Background: A seminal study found higher subgenual frontal cortex resting-state connectivity with 2 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 predefined functional magnetic resonance imaging minimum quality thresholds) were enrolled and followed over 4 months of standard care. Functional magnetic resonance imaging resting-state connectivity between the preregistered subgenual frontal cortex seed and 3 previously identified left ventromedial, ventrolateral prefrontal/insula, and dorsal midbrain regions was extracted. The clinical outcome was the percentage change on the self-reported 16-item Quick Inventory of Depressive Symptomatology. Results: We observed a reversal of our preregistered 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 (r s 39 = −0.43, p = .006). This generalized to the sample including participants with suboptimal functional magnetic resonance imaging quality (r s 43 = −0.35, p = .02). In contrast, no effects (r s 39 = 0.12, r s 39 = −0.01) were found for connectivity with the other 2 preregistered regions or in a whole-brain analysis (voxel-based familywise 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.

Original languageEnglish
Article number100308
Pages (from-to)100308
JournalBiological Psychiatry Global Open Science
Issue number3
Publication statusPublished - May 2024


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