Key PointsQuestionHow are objective cognitive deficits in depression associated with symptoms, neural circuits, and treatment outcomes?FindingsIn this secondary analysis of a randomized clinical trial in 1008 patients with major depression, 27% exhibited pretreatment global cognitive impairment and significantly decreased brain response to a cognitive task as well as worse response to standard pharmacotherapy, defining what may be categorized as a cognitive biotype. Changes in cognitive symptoms over the course of treatment mediated the association between pretreatment cognitive status and improvement in overall symptoms and psychosocial functioning.MeaningThese results suggest that consideration of treatments targeting cognitive dysfunction in a subset of patients with depression is warranted to attain symptomatic and psychosocial improvement.