{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T16:13:14Z","timestamp":1791216794854,"version":"4.1.0"},"reference-count":29,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T00:00:00Z","timestamp":1767744000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Psychiatry"],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To assess the independent efficacy and safety of probiotics in unmedicated adults with depression, with a focus on studies approximating monotherapy conditions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This systematic review and meta-analysis followed PRISMA 2020 guidelines and was registered with PROSPERO (CRD420251015474). Four major databases were searched through March 2025 for randomized controlled trials (RCTs) investigating probiotic monotherapy in individuals with depression not receiving psychotropic treatment. All forms of standardized probiotic formulations (e.g., capsules, sachets) were eligible. The primary outcome was the change in validated depression rating scales. Standardized mean differences (SMDs) were synthesized using a random-effects model. Sensitivity and subgroup analyses addressed intervention type, assessment method (self-report vs. clinician-rated scales), and funding source. Safety outcomes were systematically assessed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Six RCTs with 341 randomly assigned participants (169 probiotic, 172 placebo) were included. Probiotic monotherapy was associated with a small but statistically significant reduction in depressive symptoms (SMD = \u22120.38, 95% CI: \u22120.57 to \u22120.18, p = 0.0002, I\u00b2 = 51%). Exploratory subgroup analysis indicated potential greater benefit in mild to moderate depression compared to major depressive disorder. Sensitivity analysis excluding industry-funded trials or studies with adjunctive agents resulted in non-significant findings (SMD = \u22120.21, 95% CI: \u22120.65 to 0.23, p = 0.35). Minor adverse events were reported, with no significant difference between groups and no serious adverse events.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Probiotic monotherapy may provide modest improvement in depressive symptoms and is generally safe for unmedicated individuals with mild to moderate depression. Given the small effect size, possible industry-related bias, and study heterogeneity, these findings should be interpreted cautiously. Larger, independently-funded RCTs are warranted to confirm efficacy and clarify mechanisms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Systematic Review Registration<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link>https:\/\/www.crd.york.ac.uk\/prospero\/<\/jats:ext-link>\n                      , iidentifier CRD420251015474.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fpsyt.2025.1608238","type":"journal-article","created":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T06:53:20Z","timestamp":1767768800000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Efficacy of probiotic intervention in unmedicated depression: a systematic review and meta-analysis"],"prefix":"10.3389","volume":"16","author":[{"given":"Liu","family":"Haiyan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wang","family":"Dan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wan","family":"Xiaochao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Xiuxiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liu","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Zhiguo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liu","family":"Ting","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,1,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(21)02143-7","article-title":"Global prevalence and burden of depressive and anxiety disorders in 204 countries and territories in 2020 due to the COVID-19 pandemic","volume":"398","author":"Santomauro","year":"2021","journal-title":"Lancet"},{"key":"B2","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1016\/j.jpsychires.2024.07.054","article-title":"Change in the global burden of depression from 1990\u20132019 and its prediction for 2030","volume":"178","author":"Zhang","year":"2024","journal-title":"J Psychiatr Res"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2024.5756","article-title":"Management of depression in adults: A review","volume":"332","author":"Simon","year":"2024","journal-title":"JAMA"},{"key":"B4","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1186\/s12888-025-06518-8","article-title":"Trajectories of pharmacological therapies for treatment-resistant depression: A longitudinal study","volume":"25","author":"DiBello","year":"2025","journal-title":"BMC Psychiatry"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3389\/fpsyt.2015.00117","article-title":"Commentary: \u201cConsistent superiority of selective serotonin reuptake inhibitors over placebo in reducing depressed mood in patients with major depression","volume":"6","author":"Fried","year":"2015","journal-title":"Front Psychiatry"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1192\/bjp.2024.275","article-title":"Examining the needs, outcomes and current treatment pathways of 2461 people with treatment-resistant depression: Mixed-methods study","author":"Gill","year":"2025","journal-title":"Br J Psychiatry"},{"key":"B7","article-title":"Relative effectiveness of antidepressant treatments in treatment-resistant depression: A systematic review and network meta-analysis of randomized controlled trials. 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