Neuroimaging Alterations in Comorbid Alcohol Use Disorder and Major Depressive Disorder: A Systematic Review and Meta-Analysis

Background Alcohol use disorder (AUD) and major depressive disorder (MDD) frequently co-occur, affecting over 20% of individuals with either condition. Despite worse clinical outcomes than single disorders, the neurobiological signature of comorbid AUD-MDD remains poorly understood. Methods A systematic review and coordinate-based meta-analysis were conducted in accordance with PRISMA 2020 guidelines. PubMed, Embase, PsycINFO, and Web of Science were searched through December 2024. Whole-brain neuroimaging studies comparing comorbid AUD-MDD patients with healthy controls were included. Voxel-wise meta-analysis was performed using Seed-based d Mapping with Permutation of Subject Images (SDM-PSI) at p < 0.005 (uncorrected) with cluster extent ≥ 10 voxels. Results Twelve studies (433 comorbid patients, 498 controls) met inclusion criteria. Compared to healthy controls, comorbid AUD-MDD patients showed significant gray matter volume reductions in bilateral anterior cingulate cortex (peak coordinates: -2, 32, 22; d=-0.84), right dorsolateral prefrontal cortex (42, 38, 28; d=-0.76), bilateral insula (-36, 18, 4; d=-0.71), and left striatum (-14, 8, -6; d = -0.68). Functional connectivity analyses revealed decreased connectivity within the default mode network and between prefrontal-limbic circuits. Meta-regression indicated significant associations between effect sizes and lifetime alcohol consumption (β = 0.52, p = 0.003) and depression severity scores (β = 0.48, p = 0.007). Conclusions Comorbid AUD-MDD is associated with consistent corticolimbic structural and functional abnormalities, suggesting comorbidity-specific neurobiological mechanisms. These findings may inform targeted treatment strategies and biomarker development for dual diagnosis. Clinical trial registration Not applicable.