A systematic review and meta-analysis on glymphatic flow dysfunction in depression:Evidence from the DTI-ALPS index

Significant evidence suggests a robust link between Major Depressive Disorder (MDD) and immune dysfunction. While the glymphatic system-a critical metabolic waste clearance pathway in the brain-is well-documented in neurodegenerative pathology, its involvement in psychiatric disorders such as MDD remains poorly defined.

This systematic review and meta-analysis synthesised current evidence regarding glymphatic dysfunction in MDD, utilising the Diffusion Tensor Image Analysis Along the Perivascular Space (DTI-ALPS) index as a proxy for glymphatic activity.

A primary meta-analysis of 11 studies (comprising 1470 patients and 962 healthy controls) revealed a significant reduction in the DTI-ALPS index in MDD patients (SMD = -0.765, 95% CI [-1.203, -0.326], p < 0.001), indicating moderate impairment of the glymphatic system. This impairment was significantly correlated with symptom severity (β = -0.2429, p <0.05) and demonstrated consistent associations with depression and anxiety scale scores. Subgroup analyses identified age (p <0.05) and disease duration (p <0.05) as significant moderators of the effect size, while other demographic and technical variables remained consistent across groups. The quality of included studies was high, and no significant publication bias was detected (p <0.05).

These findings suggest that glymphatic dysfunction, as indexed by DTI-ALPS, may be associated with MDD pathophysiology, particularly in relation to disease duration, age, and clinical severity. However, given that DTI-ALPS is not a direct measure of glymphatic function and that comparisons with other established biomarkers were not performed, further studies are needed to determine whether glymphatic dysfunction represents a neurobiological marker in MDD.