Peripheral blood immune markers associated with negative symptoms in first episode psychosis: a systematic review

Background: Negative 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. Methods: A 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. Results: Seven 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. Conclusions: Peripheral 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.