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Peer-reviewedCC BY 4.0Molecular Psychiatry

Nutraceuticals and phytoceuticals for the treatment of major depressive disorder: a systematic review and network meta-analysis

  • Michele Fornaro1
  • Chiara Di Lorenzo2
  • Nicolas Nunez3,4
  • Alessandro Miola3,5
  • Raffaella Calati6
  • André Ferrer Carvalho7
  • Luca Steardo8
  • Brendon Stubbs9,10,11,12
  • David Mischoulon13
  • Christoph U. Correll14,15,16,17
  • Marco Solmi14,18,19,20
20 affiliations
  1. 1Section of Psychiatry, Federico II University of Naples, Naples, Italy
  2. 2Federico II University of Naples, Naples, Italy
  3. 3Department of Psychiatry & Psychology, Mayo Clinic, Rochester, MN USA
  4. 4Department of Psychiatry, University of Utah, Salt Lake City, UT USA
  5. 5Department of Neuroscience (DNS), Padua Neuroscience Center, University of Padova, Padua, Italy
  6. 6University of Milano-Bicocca, Milan, Italy
  7. 7Innovation in Mental and Physical Health and Clinical Treatment (IMPACT) Strategic Research Centre, School of Medicine, Barwon Health, Deakin University, Geelong, VIC Australia
  8. 8Psychiatric Unit, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
  9. 9Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, WC2R 2LS UK
  10. 10Comprehensive Center for Clinical Neurosciences and Mental Health, Medical University of Vienna, 1090 Vienna, Austria
  11. 11Division of Social Psychiatry, Department of Psychiatry and Psychotherapy, Medical University of Vienna, 1090 Vienna, Austria
  12. 12Division of Psychology and Mental Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
  13. 13Depression Clinical and Research Program, Massachusetts General Hospital, Harvard Medical School, Boston, 02114 USA
  14. 14Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin, Berlin, Germany
  15. 15The Zucker Hillside Hospital, Department of Psychiatry, Northwell Health, Glen Oaks, NY USA
  16. 16Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Department of Psychiatry and Molecular Medicine, Hempstead, NY USA
  17. 17Partner Site Berlin-Potsdam, German Center for Mental Health (DZPG), Berlin, Germany
  18. 18Department of Psychiatry, Faculty of Medicine, University of Ottawa, Ottawa, ON Canada
  19. 19Department of Mental Health, The Ottawa Hospital, Ottawa, ON Canada
  20. 20Ottawa Hospital Research Institute, OHRI, Ottawa, ON Canada
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Abstract

Background: “Nutraceuticals” and “phytoceuticals” may have antidepressant activity, prompting an in-depth network meta-analysis of randomized clinical trials (RCTs).

Methods: 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).

Results: 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.

Conclusions: Upon filtering low-quality evidence, only a few nutraceutical/phytoceuticals showed potential for depressive symptoms, warranting more rigorous trials.

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Cite

BibTeXRIS
BibTeX
@article{fornaro2026nutraceuticals,
  title = {{Nutraceuticals and phytoceuticals for the treatment of major depressive disorder: a systematic review and network meta-analysis}},
  author = {Michele Fornaro and Chiara Di Lorenzo and Nicolas Nunez and Alessandro Miola and Raffaella Calati and André Ferrer Carvalho and Luca Steardo and Brendon Stubbs and David Mischoulon and Christoph U. Correll and Marco Solmi},
  journal = {Molecular Psychiatry},
  year = {2026},
  month = sep,
  doi = {10.1038/s41380-026-03759-1},
  url = {https://doi.org/10.1038/s41380-026-03759-1},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Nutraceuticals and phytoceuticals for the treatment of major depressive disorder: a systematic review and network meta-analysis
AU  - Michele Fornaro
AU  - Chiara Di Lorenzo
AU  - Nicolas Nunez
AU  - Alessandro Miola
AU  - Raffaella Calati
AU  - André Ferrer Carvalho
AU  - Luca Steardo
AU  - Brendon Stubbs
AU  - David Mischoulon
AU  - Christoph U. Correll
AU  - Marco Solmi
PY  - 2026
DA  - 2026/09/01
JO  - Molecular Psychiatry
DO  - 10.1038/s41380-026-03759-1
UR  - https://doi.org/10.1038/s41380-026-03759-1
AB  - Background: “Nutraceuticals” and “phytoceuticals” may have antidepressant activity, prompting an in-depth network meta-analysis of randomized clinical trials (RCTs).  Methods: 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).  Results: 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.  Conclusions: Upon filtering low-quality evidence, only a few nutraceutical/phytoceuticals showed potential for depressive symptoms, warranting more rigorous trials.
SN  - 1359-4184
SN  - 1476-5578
ER  -