Systematic review finds immune markers IL-1β and TNF-α associated with negative symptoms in first episode psychosis

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Frontiers in Medicine Published April 10, 2026 Medically reviewed May 1, 2026 DOI ↗ By Dr. Ji-eun Park, MD · Brain, Mind & Pain

Key Takeaway

Consider that IL-1β and TNF-α show reproducible associations with negative symptoms in first episode psychosis, though evidence remains observational.

This systematic review analyzed 7 case-control studies comparing peripheral blood immune markers in individuals with first episode psychosis (FEP) against healthy controls. The primary outcome was the association between these immune markers and negative symptoms, with secondary outcomes including negative symptom severity and inflammatory marker levels. Follow-up duration was not reported.

FEP individuals generally showed elevated levels of inflammatory markers compared with controls, though specific effect sizes and absolute numbers were not reported. Modest but consistently positive associations were found between immune markers and negative symptom severity. Among cytokines, IL-1β and TNF-α demonstrated the most reproducible associations with negative symptom severity, while findings for other cytokines were more variable.

Safety and tolerability data were not reported. Key limitations include heterogeneity in immune measurement methods and symptom assessment approaches, with most studies relying on total negative symptom scores rather than examining symptom subdomains or dimensional constructs. Funding and conflicts of interest were not reported.

For clinical practice, these findings suggest peripheral immune dysregulation, particularly involving IL-1β and TNF-α, may be associated with negative symptom severity in FEP. However, the evidence remains observational with significant heterogeneity, limiting mechanistic interpretation. Future studies should prioritize dimensional assessment of negative symptoms, stratification by inflammatory profiles, and integration of cellular immune phenotyping.

Study Details

Study typeMeta analysis

EvidenceLevel 1

PublishedApr 2026

View Original Abstract ↓

BackgroundNegative symptoms are a core feature of psychotic disorders, evident from the first episode of psychosis (FEP), and are strongly associated with poor functional outcomes. Increasing evidence suggests that immune dysregulation may contribute to negative symptom expression in FEP individuals; however, findings remain heterogeneous. This systematic review aimed to synthesise recent evidence on the association between peripheral blood immune markers and negative symptoms in FEP.MethodsA systematic search of PubMed and Scopus was conducted following PRISMA guidelines. Observational studies published within the last five years were included if they assessed peripheral blood immune markers and negative symptoms in individuals with FEP and included a healthy control group. Study quality was evaluated using the Newcastle-Ottawa Scale. Findings were synthesised narratively due to methodological heterogeneity.ResultsSeven case-control studies met the inclusion criteria, comprising predominantly young adults with FEP, including both antipsychotic-naïve and minimally treated individuals. Across studies, a broad range of immune markers was assessed, most commonly IL-6, IL-1β, and TNF-α. FEP individuals generally showed elevated levels of inflammatory markers compared with controls. Associations between immune markers and negative symptoms were modest but consistently positive, with IL-1β and TNF-α showing the most reproducible associations with negative symptom severity. Findings for other cytokines were more variable. Notably, most studies relied on total negative symptom scores, and none examined symptom subdomains or dimensional constructs.ConclusionsPeripheral immune dysregulation, particularly involving IL-1β and TNF-α, appears to be associated with negative symptom severity in FEP. However, heterogeneity in immune measurement and symptom assessment limits mechanistic interpretation. Future studies should prioritise dimensional assessment of negative symptoms, stratification by inflammatory profiles, and integration of cellular immune phenotyping to better elucidate immune-symptom relationships in early psychosis.