Inflammatory cytokine alterations in genetic and clinical high risk groups of psychosis: a systematic review and network meta-analysis

Clinical Snapshot

Key Findings

• P Value: Not reported in abstract

• Effect Size: Higher IL-6 in CHR vs GHR; Lower IL-6 and IL-1β in GHR vs HC; Higher IL-13 in CHR converters vs non-converters

• Primary Outcome: Circulating cytokine levels (IL-6, IL-1β, IL-13) across CHR, GHR, and healthy control groups

• Nnt Or Sensitivity: Standardized mean differences used for effect size estimation

• Confidence Interval: 95% confidence intervals reported but specific values not provided in abstract

Clinical Application

Limited by availability of specialized CHR assessment tools and genetic risk profiling in routine practice Relevant to EPPIC and headspace early psychosis programs; cytokine testing not currently part of standard CHR assessment protocols under Medicare Individuals identified as clinical or genetic high-risk for psychosis in specialized early intervention services

Abstract

BACKGROUND: Inflammation has been implicated in psychosis, but its role in individuals at clinical (CHR) and genetic (GHR) high-risk remains unclear. We therefore conducted a network meta-analysis (NMA) to compare circulating cytokine levels across CHR, GHR, and healthy control (HC) groups. METHODS: We systematically searched multiple databases up to February 2025, extracting cytokine levels (plasma/serum) from CHR, GHR, and HC groups. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were estimated using random-effects models. Given that no direct head-to-head comparisons between CHR and GHR were available, indirect comparisons were performed through the common comparator (HC). The transitivity assumption was assessed by comparing key study and participant characteristics across comparisons. RESULTS: Thirty studies were included (CHR: 1601, GHR: 675, HC: 1980). NMA estimates indicated higher IL-6 levels in CHR compared with GHR, while IL-6 and IL-1β levels were lower in GHR compared with HC. In pairwise subgroup analyses, CHR converters showed higher IL-13 levels than non-converters. The evidence network was sparse and star-shaped, with all CHR-GHR estimates relying exclusively on indirect comparisons. CONCLUSIONS: This study represents the first NMA to synthesize cytokine alterations in individuals at high risk for psychosis using indirect evidence. Elevated IL-6 in CHR individuals suggests immune activation, whereas reduced IL-6 in GHR may reflect a distinct immune profile. Increased IL-13 levels in converters highlight potential involvement of Th2-related pathways during transition to psychosis. However, the sparse nature of the evidence network necessitates cautious interpretation of the findings, and larger, standardized multi-center studies are required for confirmation.

References

1. 1.Huang, H., Sun, Y., Yin, J., An, S., Liu, M., Gong, Q., Chen, Y., & Deng, H. (2026). Inflammatory cytokine alterations in genetic and clinical high risk groups of psychosis: a systematic review and network meta-analysis. Psychological Medicine. https://doi.org/10.1017/S0033291726103559