ImportanceCognitive deficits in depression have been associated with poor functional capacity, frontal neural circuit dysfunction, and worse response to conventional antidepressants. However, it is not known whether these impairments combine together to identify a specific cognitive subgroup (or "biotype") of individuals with major depressive disorder (MDD), and the extent to which these impairments mediate antidepressant outcomes. ObjectiveTo undertake a systematic test of the validity of a proposed cognitive biotype of MDD across neural circuit, symptom, social occupational function, and treatment outcome modalities. Design, Setting, and ParticipantsThis secondary analysis of a randomized clinical trial implemented data-driven clustering in findings from the International Study to Predict Optimized Treatment in Depression, a pragmatic biomarker trial in which patients with MDD were randomized in a 1:1:1 ratio to antidepressant treatment with escitalopram, sertraline, or venlafaxine extended-release and assessed at baseline and 8 weeks on multimodal outcomes between December 1, 2008, and September 30, 2013. Eligible patients were medication-free outpatients with nonpsychotic MDD in at least the moderate range, and were recruited from 17 clinical and academic practices; a subset of these patients underwent functional magnetic resonance imaging. This prespecified secondary analysis was performed between June 10, 2022, and April 21, 2023. Main Outcomes and MeasuresPretreatment and posttreatment behavioral measures of cognitive performance across 9 domains, depression symptoms assessed using 2 standard depression scales, and psychosocial function assessed using the Social and Occupational Functioning Assessment Scale and World Health Organization Quality of Life scale were analyzed. Neural circuit function engaged during a cognitive control task was measured using functional magnetic resonance imaging. ResultsA total of 1008 patients (571 [56.6%] female; mean [SD] age, 37.8 [12.6] years) participated in the overall trial and 96 patients participated in the imaging substudy (45 [46.7%] female; mean [SD] age, 34.5 [13.5] years). Cluster analysis identified what may be referred to as a cognitive biotype of 27% of depressed patients with prominent behavioral impairment in executive function and response inhibition domains of cognitive control. This biotype was characterized by a specific profile of pretreatment depressive symptoms, worse psychosocial functioning (d=-0.25; 95% CI, -0.39 to -0.11; P<.001), and reduced activation of the cognitive control circuit (right dorsolateral prefrontal cortex: d=-0.78; 95% CI, -1.28 to -0.27; P=.003). Remission was comparatively lower in the cognitive biotype positive subgroup (73 of 188 [38.8%] vs 250 of 524 [47.7%]; P=.04) and cognitive impairments persisted regardless of symptom change (executive function: eta(2)(p)=0.241; P<.001; response inhibition: eta(2)(p)=0.750; P<.001). The extent of symptom and functional change was specifically mediated by change in cognition but not the reverse. Conclusions and RelevanceOur findings suggest the presence of a cognitive biotype of depression with distinct neural correlates, and a functional clinical profile that responds poorly to standard antidepressants and instead may benefit from therapies specifically targeting cognitive dysfunction. Trial RegistrationClinicalTrials.gov Identifier: NCT00693849
