Proteomic Signatures in Major Depressive Disorder and Depression Symptom Subtypes

OBJECTIVE: Major depressive disorder (MDD) is biologically heterogeneous and encompasses diverse symptom presentations. The authors used large-scale plasma proteomics to examine proteomic associations with categorical MDD status, continuous depression symptom severity, and DSM-IV-defined melancholic and atypical symptom dimensions. METHODS: Using the SomaScan platform, the authors conducted plasma proteomic profiling of 7,289 analytes in 1,881 participants from the Netherlands Study of Depression and Anxiety, including individuals with current MDD (N=469), individuals with remitted MDD (N=918), and healthy control subjects (N=494). They evaluated associations with diagnostic status, symptom severity, and melancholic and atypical symptom dimensions, followed by pathway enrichment analyses. RESULTS: Eight aptamers, representing seven unique proteins, differed significantly between the current MDD and healthy control groups after false discovery rate (FDR) correction. Overall depression symptom severity was associated with 18 significant aptamers corresponding to 18 unique proteins, whereas atypical symptoms were associated with 58 significant aptamers corresponding to 57 unique proteins. In contrast, no individual proteins reached FDR significance for melancholic symptoms. Pathway analyses showed enrichment for extracellular matrix organization, collagen formation, complement cascade signaling, platelet activation, and hemostasis in relation to overall depression symptom severity. Gene set enrichment analysis of proteins ranked by association with melancholic symptoms identified pathway-level enrichment despite the absence of FDR-significant individual proteins, including mitochondrial stress response, protein translation, complement signaling, and nervous system development. Atypical symptoms showed enrichment of extracellular matrix organization, collagen formation, complement cascade signaling, insulin-like growth factor transport, and chromatin regulatory processes. CONCLUSIONS: These findings support biological heterogeneity within MDD and suggest that peripheral proteomic alterations are more strongly represented for specific symptom dimensions than for categorical diagnosis alone. Atypical symptoms showed pathway-level enrichment with significant individual protein associations. A dimensional framework may improve biological stratification of depression and refine biomarker-informed approaches to clinical symptom profiles.