Peripheral blood inflammatory markers in patients with attention deficit/hyperactivity disorder (ADHD): A systematic review and meta-analysis

It has been observed that subclinical inflammation might be involved in the pathophysiology of attention deficit/hyperactivity disorder (ADHD). However, studies investigating peripheral blood levels of immune-inflammatory markers have provided mixed findings. We performed a systematic review and meta-analysis of studies comparing unstimulated serum or plasma levels of C-reactive protein (CRP) and cytokines in subjects with ADHD and healthy controls (the PROSPERO registration number: CRD 42021276869). Online searches covered the publication period until 30th Sep 2021 and random-effects meta-analyses were carried out. Out of 1844 publication records identified, 10 studies were included. The levels of interleukin (IL)-6 were significantly higher in studies of participants up to the age of 18 years (k = 10, g = 0.70, 95%CI: 0.10-1.30, p = 0.023) and after including those above the age of 18 years (k = 10, g = 0.71, 95%CI: 0.12-1.31, p = 0.019). In turn, the levels of tumor necrosis factor-alpha (TNF-alpha) were significantly lower in subjects with ADHD compared to healthy controls (k = 7, g = -0.16, 95%CI: -0.30 - -0.03, p = 0.020). Individual studies had a high contribution to the overall effect, since the overall effect was no longer significant after removing single studies. No significant differences were found with respect to the levels of CRP, IL-1 beta, IL-10 and interferon-y. The present findings indicate that individuals with ADHD tend to show elevated levels of IL-6 and reduced levels of TNF-alpha. Larger and longitudinal studies recording potential confounding factors and comorbid psychopathology are needed to confirm our findings.