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

Abstract

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. Initially, 218 participants underwent screening for this cross-sectional study. Ultimately, 75 first-episode drug-naive patients with MDD and 40 healthy controls met the inclusion criteria. Depression and anxiety symptoms were assessed by Hamilton Depression Rating Scale-24 (HAMD-24), Hamilton Anxiety Rating Scale-14 (HAMA-14), Beck Depression Inventory-II (BDI-II) and 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. Meso Scale Discovery was used to measure the amounts of eighteen cytokines and chemokines in peripheral blood. We use the sequential path model (model 6) and the moderated path model (model 59) in the PROCESS to examine the relationship between variables. A Gaussian Graphical Model (GGM), Gradient Boosted Regression (GBR) algorithm, SHapley Additive exPlanations (SHAP) values and Partial Dependence Plots (PDP) were used to visualize the primary features on model predictions. MDD patients displayed significantly higher IL-1α levels, lower 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). A sequential path model and a moderated path model 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. The findings highlight IL-1α and CRP as key inflammatory markers associated with the relationship between pain, anxiety, and depressive symptoms. These results suggest the potential relevance of inflammation-related pathways in the clinical assessment of pain within the context of MDD.