Vortioxetine Improves Brain Glymphatic System Function, Functional Connectivity, and Cognitive Functions in Major Depressive Disorder

<b>Background:</b> The therapeutic effects of vortioxetine on mood and cognition have been documented in major depressive disorder (MDD). This study aims to examine whether vortioxetine can improve brain glymphatic system function and connections among functional brain networks and to explore the underlying relationships among these changes. <b>Methods:</b> A total of 34 patients with MDD and 41 healthy controls (HCs) were recruited in the study. All participants underwent mood and cognitive assessment, and diffusion tensor imaging (DTI) and resting-state functional MRI scans at baseline and 8-week follow-up. The DTI analysis along the perivascular space (DTI-ALPS) index, and functional connectivity (FC) were assessed. Cognitive assessment was conducted using the Chinese version of Measurement Consensus Cognitive Battery (MCCB). Correlation analysis was subsequently performed to explore underlying association among these indexes. <b>Results:</b> Compared to HCs, patients with MDD showed decreased DTI-ALPS indexes at baseline; patients with MDD showed increased the default mode network (DMN) FC between the posterior cingulate cortex (PCC)-precuneus; patients with MDD displayed decreased attention/vigilance, verbal learning, visual learning, social cognition, and global cognition. Treatment with vortioxetine, patients with MDD displayed reduced depressive symptoms, increased DTI-ALPS indexes, decreased DMN FC, and improved attention/vigilance, verbal learning, visual learning, social cognition, and global cognition. Moreover, the increased DTI-ALPS indexes correlated with improved global cognition, and decreased DMN FC in MDD, respectively. <b>Conclusions:</b> The current study indicated vortioxetine improves glymphatic system function and brain connections within the DMN in MDD. Furthermore, the restoration of glymphatic function is linked to improved brain function and cognition. <b>Trial Registration</b>: ClinicalTrials.gov identifier: ChiCTR2200057820.