Serum Lipidome Change in Japanese Patients with Major Depressive Disorder: A Real-World Exploratory Study

Abstract

Purpose: Major depressive disorder (MDD) is a highly prevalent psychiatric condition with complex and heterogeneous biological underpinnings. Lipid dysregulation has emerged as a potential contributor to MDD pathophysiology. However, comprehensive lipidomic profiling studies in Japanese individuals remain limited. This study aimed to investigate serum lipidomic alterations in Japanese patients with MDD and explore the potential associations with depression severity.

Patients and methods: We conducted a real-world observational study including 30 Japanese patients with MDD and 30 healthy controls. Depression severity was assessed using the Montgomery-Asberg Depression Rating Scale. Lipidomic analysis identified 344 lipid peaks from serum samples. Multivariate and univariate statistical analyses were employed to identify differentially expressed lipids and their correlations with clinical symptoms.

Results: Thirty lipids were found to differ significantly between groups, with 7 elevated and 23 reduced in the MDD cohort. Pathway enrichment analysis highlighted disruptions in lysophosphatidylcholine (LPC), lysophosphatidylethanolamine (LPE), N-acylethanolamines, and fatty acylcarnitines. Notably, levels of LPC (20:3), platelet-activating factor (20:5), and platelet-activating factor (18:3) were negatively correlated with depression severity, suggesting a potential link to mood regulation.

Conclusion: The pronounced enrichment changes observed in LPC and LPE-lipid species involved in membrane remodeling and cellular signal transduction-are consistent with previous findings. However, the observed negative correlations with psychiatric symptom severity were contrary to prior expectations. These results underscore the importance of interpreting lipidomic data in the context of specific population characteristics, methodological frameworks, and clinical settings. They suggest potentially meaningful metabolic alterations associated with MDD and provide a foundation for future longitudinal and mechanistic investigations.

Keywords: lipidome; lipidomics; lysophosphatidylcholine; major depressive disorder; platelet-activating factor.

Figure 1

OPLS-DA analysis and VIP score. Figure 1 illustrates OPLS-DA analysis (A) and VIP score > 1.5 (B). Of the 30 lipid types identified, 7, including AEA (22:4), AEA (20:4), AEA (18:2), AC (20:3), AC (20:4), AC (22:5), and AC (22:4), were higher in patients with MDD than in HC.

Figure 2

Overview of lipid pathway enriched metabolites set. Following pathway enrichment analysis, we identify LPC, LPE, N-acylethanolamines, fatty acylcarnitines, and 1-alkyl-2-acylglycerophoshocholines as high enrichment ratios.

Figure 3

Relation between detected lipidome and depressive symptoms. Figure 3 shows the relationship between the detected lipids and MADRS. Univariate analysis revealed that LPC (20:3), PAF (20:5), and PAF (18:3) exhibited moderately negative correlations with MADRAS (β = −0.391, p = 0.032; β = −0.414, p = 0.023; and β = −0.395, p = 0.030, respectively).

Figure 4

Graphical abstract summarizing this study’s key findings. This illustration provides an overview of the study design, major results, and key interpretations.