Systematic review and meta-analysis of randomized clinical trials of anti-inflammatory agents in early-stage psychotic disorders

Background and Hypothesis

Accumulating evidence suggests that immune dysregulation is present in psychosis, however, evidence for anti-inflammatory treatments is mixed. This may be because studies need to focus on when inflammation offers a modifiable target. This review and meta-analysis sought to clarify the effects of anti-inflammatory agents from high-quality randomized trials in patients at clinical high risk for psychosis (CHR) and first-episode of psychosis (FEP).

Study Design

Databases were searched until January 2025 for double-blind, randomized, placebo-controlled trials evaluating the effect of anti-inflammatory treatment compared with placebo in CHR and FEP populations. Primary outcomes were transition rates to psychosis in CHR and changes in total psychotic symptoms in FEP. Secondary outcomes included changes in symptoms in CHR and changes in symptom sub-scores in FEP.

Study Results

Searches retrieved 2168 articles, with 17 meeting inclusion criteria (5 for CHR, 12 for FEP). In CHR, anti-inflammatory treatment was not associated with a significant reduction in transition to psychosis (odds ratio 0.88, 95% CI, 0.26-3.01, P = .80). In FEP, anti-inflammatory treatment demonstrated a significant reduction in total psychotic symptoms; (standardized mean differences = −0.38, 95% CI, −0.76 to 0.00, P = .05). Secondary outcomes showed no change in symptoms in CHR, and significant changes in Positive and Negative Syndrome Scale positive sub-scores in FEP.

Conclusions

Adjuvant anti-inflammatory treatment may be efficacious in FEP. However, high heterogeneity was present across studies, with possible publication bias and small-study effects. We highlight the need for further, large, stage-specific trials to conclusively understand the potential therapeutic benefit of anti-inflammatory treatments in early psychosis.