Probiotics in reducing negative symptoms of schizophrenia: A systematic review and meta-analysis

Negative symptoms are a core feature of schizophrenia and a major determinant of functional outcomes, yet effective treatments remain limited. Emerging evidence implicates the gut-brain axis in schizophrenia pathophysiology, prompting interest in probiotics as adjunctive therapy. This systematic review and meta-analysis evaluated the efficacy, safety, and tolerability of probiotics for negative symptoms in schizophrenia, and their effects on inflammatory biomarkers. A PRISMA-compliant search of PubMed, CENTRAL, PsycInfo, Cochrane, and LILACS identified randomized controlled trials (RCTs) of probiotics added to antipsychotics in adults with schizophrenia. The primary outcome was change in PANSS negative subscale scores, analyzed using random-effects models (Hedges' g). Six RCTs met inclusion criteria, but only three reported negative symptoms separately. The pooled analysis showed no significant effect of probiotics on negative symptoms (k = 3; Hedges' g = -0.26; 95% CI: -0.73 to 0.22; I² = 57%). Probiotics were safe and well tolerated, with no serious adverse events. Secondary analyses indicated a significant reduction in inflammatory markers, particularly hs-CRP (k = 3; Hedges' g = -1.18; 95% CI: -1.57 to -0.79). Limitations include the small number of trials, modest sample sizes, and heterogeneity in probiotic strains, dosages, populations, and background treatments. Short study durations, lack of enrichment for persistent negative symptoms, and absence of functional outcomes further limit interpretation. In conclusion, adjunctive probiotics appear safe and may reduce inflammation, but their effect on negative symptoms is not different from placebo in this meta-analysis, and remains uncertain given the very low certainty of current evidence. Larger, well-designed trials are needed.