BackgroundCognitive–behavioural therapy is efficacious in the treatment of major depressive disorder but response rates are still far from satisfactory.AimsTo better understand brain responses to individualised emotional stimuli and their association with outcome, to enhance treatment.MethodFunctional magnetic resonance imaging data were collected prior to individual psychotherapy. Differences in brain activity during passive viewing of individualised self-critical material in 23 unmedicated out-patients with depression and 28 healthy controls were assessed. The associations between brain activity, cognitive and emotional change, and outcome were analysed in 21 patients.ResultsPatients showed enhanced activity in the amygdala and ventral striatum compared with the control group. Non-response to therapy was associated with enhanced activity in the right amygdala compared with those who responded, and activity in this region was negatively associated with outcome. Emotional but not cognitive changes mediated this association.ConclusionsAmygdala hyperactivity may lessen symptom improvement in psychotherapy for depression through attenuating emotional skill acquisition.