587. Female-specific role of interleukin 6 and C-reactive protein in individuals with major depressive disorder and comorbid obesity

Abstract Background Major depressive disorder (MDD) is highly prevalent in individuals with obesity, with both conditions occurring more frequently in females than males; however, the mechanisms underlying these sex differences remain poorly understood. Immune system hyperactivation has been proposed as a shared biological mechanism [1], as obesity is characterised by chronic low-grade inflammation and depression is associated with elevated inflammatory markers in a clinically relevant subgroup of patients. A lack of sex-specific data has limited insight into the distinct pathophysiology of these conditions in females. In this context, emerging evidence highlights the importance of understanding sex differences in depression, particularly in relation to the co-occurrence of obesity and increased immune activation. Aims & Objectives Given the role of increased inflammation in both conditions, we aim to investigate immune profiles in patients with MDD and comorbid obesity. Specifically, we examined sex-specific associations between immune-inflammatory biomarkers and MDD in individuals with severe obesity undergoing bariatric surgery, and assessed the relationship between inflammatory markers and depressive symptom severity, as well as the diagnostic potential of interleukin-6 for immunometabolic depression. Method From the Bariatric Surgery & Depression study [2], we included 85 bariatric patients (BMI≥35 kg/m2), 41 with MDD (cases, 37% males; 63% females) and 44 controls (43% males; 57% females). We measured serum high-sensitivity C-reactive protein (hsCRP), interleukin (IL)-6, IL-2, IL-8, IL-1β, IL-4, IL-10, IL-12p70, IL-13, tumour necrosis factor-α, and interferon-γ. Depressive symptoms were measured by the Structured Interview Guide for the Hamilton Depression Rating Scale with Atypical Depression Supplement combining the HAMD-17 and the NIHM addition of 8 atypical symptoms. In within-sex non-parametric analyses, Mann–Whitney U-test investigated group differences in immune biomarkers, and Spearman’s correlations investigated associations between relevant immune biomarkers and depressive symptoms in cases and controls together. Analyses were covaried for age, BMI, ethnicity, diabetic status, antidepressant use, and smoking status. ROC curve analysis assessed the diagnostic performance of IL-6 and CRP in females. Results In females, cases showed increased IL-6 (p<0.001) and hsCRP (p<0.05) levels, with IL-6 significantly correlating with depressive symptom severity (HAMD-17, p<0.05; atypical symptoms, p<0.05). In males, there were no significant differences in immune biomarker levels between controls and cases. In females, an optimal IL-6 cut-off of 1.60 pg/mL moderately distinguished MDD from controls (AUC=0.763, 95%CI: 0.629–0.897; 80% sensitivity, 72% specificity), while CRP showed borderline moderate discriminatory ability between the two groups (AUC=0.695, 95%CI: 0.547–0.843; 68% sensitivity, 62.5% specificity). Discussion & Conclusions Increased IL-6 and hsCRP showed a female-specific role in immunometabolic depression, with IL-6 emerging as a potential diagnostic biomarker. In conclusion, these findings highlight the need to further investigate sex-specific immune biomarkers to inform sex-specific targeted treatments for this population. References [1] Milaneschi et al., (2019). Depression and obesity: evidence of shared biological mechanisms. Molecular psychiatry, 24(1), 18–33. https://doi.org/10.1038/s41380-018-0017-5 [2] McLaughlin et al., (2024). Peripheral inflammation associated with depression and reduced weight loss: a longitudinal study of bariatric patients. Psychological medicine, 54(3), 601–610. https://doi.org/10.1017/S0033291723002283