Multiple peripheral inflammatory markers in adolescents with major depressive disorder treated with repeated esketamine infusions: results from a randomized controlled trial

Clinical Snapshot

Key Findings

• P Value: Exploratory correlations: IL-8 with C-SSRS (p=0.026), IFN-γ with MADRS (p=0.048)

• Effect Size: Significant time effects for all markers but no between-group differences

• Primary Outcome: No significant drug main effects observed for any inflammatory markers

• Nnt Or Sensitivity: Cannot be calculated due to lack of significant treatment effects

• Confidence Interval: Not reported

Clinical Application

Limited by small sample size and lack of demonstrated efficacy on inflammatory outcomes Esketamine (Spravato) is TGA-approved for treatment-resistant depression in adults; adolescent use remains off-label and requires specialist supervision Adolescents with major depressive disorder, particularly those with treatment-resistant depression

Abstract

OBJECTIVE: While inflammatory dysregulation is well-documented in major depressive disorder (MDD), its response to esketamine treatment in adolescents remains poorly understood. We aimed to examine the effects of esketamine on the inflammatory cytokines in adolescent MDD. METHODS: This randomized, double-blind trial assigned 49 adolescents with MDD to receive three infusions of esketamine or midazolam over five days between December 2020 and April 2022. Suicidal ideation (measured by Columbia Suicide Severity Rating Scale, C-SSRS), depressive symptoms (measured by Montgomery-Åsberg Depression Rating Scale, MADRS) and plasma levels of 10 inflammatory markers were assessed at baseline, Day 6, and Day 12. RESULTS: Linear mixed model revealed significant time effects for all markers, but no significant drug main effect was observed. In esketamine group, alterations in IL-8 were associated with the reduction of C-SSRS Intensity at Day 6 (r = 0.444, p = 0.026), and alterations in IFN-γ were correlated with the reduction of MADRS (r = 0.399, p = 0.048) and C-SSRS Intensity (r = 0.427, p = 0.033) at Day 12. Baseline C4 negatively related to the reductions of MADRS and C-SSRS Ideation at Day 6 and 12 (all p < 0.005). CONCLUSIONS: Our study found no significant drug main effects for inflammatory markers, with most changes representing time effects observed in both groups. Exploratory results indicate that IL-8, IFN-γ, and C4 may warrant further investigation as potential biomarkers of esketamine response in adolescent MDD.

References

1. 1.Lan, X., Wu, Z., Wang, C., Liu, G., Zhang, M., Li, W., Luo, Z., Shen, J., Chen, Z., Ning, Y., & Zhou, Y. (2026). Multiple peripheral inflammatory markers in adolescents with major depressive disorder treated with repeated esketamine infusions: results from a randomized controlled trial. Journal of Affective Disorders, 121488. https://doi.org/10.1016/j.jad.2026.121488