The role of subgenual resting-state connectivity networks in predicting prognosis in major depressive disorder

Background A seminal study found higher subgenual frontal cortex resting-state connectivity with two left ventral frontal regions and the dorsal midbrain to predict better response to psychotherapy versus medication in individuals with treatment-naïve major depressive disorder (MDD). Here, we examined whether these subgenual networks also play a role in the pathophysiology of clinical outcomes in MDD with early treatment-resistance in primary care. Methods Forty-five people with current MDD who had not responded to ≥2 serotonergic antidepressants (n=43, meeting pre-defined fMRI minimum quality thresholds) were enrolled and followed up over four months of standard care. Functional MRI resting-state connectivity between the pre-registered subgenual frontal cortex seed and three previously identified left ventromedial, ventrolateral prefrontal/insula, and dorsal midbrain regions was extracted. Clinical outcome was the percentage change on the self-reported Quick Inventory of Depressive Symptomatology (16-item). Results We observed a reversal of our pre-registered hypothesis in that higher resting-state connectivity between the subgenual cortex and the a priori ventrolateral prefrontal/insula region predicted favorable rather than unfavorable clinical outcomes (rs[39]=-.43, p=.006). This generalized to the sample including participants with suboptimal fMRI quality (rs[43]=-.35, p=.02). In contrast, no effects (rs[39]=.12, rs[39]=-.01) were found for connectivity with the other two pre-registered regions and in a “whole brain” analysis (voxel-based Family-Wise Error-corrected p<.05). Conclusions Subgenual connectivity with the ventrolateral prefrontal cortex/insula is relevant for subsequent clinical outcomes in current MDD with early treatment-resistance. Its positive association with favorable outcomes could be explained primarily by psychosocial rather than the expected pharmacological changes during the follow-up period.