{
  "abstract": "Background: “Nutraceuticals” and “phytoceuticals” may have antidepressant activity, prompting an in-depth network meta-analysis of randomized clinical trials (RCTs).\n\nMethods: Systematic review and network meta-analysis (PubMed/MEDLINE/EMBASE/Scopus/PsycINFO/CENTRAL/ClinicalTrials.gov (until 01/07/2025) of RCTs vs. placebo or treatment as usual (TAU = antidepressants) testing nutraceuticals/phytoceuticals in major depressive disorder (MDD). Change in depressive symptomatology (standardized-mean-difference = SMD), treatment response, and all-cause discontinuation (acceptability) (risk ratio = RR) were co-primary outcomes. Secondary outcomes were anxiety symptom changes, adverse event-related discontinuation (“tolerability”), and symptom remission. We conducted subgroup, transitivity, and sensitivity analyses to explore/reduce heterogeneity, and assessed global/local inconsistency, publication bias, risk of bias (RoB), and confidence in the evidence (CINeMA/AMSTAR-Plus).\n\nResults: Across 163 studies (n = 15,757, distinct compounds’ combinations n = 137), several molecules/classes outperformed placebo with very large effect sizes. Restricting analyses to compounds with ≥2RCTs/non-TAU antidepressants/low RoB/non-sponsored trials/non-outliers, higher-than-expected/unrealistic effect sizes emerged vs. placebo for eicosapentaenoic acid (EPA) (k = 20, n = 8483; SMD = −1.67;95%C.I. = −2.38;−0.97), vitamin D3 (k = 3, n = 344; SMD = −1.59;95%C.I. = −2.71;−0.46), and St. John’s-wort-extract-ZE117 (k = 3,n = 207;SMD = −1.02;95%C.I = −1.90;−0.15) regarding depressive symptomatology. Substantial heterogeneity (I2 = 85.3%;95%C.I. = 81.9%;88.0%) and global inconsistency (Q-between-designs = 186.91, p < 0.0001) emerged, explained by subgroup and sensitivity analyses, without publication bias. Additionally, a medium effect size emerged vs. placebo for curcumin (k = 2,n = 89;SMD = −0.58;95%C.I. = −0.99;−0.18) regarding anxiety reduction in low RoB analyses. Shugan granules, EPA, EPA+Docosahexaenoic Acid, ZE117, and fluoxetine+EPA response and St. John’s wort extract WS5570/ZE117 remission significantly outperformed placebo. Citicoline was associated with significantly more dropouts than placebo. A meta-regression of efficacy effect sizes against adapted AMSTAR-Plus scores showed that larger SMDs were associated with lower AMSTAR scores, indicating lower study quality. Confidence in the evidence was low to very low.\n\nConclusions: Upon filtering low-quality evidence, only a few nutraceutical/phytoceuticals showed potential for depressive symptoms, warranting more rigorous trials.",
  "abstract_shown": true,
  "affiliations": [
    "Section of Psychiatry, Federico II University of Naples, Naples, Italy",
    "Federico II University of Naples, Naples, Italy",
    "Department of Psychiatry & Psychology, Mayo Clinic, Rochester, MN USA",
    "Department of Psychiatry, University of Utah, Salt Lake City, UT USA",
    "Department of Neuroscience (DNS), Padua Neuroscience Center, University of Padova, Padua, Italy",
    "University of Milano-Bicocca, Milan, Italy",
    "Innovation in Mental and Physical Health and Clinical Treatment (IMPACT) Strategic Research Centre, School of Medicine, Barwon Health, Deakin University, Geelong, VIC Australia",
    "Psychiatric Unit, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy",
    "Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, WC2R 2LS UK",
    "Comprehensive Center for Clinical Neurosciences and Mental Health, Medical University of Vienna, 1090 Vienna, Austria",
    "Division of Social Psychiatry, Department of Psychiatry and Psychotherapy, Medical University of Vienna, 1090 Vienna, Austria",
    "Division of Psychology and Mental Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK",
    "Depression Clinical and Research Program, Massachusetts General Hospital, Harvard Medical School, Boston, 02114 USA",
    "Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin, Berlin, Germany",
    "The Zucker Hillside Hospital, Department of Psychiatry, Northwell Health, Glen Oaks, NY USA",
    "Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Department of Psychiatry and Molecular Medicine, Hempstead, NY USA",
    "Partner Site Berlin-Potsdam, German Center for Mental Health (DZPG), Berlin, Germany",
    "Department of Psychiatry, Faculty of Medicine, University of Ottawa, Ottawa, ON Canada",
    "Department of Mental Health, The Ottawa Hospital, Ottawa, ON Canada",
    "Ottawa Hospital Research Institute, OHRI, Ottawa, ON Canada"
  ],
  "article_type": "review article",
  "arxiv": null,
  "author_total": 11,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Michele Fornaro",
      "orcid": "0000-0002-9647-0853"
    },
    {
      "affs": [
        1
      ],
      "name": "Chiara Di Lorenzo"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Nicolas Nunez"
    },
    {
      "affs": [
        2,
        4
      ],
      "name": "Alessandro Miola"
    },
    {
      "affs": [
        5
      ],
      "name": "Raffaella Calati",
      "orcid": "0000-0001-8130-437X"
    },
    {
      "affs": [
        6
      ],
      "name": "André Ferrer Carvalho",
      "orcid": "0000-0002-2500-5671"
    },
    {
      "affs": [
        7
      ],
      "name": "Luca Steardo"
    },
    {
      "affs": [
        8,
        9,
        10,
        11
      ],
      "name": "Brendon Stubbs"
    },
    {
      "affs": [
        12
      ],
      "name": "David Mischoulon",
      "orcid": "0000-0001-7233-5860"
    },
    {
      "affs": [
        13,
        14,
        15,
        16
      ],
      "name": "Christoph U. Correll",
      "orcid": "0000-0002-7254-5646"
    },
    {
      "affs": [
        13,
        17,
        18,
        19
      ],
      "name": "Marco Solmi",
      "orcid": "0000-0003-4877-7233"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/dtbem0gfgy35w.bib",
  "cited_by": 1,
  "doi": "10.1038/s41380-026-03759-1",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13736492/",
  "id": "dtbem0gfgy35w",
  "issns": [
    "1359-4184",
    "1476-5578"
  ],
  "landing_url": "https://doi.org/10.1038/s41380-026-03759-1",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Systematic Review"
    ],
    [
      "openalex",
      "2736|Treatment of Major Depression"
    ]
  ],
  "openalex": "W7204943338",
  "pdf_url": "https://www.nature.com/articles/s41380-026-03759-1.pdf",
  "pmcid": "PMC13736492",
  "pmid": "42680855",
  "published": "2026-09-01",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/dtbem0gfgy35w.ris",
  "sources": [
    {
      "first_seen": "2026-11-09T12:21:55Z",
      "native_id": "PMC13736492",
      "source": "pmc",
      "url": "https://doi.org/10.1038/s41380-026-03759-1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2736|Treatment of Major Depression",
      "subfield": "pharmacology-toxicology"
    }
  ],
  "title": "Nutraceuticals and phytoceuticals for the treatment of major depressive disorder: a systematic review and network meta-analysis",
  "title_text": "Nutraceuticals and phytoceuticals for the treatment of major depressive disorder: a systematic review and network meta-analysis",
  "type": "peer-reviewed",
  "updated_at": "2026-11-09T12:21:55Z",
  "url": "https://research.draconitic.com/paper/dtbem0gfgy35w",
  "venue": "Molecular Psychiatry",
  "versions": []
}