ABSTRACT: Older adults with moderate-to-severe depression symptoms (i.e., PHQ-9 scores ≥ 10) plus active suicidal ideation (SI) and/or a history of attempt are at high risk for suicidal behaviors and death. Data suggest that sleep-wake rhythm disruption could provide a modifiable target mechanism to improve depression treatment outcomes. Controlled pilot data from a sample of older adults with serious mental illness show, compared with treatment as usual (TAU), a behavioral approach called the Transdiagnostic Intervention for Sleep and Circadian Dysfunction (TranS-C) may improve sleep-wake rhythm stability and lead to more sustained depression responses six-months later. We propose to confirm TranS-C’s target engagement (Aim 1) and efficacy for depression (Aim 2A) in older adults with depression symptoms plus high suicide risk. The primary efficacy outcome is clinically significant: depression symptom response rates six-months post- treatment (≥50% reductions in pre-treatment non-sleep GRID Hamilton Depression Rating Scale scores). Key secondary outcomes include SI rates six-months post-treatment (i.e., active SI with a method defined as Columbia Suicide Severity Rating Scale ideation scores ≥ 3) and the incidence of a suicidal behavior composite (i.e., escalating planning/attempt/suicide-related hospitalization) over six-months. Pilot data support the hypothesized target engagement and efficacy, but as is typical of psychiatric treatments, we anticipate treatment response variability. Exploratory Aim 3 is therefore to develop an algorithm indicating for whom TranS-C is efficacious. To accomplish these aims, we will conduct a three-site, double-blind, randomized controlled trial (n=420) testing 8-weeks of TranS-C+TAU versus a contact-time matched active listening control plus TAU (AL+TAU). Eligibility criteria include being 55+ years old, having PHQ-9 scores ≥ 10, Scale for Suicide Ideation scores ≥ 3 or a past suicide attempt, and elevated sleep disturbances/impairment (PROMIS) despite TAU with at least the minimum effective depression pharmacotherapy dose. The main target engagement measure is actigraphy inter-daily stability post-treatment, an objective rhythm measure, which correlated with depression symptom reductions six-months after TranS-C in our pilot. Therapists will be centrally-trained and carefully monitored for fidelity. Assessments pre-, post-, and 6-months post-treatment include diagnostic interviews, self-report measures, and a week of actigraphy/sleep diary. Weekly during the treatment phase, and monthly six-months thereafter, participants will receive calls from blinded assessors charting treatment effects and actively monitoring for safety. Participants will also wear wrist actigraphy in the treatment phase to objectively track changes in sleep-wake patterns. Analyses seek to confirm if TranS-C has efficacy for sustained depression responses; and to evaluate mediation via the target/alternative mechanisms. Moderator analyses w...