Stage-dependent gray matter morphological alterations across the clinical spectrum of depressive disorder

Previous studies have reported gray matter volume (GMV) deficits in different illness stages of depression; however, whether patients at different stages show shared or distinct GMV abnormality patterns has not been systematically characterized.

We conducted a quantitative voxel-wise meta-analysis of whole-brain voxel-based morphometry (VBM) studies in individuals with subthreshold depression (STD), first-episode drug-naïve depression (FEND), and long-term major depressive disorder (MDD). Separate, pooled and comparative meta-analyses were performed using the Seed-based d Mapping (SDM) toolbox. Meta-regression analyses were conducted to explore age- and disease-related alterations in depression.

Twelve studies including 467 individuals with STD, 19 studies including 854 patients with FEND, and 14 studies including 525 patients with long-term depression were included. Compared with controls, STD and FEND exhibited mixed patterns of GMV increases and decreases predominantly involving key emotional and default mode network regions. In contrast, long-term MDD showed consolidated GMV reductions confined to the paracingulate gyrus and left middle temporal gyrus extending to insula. Direct comparisons across stages confirmed that GMV alterations in prefrontal and temporal regions showed progressive divergence from early to chronic depression. Meta-regression analyses revealed stage-specific associations between clinical characteristics and GMV changes.

This meta-analysis reveals stage-specific GMV abnormalities across depression. GMV changes shift from mixed alterations in early stages to purely atrophic reductions in chronic MDD, supporting a progressive model. Fronto-limbic deficits at the subthreshold stage may serve as early vulnerability markers, while GMV consolidation in long-term MDD underscores the importance of early intervention.