Objectives
A third of people suffering from major depressive disorder do not experience a significant improvement in their symptoms even after adequate treatment with two different antidepressant medications. This common condition, termed treatment-resistant depression (TRD), severely affects the quality of life of millions of people worldwide, causing long-lasting interpersonal problems and social costs. Given its epidemiological and clinical relevance and the little consensus on whether the neurobiological underpinnings of TRD differ from treatment-sensitive depression (TSD), we sought to highlight the convergent morphometric and functional neuroimaging correlates of TRD.

Methods
We systematically reviewed the published literature on structural and resting-state functional neuroimaging of TRD compared to TSD and healthy controls (HC) and performed exploratory coordinate-based meta-analyses (CBMA) of significant results separately for each modality and multimodally (“all-effects”). CBMAs were also performed for each direction and combining both directions of group contrasts.

Results
Out of the initial 1929 studies, only eight involving 555 participants (189 patients with TRD, 156 with TSD, and 210 HC) were included. In all-effects CBMA, precentral/superior frontal gyrus showed a significant difference between TRD and HC. Functional and structural imaging meta-analyses did not yield statistically significant results. A marginally significant cluster of altered intrinsic activity was found between TRD and HC in the cerebellum/pons.

Conclusions
Frontal, cerebellar, and brainstem functions can be involved in the pathophysiology of TRD. However, the design and heterogeneity of the (scarce) published literature hinder the generalizability of the findings.

depression functional magnetic resonance imaging mag-netic resonance imaging treatment-resistant depression voxel-basedmorphometry