Systemic low-grade inflammation associated with specific depressive symptoms: insights from network analyses of five independent NHANES samples

Major depressive disorder (MDD) is a heterogeneous disorder with varying symptom presentations and underlying biological mechanisms. 1 The mainstream neurobiological hypotheses of depression involve monoamine neurotransmitters, hypothalamic-pituitary-adrenal axis, immuneinflammation and the glutamate system. 1 Numerous meta-analyses have reported that patients with MDD have a higher level of peripheral and cerebrospinal inflammatory markers, including C-reactive protein (CRP), interleukin 1beta (IL-1β), IL-6 and tumour necrosis factor-alpha (TNF-α). 2 3 CRP, as an acute marker of reactant, is the most wellstudied biomarker of MDD; numerous investigations revealed that elevated CRP was linked to core symptoms of MDD, including increased depressive mood 4 and greater anhedonia. 5Several studies also have discovered links between CRP and cognitive symptoms (eg, difficulty concentrating) 6 and suicidal behaviours. 7Moreover, CRP is more commonly reported in association with neurovegetative symptoms, including fatigue or loss of energy, changes in appetite and sleep problems. 6The association between CRP and specific symptoms remains unknown; uncovering specific symptoms driven by CRP could help identify the possible inflammatory subtypes of depression to pave the way for more specific anti-inflammatory treatments.