IL-1α and CRP as key inflammatory mediators linking neuropathic pain, anxiety, and depression in major depressive disorder

Background: It’s common comorbidity for Major Depressive Disorder (MDD), anxiety, and pain, underpinned by shared chronic inflammatory processes, this study aimed to identify etiological inflammatory biomarkers, focusing on MDD individuals with anxiety and pain symptoms. Methods : This cross-sectional study enrolled 115 participants (75 MDD, 40 healthy controls). Depression and anxiety symptoms were assessed by Hamilton Depression Rating Scale-24 (HAMD-24)/ Beck Depression Inventory-II (BDI-II) and Hamilton Anxiety Rating Scale-14 (HAMA-14)/Beck Anxiety Inventory (BAI),respectively. Short-Form McGill Pain Questionnaire-2 (SF-MPQ-2) and Prospective and Retrospective Memory Questionnaire (PRMQ) were to evaluate the pain feature and memory function respectively. Serum levels of 18 cytokines and chemokines, including interleukin-1α ( IL-1α) and C-reactive protein (CRP), were validated using Meso Scale Discovery. Data analysis included robust Ordinary Least Squares (OLS) regression, serial mediation (PROCESS models), Gaussian Graphical Models, and Gradient Boosted Regression (GBR) with SHapley Additive exPlanations (SHAP) values. Results: MDD patients displayed significantly higher IL-1α and CRP levels, greater pain sensitivity, and more cognitive impairment compared to controls. Multivariate regression confirmed a significant positive link between IL-1α and neuropathic pain ( β =0.25, p =0.014). Serial mediation models revealed a crucial indirect pathway: IL-1α did not directly cause depressive symptoms but acted sequentially: IL-1α → neuropathic pain → subjective anxiety → depressive symptoms. High CRP levels exacerbated the relationship between anxiety and neuropathic pain. GBR analysis confirmed IL-1α as the most significant feature predicting pain. Conclusions: The findings highlight IL-1α and CRP as key inflammatory mediators contributing to the interplay between pain, anxiety, and depressive symptoms. These results underscore the importance of targeting inflammation-related pathways in the assessment and treatment of pain in the MDD.