Project Summary/Abstract The overall goal of this project is to conduct a well-powered confirmatory efficacy trial comparing a gamified, attention bias modification (ABM) mobile application and traditional ABM to sham ABM among adults with elevated symptoms of depression. The proposed R01 efficacy trial follows the NIMH intervention development sequence as it builds upon prior NIMH-funded experimental therapeutics work, specifically R21MH092430 “Attention training for Major Depressive Disorder” and R33MH109600 “Development of attention bias modification for depression”. This prior work demonstrates that active ABM engages and alters negative attention bias and there is a preliminary efficacy signal that ABM reduces depression. Although traditional ABM is efficacious for the treatment of depression, “gamified” forms of ABM have the potential to be more accessible and engaging than traditional ABM. Pilot work suggests that a gamified ABM can reduce negative affect; however, its effectiveness for depression has not yet been established. Thus, we are proposing to conduct a well-powered, confirmatory efficacy trial to determine ABM’s potential for the treatment of depression. In Aim 1, we will examine the efficacy of ABM in a large sample of adults (N = 600) with elevated symptoms of depression. We hypothesize that gamified and traditional ABM will lead to significantly greater reductions in self-reported and interviewer-rated depression symptoms than sham ABM. We further hypothesize that traditional ABM will be non-inferior to gamified ABM (we will also test for treatment superiority between the ABM conditions). In Aim 2, we will examine putative moderators and mediators of ABM. Based on ABM research with anxious populations, we predict that people with a strong initial attentional bias for sad stimuli will experience greater reductions in depression in response to either gamified or traditional ABM than sham ABM. In terms of mediation, compared to sham ABM, we hypothesize that gamified and traditional ABM will: (1) decrease negative attentional bias measured behaviorally with reliable eye tracking methods; (2) significantly reduce depression; and (3) improve depression symptoms via their influence on negative attentional bias. Selection of the putative mediators is informed by our prior R33 ABM trial, where we found gaze bias away from sad stimuli mediated the effect of traditional ABM on depression symptom change. In Aim 3, an exploratory aim, we will estimate the durability of ABM by collecting post-treatment symptom data 1-, 2-, 3-, and 6-months after ABM completion. Symptom change and reliable recovery across a six-month follow-up period will be estimated. Currently, the durability of ABM effects for depression is unknown, as few well-powered ABM studies for depression have obtained follow-up data. This trial would provide the most definitive data to date regarding whether ABM for depression is a promising treatment for depression.