Structural and functional features of treatment-resistant depression: A systematic review and exploratory coordinate-based meta-analysis of neuroimaging studies

Psychiatry Clin Neurosci. 2023 May;77(5):252-263. doi: 10.1111/pcn.13530. Epub 2023 Feb 3.


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.

Keywords: depression; functional magnetic resonance imaging; magnetic resonance imaging; treatment-resistant depression; voxel-based morphometry.

Publication types

  • Systematic Review
  • Meta-Analysis
  • Review

MeSH terms

  • Depression / therapy
  • Depressive Disorder, Major* / diagnostic imaging
  • Depressive Disorder, Major* / drug therapy
  • Humans
  • Magnetic Resonance Imaging / methods
  • Neuroimaging
  • Quality of Life