Depression with immuno-metabolic dysregulation: Testing pragmatic criteria to stratify patients

• There is a dose-response pattern between higher CRP and AES and immuno-metabolic dysregulation in depressed patients. • Combining CRP and AES can be an effective strategy to select depressed patients with immuno-metabolic dysregulation. • A CRP cutoff of > 1 mg/L yields a similarly dysregulated sample as a CRP cutoff of > 3 mg/L, when combined with AES. • The patients included in the INFLAMED trial will be the first to receive treatment based on stratification on CRP and AES. Inflammatory and metabolic processes are linked to depression, but only 25–30% of depressed patients show low-grade inflammation and metabolic dysregulation associated with atypical, energy-related symptoms (AES). Interventions targeting immuno-metabolic dysregulation could benefit depressed patients, but currently no consensus exists how to best select patients with immuno-metabolic dysregulations. Therefore, we investigated which combinations of circulating C-reactive protein (CRP) and AES could identify those depressed individuals with significant immuno-metabolic dysregulation. Data are from 1,077 persons with a current Major Depressive Disorder (MDD) of the Netherlands Study of Depression and Anxiety. Immuno-metabolic markers were Interleukin-6 (IL-6), Tumor Necrosis Factor alpha (TNF-α), glycoprotein acetyls, body mass index (BMI), waist circumference, triglycerides, high-density-lipoprotein cholesterol (HDL cholesterol), glucose and leptin. Strata for CRP (≤ 1, 3 mg/L) and AES (score of ≤ 3, 4–5, ≥ 6) were compared on immuno-metabolic markers using analyses of covariance. Across strata of CRP and AES, there was a dose–response pattern with all higher immuno-metabolic marker levels across higher strata of CRP and AES, with the exception for an association between AES and TNF-α. Persons with both elevated CRP (> 1 mg/L) and high AES (≥ 6) showed a more dysregulated inflammatory and metabolic profile compared to persons with lower CRP and/or AES ( p < 0.001). Our results show a dose–response relationship between both CRP levels and AES with immuno-metabolic risk biomarkers, indicating that CRP and AES combined can capture immuno-metabolic features of MDD. Combining these available and scalable indexes may be an effective strategy to select a patient sample with immuno-metabolic dysregulation who may benefit from treatments targeting inflammatory or metabolic pathways.