three units of analysis to assess positive valence system function: physiology (event-related potentials), self-reports, and behavior. It will compare Engage-treated participants with 35 depressed participants, group-matched on age, receiving manualized supportive therapy. Additional analyses will assess whether low baseline positive valence function, or increases in positive valence function during treatment, predict improvement of anhedonia with Engage, and whether reward function mediates change in anhedonia. The proposed training plan complements the research study with individualized tutorials, formal coursework, research collaborations, and manuscript preparation that will provide the PI with knowledge and skills in several areas: 1) Age-related neurobiological changes in the positive valence system and related networks; 2) Advanced statistical techniques to identify distinct neural abnormalities in depressed individuals based on their ERP profiles; and 3) Clinical trial design for psychotherapeutic interventions. The proposed project may provide important information about target engagement and mechanisms of a biologically informed, easily implemented treatment for late-life depression that has potential for dissemination. It will also provide pilot data for an R-series study using machine learning methods to predict response to Engage and will serve as an important stepping-stone for the PI as she prepares for an independent research career.

Late-life depression is prevalent and devastating, and response rates to even the most effective treatments are low. Outcomes may be improved by developing targeted interventions such as Engage – a new, easily disseminated, neurobiologically informed psychotherapy for late-life depression designed to restore impaired function of the positive valence system. The proposed study will use event-related potentials and a panel of other positive valence system measures to assess target engagement in 35 depressed older adults (age ≥ 60) receiving Engage therapy, with a comparison group of 35 age-group-matched depressed peers receiving supportive therapy.