The therapeutic readiness of probiotics in major depressive disorder: A systematic review of randomised controlled trials

Background: Major depressive disorder (MDD) is a globally prevalent psychiatric condition associated with significant morbidity and often suboptimal treatment outcomes. Probiotics have emerged as a promising adjunctive therapy targeting the gut–brain axis in MDD. Aims: This systematic review aimed to critically evaluate the efficacy of probiotics in the treatment of clinically diagnosed MDD, assess methodological quality and therapeutic readiness, and identify research gaps relevant to clinical application. Methods: A systematic search of MEDLINE, Web of Science, and PubMed was conducted in June 2023 in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Double-blind, placebo-controlled, randomised controlled trials (RCTs) involving adults with MDD were included. Risk of bias was assessed using the Cochrane Risk of Bias tool. Results: Thirteen RCTs involving 437 adults aged 18–75 years with MDD were included. Most trials reported improvements in depressive symptoms, particularly in outpatients with mild-to-moderate MDD treated with multi-strain formulations containing Lactobacillus and Bifidobacterium over 4–8 weeks. Secondary outcomes across metabolic, inflammatory, cognitive, neurotrophic, and gastrointestinal domains showed variable improvements. Probiotic benefits were most consistent in Iranian outpatients, more modest in European inpatients, and positive but variable in East Asian outpatients. Risk of bias was predominantly low, though attrition, selective reporting, and methodological heterogeneity remained sources of bias. Conclusions: Probiotics appear safe and well-tolerated, with modest adjunctive benefit in MDD, most evident for multi-strain formulations in younger, outpatient populations with mild-to-moderate symptoms, supporting an individualised, context-dependent approach. Future trials should stratify patients, extend intervention durations, and integrate mechanistic endpoints to refine patient-tailored recommendations.