Neuroimmune lipidome dysregulation in major depressive disorder: A meta-analysis of peripheral endocannabinoid and n-acylethanolamine signaling.

Abstract

Major depressive disorder (MDD) is a prevalent psychiatric condition characterized by substantial biological heterogeneity. Evidence suggests that the endocannabinoid system (ECS), which regulates stress responses, emotional processing, and neuroimmune signaling, may contribute to depression pathophysiology. However, clinical studies examining circulating endocannabinoids (eCBs) and N-acylethanolamines (NAEs) in MDD have produced inconsistent findings. We therefore conducted a systematic review and meta-analysis to quantify peripheral alterations in eCBs and NAEs in individuals with MDD. Following PRISMA guidelines, case-control and cross-sectional studies comparing circulating levels of eCBs and NAEs between patients with MDD and healthy controls were identified. Standardized mean differences (SMDs) with 95 % confidence intervals (CIs) were calculated using a random-effects model. Between-study heterogeneity was assessed by using Cochran's Q test and further explored in subgroups analysis. Nine studies, including 514 individuals with MDD and 417 healthy controls, met the inclusion criteria. Patients with MDD exhibited significantly higher circulating levels of anandamide (AEA; SMD = 0.32, 95 % CI: 0.10---0.54, p = 0.005) and palmitoylethanolamide (PEA; SMD = 0.35, 95 % CI: 0.04---0.65, p = 0.03) compared with controls, whereas no significant differences were observed for 2-arachidonoylglycerol (2-AG) or oleoylethanolamide (OEA). Subgroup analyses indicated that the elevation in AEA levels were more pronounced among medicated patients and individuals with psychiatric comorbidities. These findings suggest selective alterations in ECS-related lipid mediators in individuals with MDD and support dysregulation of the ECS-NAE signaling axis in depression. Circulating lipid signaling molecules such as AEA and PEA may represent potential peripheral biomarkers of MDD, although longitudinal and mechanistic studies are needed to clarify the influence of treatment and comorbidities.