Published online Mar 9, 2026. doi: 10.5409/wjcp.v15.i1.115246
Revised: October 28, 2025
Accepted: January 6, 2026
Published online: March 9, 2026
Processing time: 145 Days and 12.3 Hours
Generalized anxiety disorder (GAD) is a prevalent psychiatric condition in children and adolescents, frequently linked to difficulties in daily functioning and academic performance. Increasing evidence suggests that immune dysregulation and neuroinflammatory pathways contribute to its pathophysiology, yet studies examining circulating cytokines and related biomarkers in pediatric populations are still scarce.
To investigate serum levels of C-reactive protein (CRP), tumor necrosis factor-like weak inducer of apoptosis, neopterin, interleukin-6, tumor necrosis factor-alpha, interferon-gamma, and zinc in drug-naïve children and adolescents with GAD, to gain insight into potential immune-related alterations.
The observational case-control design was conducted, including 25 drug-naïve patients with ‘pure’ GAD and 30 healthy controls aged 8-18 years. Psychiatric diagnoses were confirmed by the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version, Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition and the Revised Child Anxiety and Depression Scale. Venous blood samples were analyzed using enzyme-linked immunosorbent assay, nephelometry, and electro-chemiluminescence assays. Group comparisons were performed using the Mann-Whitney U test and the χ2 test, and correlations were assessed using Spearman's correlation.
CRP levels were significantly higher in the GAD group than controls (median 1.7 mg/L vs 1.3 mg/L, P = 0.034, r = 0.32). No significant group differences were observed for tumor necrosis factor-alpha tumor necrosis factor-like weak inducer of apoptosis, interleukin-6, interferon-gamma, zinc, or neopterin. Time since symptom onset was positively correlated with total anxiety severity (r = 0.729, P = 0.001). Receiver operating characteristic analysis showed modest diagnostic value for CRP (area under the curve = 0.665, 95% confidence interval: 0.511-0.820).
This study demonstrates a moderate elevation in CRP levels in drug-naïve patients with GAD. Although no change in other inflammatory markers was observed in our study, this may suggest a low-grade inflammatory response. The early detection of symptoms is still critical, and more longitudinal studies with larger samples are necessary further to elucidate the role of inflammation in childhood anxiety pathophysiology.
Core Tip: This study investigated the potential relationship between generalized anxiety disorder (GAD) and systemic inflammation in drug-naïve children and adolescents. Significantly higher C-reactive protein levels compared to healthy controls suggest a low-grade inflammatory process may be present in pediatric GAD. In contrast, no significant group differences were found in other circulatory immune markers. This selective pattern of elevation suggests that specific components of the inflammatory response may be activated in a limited manner in GAD. Furthermore, the positive correlation between clinical symptom severity and illness duration supports the potential impact of early diagnosis and intervention on symptom progression. However, larger sample sizes and longitudinal studies are needed to define causal relationships and clinical outcomes more robustly.