The neurobiology of treatment-resistant depression: A systematic review of neuroimaging studies

Neurosci Biobehav Rev. 2022 Jan:132:433-448. doi: 10.1016/j.neubiorev.2021.12.008. Epub 2021 Dec 7.


Treatment-resistant depression (TRD) is a debilitating condition associated with higher medical costs, increased illness burden, and reduced quality of life compared to non-treatment-resistant major depressive disorder (MDD). The question arises whether TRD can be considered a distinct MDD sub-type based on neurobiological features. To answer this question we conducted a systematic review of neuroimaging studies investigating the neurobiological differences between TRD and non-TRD. Our main findings are that patients with TRD show 1) reduced functional connectivity (FC) within the default mode network (DMN), 2) reduced FC between components of the DMN and other brain areas, and 3) hyperactivity of DMN regions. In addition, aberrant activity and FC in the occipital lobe may play a role in TRD. The main limitations of most studies were related to inherent confounding factors for comparing TRD with non-TRD, such as differences in disease chronicity/severity and medication history. Future studies may use prospective longitudinal neuroimaging designs to delineate which effects are present in treatment-naive patients and which effects are the result of disease progression.

Keywords: Magnetic resonance imaging; Major depressive disorder; Neuroimaging; Resting-state; Systematic review; Treatment-resistant depression.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review
  • Systematic Review

MeSH terms

  • Brain Mapping
  • Depression
  • Depressive Disorder, Major*
  • Humans
  • Magnetic Resonance Imaging
  • Neuroimaging
  • Prospective Studies
  • Quality of Life