IMPORTANCE Patients with remitted major depressive disorder (MDD) were previously found to display abnormal functional magnetic resonance imaging connectivity (fMRI) between the right superior anterior temporal lobe (RSATL) and the subgenual cingulate cortex and adjacent septal region (SCSR) when experiencing self-blaming emotions relative to emotions related to blaming others (eg, "indignation or anger toward others"). This finding provided the first neural signature of biases toward overgeneralized self-blaming emotions (eg, "feeling guilty for everything"), known to have a key role in cognitive vulnerability to MDD. It is unknown whether this neural signature predicts risk of recurrence, a crucial step in establishing its potential as a prognostic biomarker, which is urgently needed for stratification into pathophysiologically more homogeneous subgroups and for novel treatments. OBJECTIVE To use fMRI in remitted MDD at baseline to test the hypothesis that RSATL-SCSR connectivity for self-blaming relative to other-blaming emotions predicts subsequent recurrence of depressive episodes. DESIGN, SETTING, AND PARTICIPANTS A prospective cohort study from June 16, 2011, to October 10, 2014, in a clinical research facility completed by 75 psychotropic medication-free patients with remitted MDD and no relevant comorbidity. In total, 31 remained in stable remission, and 25 developed a recurring episode over the 14 months of clinical follow-up and were included in the primary analysis. Thirty-nine control participants with no personal or family history of MDD were recruited for further comparison. MAIN OUTCOMES AND MEASURES Between-group difference (recurring vs stable MDD) in RSATL connectivity, with an a priori SCSR region of interest for self-blaming vs other-blaming emotions. RESULTS We corroborated our hypothesis that during the experience of self-blaming vs other-blaming emotions, RSATL-SCSR connectivity predicted risk of subsequent recurrence. The recurring MDD group showed higher connectivity than the stable MDD group (familywise error-corrected P < .05 over the a priori SCSR region of interest) and the control group. In addition, the recurring MDD group also exhibited RSATL hyperconnectivity with the right ventral putamen and claustrum and the temporoparietal junction. Together, these regions predicted recurrence with 75% accuracy. CONCLUSIONS AND RELEVANCE To our knowledge, this study is the first to provide a robust demonstration of an fMRI signature of recurrence risk in remitted MDD. Additional studies are needed for its further optimization and validation as a prognostic biomarker.

BackgroundCognitive models predict that vulnerability to major depressive disorder (MDD) is due to a bias to blame oneself for failure in a global way resulting in excessive self-blaming emotions, decreased self-worth, hopelessness and depressed mood. Clinical studies comparing the consistency and coherence of these symptoms in order to probe the predictions of the model are lacking.Methods132 patients with remitted MDD and no relevant lifetime co-morbid axis-I disorders were assessed using a phenomenological psychopathology-based interview (AMDP) including novel items to assess moral emotions (n=94 patients) and the structured clinical interview-I for DSM-IV-TR. Cluster analysis was employed to identify symptom coherence for the most severe episode.ResultsFeelings of inadequacy, depressed mood, and hopelessness emerged as the most closely co-occurring and consistent symptoms (≥90% of patients). Self-blaming emotions occurred in most patients (>80%) with self-disgust/contempt being more frequent than guilt, followed by shame. Anger or disgust towards others was experienced by only 26% of patients. 85% of patients reported feelings of inadequacy and self-blaming emotions as the most bothering symptoms compared with 10% being more distressed by negative emotions towards others.LimitationsSymptom assessment was retrospective, but this is unlikely to have biased patients towards particular emotions relative to others.ConclusionsAs predicted, feelings of inadequacy and hopelessness were part of the core depressive syndrome, closely co-occurring with depressed mood. Self-blaming emotions were highly frequent and bothering but not restricted to guilt. This calls for a refined assessment of self-blaming emotions to improve the diagnosis and stratification of MDD.