Efficacy of Probiotic Supplementation for Major Depressive Disorder: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Abstract

Background: Major depressive disorder (MDD) is a common and disabling psychiatric condition with heterogeneous biological mechanisms and variable treatment response. Growing evidence implicates the microbiota–gut–brain axis in pathways relevant to mood regulation, creating interest in probiotics as a potential adjunctive intervention. This systematic review and meta-analysis evaluated the efficacy of probiotic supplementation in adults with MDD.
Methods: PubMed, Embase, Scopus, and Web of Science were searched for peer-reviewed randomized placebo-controlled studies published between January 2011 and 26 August 2026. Eligible studies included adults with clinically diagnosed MDD receiving oral probiotic supplementation, either alone or alongside standard treatment. Depressive symptom severity measured using validated scales was the primary outcome. Arm-level sample sizes, means, and standard deviations were extracted from primary RCT reports; Hedges’ g and 95% confidence intervals (CIs) were calculated independently, and heterogeneity was assessed using I² and τ².
Results: Four independent RCT cohorts involving 169 participants provided sufficient primary numerical data for the principal meta-analysis. The random-effects estimate favored probiotic supplementation (Hedges’ g = 0.71, 95% CI 0.39–1.02), with I² = 0% and τ² = 0.00. Sensitivity analyses produced pooled estimates from 0.64 to 0.72, and leave-one-out analyses did not materially alter the direction of effect. Considerable variation was observed across probiotic strains, formulations, treatment durations, antidepressant co-treatment, participant characteristics, and depression measures. The available literature also included multiple reports derived from a smaller number of independent randomized cohorts.
Conclusion: Probiotic supplementation may provide a modest adjunctive benefit for depressive symptoms in adults with MDD. However, the limited number of independent cohorts, clinical heterogeneity, risk-of-bias concerns, and imprecision resulted in low-certainty evidence according to GRADE. Larger, rigorously designed trials with standardized outcomes and clearly characterized probiotic interventions are needed