Dual role of Interleukin-18 in linking metabolic and psychiatric symptoms: Insights from machine learning in schizophrenia

Interleukin-18 (IL-18) has been implicated in both metabolic syndrome (MetS) and schizophrenia, but its dual role in their comorbidity remains unclear. This study aimed to explore how IL-18 interacts with metabolic and psychiatric aspects in this context. We recruited 146 participants divided into three groups: MetS (n = 48), non-MetS (n = 54), and healthy controls (n = 44). Psychiatric symptoms were assessed using the Positive and Negative Syndrome Scale, while biochemical parameters were measured via an automatic biochemistry analyzer. Levels of 14 cytokines/chemokines, including IL-4, IL-8, IL-10, IL-13, IL-18, and Eotaxin were detected using Meso Scale Discovery (MSD) technology. Linear regression and Gradient Boosting Machine (GBM) models revealed that IL-18 significantly impacted metabolic indices (e.g., triglycerides, waist circumference, BMI) and psychiatric symptoms (e.g., psychopathology score, aggressiveness score, PANSS total score) in the MetS group. Analysis using Partial Dependence Plots (PDP) and Accumulated Local Effects (ALE) plots revealed that IL-18 had complex, non-linear interactions with metabolic markers and clinical symptoms. To further elucidate the comprehensive effects of IL-18 on metabolism and symptoms, we integrated these markers into two overarching domains: metabolic and symptomatic. Extreme Gradient Boosting (XGBoost) regression models and SHapley Additive exPlanations (SHAP) values were then employed to quantify the influence of IL-18 on these domains. Results indicated that IL-18's impact on clinical symptoms was more pronounced at lower levels, diminishing as its concentration increased, while its metabolic impact was more significant at higher levels. This study highlights IL-18's dual role as an inflammatory bridge between metabolic dysregulation and psychopathology in comorbidity and underscores the need for further investigation into the underlying mechanisms driving these non-linear interactions.