Differential associations of inflammatory-metabolic markers with depressive symptom dimensions: Towards a clinical phenotyping of immune-metabolic depression.
BACKGROUND Depression is increasingly conceptualized as a biologically heterogeneous condition, with immune-inflammatory and metabolic dysregulation implicated in specific symptom dimensions rather than overall depressive severity. However, it remains unclear whether different combinations of inflammatory and metabolic burden define distinct clinical depressive phenotypes. METHODS In this cross-sectional multicenter study on major depressive episodes (MDE), inflammatory and metabolic burden were indexed by C-reactive protein (CRP) and a composite continuous metabolic syndrome score (cMetS). Participants were classified into four immune-metabolic profiles based on the combination of high/low CRP status and high/low metabolic burden. Somatic symptoms, anhedonia, subjective cognitive complaints, and objective cognitive performance were assessed using standardized psychometric and neuropsychological measures. Associations were examined using covariance and multivariable regression models, including four-category profiles and CRP-cMetS interaction terms, with sensitivity analyses using continuous biomarkers. RESULTS Among 221 patients, immune-metabolic profiles differed for somatic symptoms (p = 0.001; η²p = 0.079), anhedonia (p = 0.006; η²p = 0.065), and cognition (Digit-Symbol-Substitution Test [DSST]: p = 0.039; η²p = 0.042). In regression models, the High CRP/High cMetS group was associated with greater somatic symptom burden (β = 5.10, p = 0.001) and poorer cognitive performance (DSST: β = -7.43, p = 0.036; Trail-Making Test-B: β = 41.44, p = 0.008), whereas the High CRP/Low cMetS profile was selectively associated with greater anhedonia (β = 2.93, p < 0.001). Significant CRP×cMetS interactions emerged for anhedonia (p = 0.023). Sensitivity analyses using continuous biomarkers showed convergent results. CONCLUSIONS These findings suggest that distinct combinations of inflammatory and metabolic burden may characterize partly distinct depressive phenotypes across hedonic, somatic, and cognitive domains, supporting the relevance of integrated immune-metabolic profiling for biologically informed stratification and potentially more targeted therapeutic approaches.