Despite depression being a leading cause of disability worldwide, traditional antidepressants are ineffective in around 30% of patients. This subset, labelled treatment-resistant (TR), further exhibit more severe depressive symptoms along with higher levels of suicidal thoughts and tendencies. While MRI studies reveal numerous brain alterations, findings are inconsistent due to varied methodologies. This systematic review synthesizes MRI-based evidence on TRD, comparing structural and functional changes with non-TR MDD. A search was conducted accross PubMed, Scopus, Web of Science, and EMBASE. Inclusion criteria required studies to compare TRD with another MDD subgroup such as treatment sensitive depression (TSD). A total of 27 studies with 22 TRD cohorts met inclusion criteria, comprising 14 studies with a TSD comparison group and 13 with non-TRD MDD comparisons. Regarding structural alterations in TRD, we highlight two major findings. The most robust is that of reduced hippocampal volume in TRD patients compared to non-TRD. The second is a reduction in white matter volume and integrity, although inconsistencies across studies make it unclear whether this is widespread or region-specific. Regarding FC, we highlighted regions of the frontal, temporal, and parietal lobes, along with the cerebellum to be altered in TRD. The DMN was also repeatedly implicated in TRD, with both hyper- and hypoconnectivity reported. This review suggests that, while treatment resistance in MDD likely presents with specific brain correlates, methodological variability prevents definitive conclusions. Standardised approaches, larger studies and accountability of various clinical factors are needed to better establish the underlying neurobiology of TRD. • Systematic review of studies investigating TRD vs non-TRD via MRI techniques. • Reduced GM in hippocampus found in TRD • Reductions in WM volume & integrity found in TRD • Widespread alterating in functional connectivity found in TRD with particular emphasis on the DMN
Carter et al. (Fri,) studied this question.