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Background: Amygdala and dorsal anterior cingulate cortex responses to facial emotions have shown promise in predicting treatment response in medication-free major depressive disorder (MDD). Here, we examined their role in the pathophysiology of clinical outcomes in more chronic, difficult-to-treat forms of MDD.

Methods: Forty-five people with current MDD who had not responded to ≥2 serotonergic antidepressants (n=42, meeting pre-defined fMRI minimum quality thresholds) were enrolled and followed up over four months of standard primary care. Prior to medication review, subliminal facial emotion fMRI was used to extract blood-oxygen level-dependent effects for sad vs. happy faces from two pre-registered a priori defined regions: bilateral amygdala and dorsal/pregenual anterior cingulate cortex. Clinical outcome was the percentage change on the self-reported Quick Inventory of Depressive Symptomatology (16-item).

Results: We corroborated our pre-registered hypothesis (NCT04342299) that lower bilateral amygdala activation for sad vs. happy faces predicted favourable clinical outcomes (rs[38]=.40, p=.01). In contrast, there was no effect for dorsal/pregenual anterior cingulate cortex activation (rs[38]=.18, p=.29), nor when using voxel-based whole-brain analyses (voxel-based Family-Wise Error-corrected p<.05). Predictive effects were mainly driven by the right amygdala whose response to happy faces was reduced in patients with higher anxiety levels.

Conclusions: We confirmed the prediction that a lower amygdala response to negative vs. positive facial expressions might be an adaptive neural signature, which predicts subsequent symptom improvement also in difficult-to-treat MDD. Anxiety reduced adaptive amygdala responses.
Original languageEnglish
JournalPsychological Medicine
Publication statusAccepted/In press - 17 Apr 2024


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