Brain grey matter abnormalities in medication-free patients with major depressive disorder: a meta-analysis

Psychol Med. 2014 Oct;44(14):2927-37. doi: 10.1017/S0033291714000518. Epub 2014 Mar 21.


Background: Because cerebral morphological abnormalities in major depressive disorder (MDD) may be modulated by antidepressant treatment, inclusion of medicated patients may have biased previous meta-analyses of voxel-based morphometry (VBM) studies. A meta-analysis of VBM studies on medication-free MDD patients should be able to distinguish the morphological features of the disease itself from those of treatment.

Method: A systematic search was conducted for the relevant studies. Effect-size signed differential mapping was applied to analyse the grey matter differences between all medication-free MDD patients and healthy controls. Meta-regression was used to explore the effects of demographics and clinical characteristics.

Results: A total of 14 datasets comprising 400 medication-free MDD patients and 424 healthy controls met the inclusion criteria. The pooled meta-analysis and subgroup meta-analyses showed robustly reduced grey matter in prefrontal and limbic regions in MDD. Increased right thalamus volume was only seen in first-episode medication-naive patients, and increased grey matter in the bilateral anterior cingulate cortex only in medication wash-out patients. In meta-regression analyses the percentage of female patients in each study was negatively correlated with reduced grey matter in the right hippocampus.

Conclusions: By excluding interference from medication effects, the present study identified grey matter reduction in the prefrontal-limbic network in MDD. The subgroup meta-analysis results suggest that an increased right thalamus volume might be a trait directly related to MDD, while an increased anterior cingulate cortex volume might be an effect of medication. The meta-regression results perhaps reveal the structural underpinning of the sex differences in epidemiological and clinical aspects of MDD.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Depressive Disorder, Major / pathology*
  • Female
  • Gray Matter / pathology*
  • Humans
  • Limbic System / pathology*
  • Magnetic Resonance Imaging*
  • Male
  • Prefrontal Cortex / pathology*
  • Thalamus / pathology*