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Context 40–60% of unmedicated depressed individuals respond to Cognitive Therapy (CT) in controlled trials. Multiple previous studies suggest that activity in the subgenual anterior cingulate predicts outcome in CT for depression, but there have been no prospective replications. Objective This study prospectively examined whether subgenual cingulate activity is a reliable and robust prognostic outcome marker for CT for depression and whether its activity changes in treatment. Design Two inception cohorts were assessed with fMRI on different scanners on a task sensitive to sustained emotional information processing before and after 16–20 sessions of CT, along with a sample of control participants tested at comparable intervals. Setting Therapy took place in a hospital outpatient clinic. Patients Participants included 49 unmedicated depressed adults and 35 healthy control participants. Main Outcome Measures Pre-treatment subgenual anterior cingulate activity in an a priori region in response to negative words was correlated with residual severity and used to classify response and remission. Results As expected, in both samples, participants with the lowest pre-treatment sustained subgenual cingulate (sgACC; BA25) reactivity in response to negative words displayed the most improvement in CT (R2=.29, >75% correct classification of response, >70% correct classification of remission). Other a priori regions explained additional variance. Response/Remission in Cohort 2 was predicted based on thresholds from Cohort 1. sgACC activity remained low for remitters following treatment. Conclusions Neuroimaging provides a quick, valid, and clinically applicable way of assessing neural systems associated with treatment response/remission. sgACC activity, in particular, may reflect processes which interfere with treatment, e.g,. emotion generation in addition to its putative regulatory role; alternately, its absence may facilitate treatment response.

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