Treatment-resistant depression (TRD) imposes greater illness burden and worse clinical outcomes than its non-TRD counterpart. Previous neuroimaging research on the brain substrates of TRD and non-TRD has yielded divergent results, which may be reconciled by updated network localization. We initially synthesized published neuroimaging literature to identify brain locations with structural or functional differences between TRD vs. healthy controls (HC), non-TRD vs. HC, and TRD vs. non-TRD. By combining these affected brain locations with large-scale discovery (1113 healthy individuals) and validation (1093 healthy individuals and 255 MDD patients) resting-state functional MRI datasets, we then employed novel functional connectivity network mapping to construct three brain networks. The brain network of TRD vs. HC comprised a broadly distributed set of brain regions predominantly implicating the canonical ventral attention, subcortical, default, somatomotor, and frontoparietal networks. The network of non-TRD vs. HC also manifested as a widely distributed pattern of regions primarily involving the default, limbic, and frontoparietal networks. The network of TRD vs. non-TRD mainly implicated the ventral attention and default networks. Our findings can contribute to elucidating the differential neuropathological processes underlying TRD and non-TRD. • Synthesizing neuroimaging literature to identify brain locations associated with TRD. • Combining the novel FCNM approach and large-scale functional brain connectome data. • Constructing the brain networks associated with TRD and non-TRD.
an et al. (2026) studied this question.