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Nutraceuticals and phytoceuticals in the treatment of schizophrenia: a systematic review and network meta-analysis “Nutra NMA SCZ”

Molecular Psychiatry volume 30, pages 168–187 (2025)Cite this article

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Abstract

Sub-optimal response in schizophrenia is frequent, warranting augmentation strategies over treatment-as-usual (TAU). We assessed nutraceuticals/phytoceutical augmentation strategies via network meta-analysis. Randomized controlled trials in schizophrenia/schizoaffective disorder were identified via the following databases: PubMed, MEDLINE, EMBASE, Scopus, PsycINFO, CENTRAL, and ClinicalTrials.gov. Change (Standardized Mean Difference = SMD) in total symptomatology and acceptability (Risk Ratio = RR) were co-primary outcomes. Secondary outcomes were positive, negative, cognitive, and depressive symptom changes, general psychopathology, tolerability, and response rates. We conducted subset analyses by disease phase and sensitivity analyses by risk of bias and assessed global/local inconsistency, publication bias, risk of bias, and confidence in the evidence. The systematic review included 49 records documenting 50 studies (n = 2384) documenting 22 interventions. Citicoline (SMD =−1.05,95%CI = –1.85; −0.24), L-lysine (SMD = –1.04,95%CI = –1.84; −0.25), N-acetylcysteine (SMD = –0.87, 95%CI = –1.27; −0.47) and sarcosine (SMD = –0.5,95%CI = –0.87–0.13) outperformed placebo for total symptomatology. High heterogeneity (tau2 = 0.10, I2 = 55.9%) and global inconsistency (Q = 40.79, df = 18, p = 0.002) emerged without publication bias (Egger’s test, p = 0.42). Sarcosine improved negative symptoms (SMD = –0.65, 95%CI = –1.10; −0.19). N-acetylcysteine improved negative symptoms (SMD = –0.90, 95%CI = –1.42; −0.39)/general psychopathology (SMD = –0.76, 95%CI = –1.39; −0.13). No compound improved total symptomatology within acute phase studies (k = 7, n = 422). Sarcosine (SMD = –1.26,95%CI = –1.91; −0.60), citicoline (SMD = –1.05,95%CI = –1.65;-0.44), and N-acetylcysteine (SMD = –0.55,95%CI = –0.92,−0.19) outperformed placebo augmentation in clinically stable participants. Sensitivity analyses removing high-risk-of-bias studies confirmed overall findings in all phases and clinically stable samples. In contrast, the acute phase analysis restricted to low risk-of-bias studies showed a superior effect vs. placebo for N-acetylcysteine (SMD = −1.10, 95%CI = –1.75,−0.45), L-lysine (SMD = –1.05,95%CI = –1.55, −0.19), omega-3 fatty acids (SMD = –0.83,95%CI = –1.31, −0.34) and withania somnifera (SMD = –0.71,95%CI = –1.21,−0.22). Citicoline (SMD = –1.05,95%CI = –1.86,−0.23), L-lysine (SMD = –1.04,95%CI = –1.84,−0.24), N-acetylcysteine (SMD = –0.89,95%CI = –1.35,−0.43) and sarcosine (SMD = –0.61,95%CI = –1.02,−0.21) outperformed placebo augmentation of TAU (“any phase”). Drop-out due to any cause or adverse events did not differ between nutraceutical/phytoceutical vs. placebo+TAU. Sarcosine, citicoline, and N-acetylcysteine are promising augmentation interventions in stable patients with schizophrenia, yet the quality of evidence is low to very low. Further high-quality trials in acute phases/specific outcomes/difficult-to-treat schizophrenia are warranted.

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Fig. 1
Fig. 2: Forest plot showing effects of nutraceuticals and phytoceuticals on change in schizophrenia-specific total symptomatology, compared to placebo+TAU.
Fig. 3: Forest plot showing effects of nutraceuticals and phytoceuticals on change in positive and negative symptoms and general symptomatology.
Fig. 4: Forest plot showing effects of nutraceuticals and phytoceuticals on acceptability and tolerability.

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Data availability

With the publication of this article, the entire dataset will be available to the final reader upon request. All authors had access to the data and were responsible for the decision to submit it for publication.

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Funding

MB is supported by an NHMRC Senior Principal Research Fellowship and Leadership 3 Investigator grant (1156072 and 2017131). WM is currently funded by an NHMRC Investigator Grant (#2008971)

Author information

Author notes

  1. These authors contributed equally: Michele Fornaro, Claudio Caiazza.

Authors and Affiliations

  1. Department of Neuroscience, Reproductive Sciences, and Dentistry, Section of Psychiatry, University School of Medicine Federico II, Naples, Italy

    Michele Fornaro, Claudio Caiazza, Martina Billeci, Rosanna Pezone, Giuseppe De Simone, Niccolò Solini, Felice Iasevoli & Andrea de Bartolomeis

  2. Deakin University, IMPACT, the Institute for Mental and Physical Health and Clinical Translation Strategic Research Centre, School of Medicine, Geelong, VIC, Australia

    Michael Berk

  3. Mental Health Drug and Alcohol Services, Barwon Health, Geelong, VIC, Australia

    Michael Berk

  4. Orygen, The National Centre of Excellence in Youth Mental Health, Melbourne, VIC, Australia

    Michael Berk

  5. Centre for Youth Mental Health, Florey Institute for Neuroscience and Mental Health, Melbourne, VIC, Australia

    Michael Berk

  6. Department of Psychiatry, The University of Melbourne, Melbourne, VIC, Australia

    Michael Berk

  7. Food & Mood Centre, Deakin University, IMPACT (the Institute for Mental and Physical Health and Clinical Translation), Geelong, VIC, Australia

    Wolfgang Marx

  8. Teaching Unit of Psychiatry and Psychological Medicine, Department of Medicine, Centro de Investigación Biomédica En Red de Salud Mental (CIBERSAM), University of Valencia, Valencia, Spain

    Vicent Balanzá-Martinez

  9. Bipolar and Depressive Disorders Unit, Institute of Neuroscience, Hospital Clinic, CIBERSAM, University of Barcelona, IDIBAPS, Barcelona, Catalonia, Spain

    Michele De Prisco

  10. Section of Psychiatry, Laboratory of Translational and Molecular Psychiatry and Unit of Treatment-Resistant Psychosis, Department of Neuroscience, Reproductive Sciences and Odontostomatology, University Medical School of Naples “Federico II”, Naples, Italy

    Felice Iasevoli & Andrea de Bartolomeis

  11. Department of Psychiatry, Strasbourg University Hospital, University of Strasbourg, Strasbourg, France

    Fabrice Berna

  12. CEReSS-Health Service Research and Quality of Life Center, UR3279, Assistance Publique des Hôpitaux de Marseille, Aix-Marseille University, Marseille, France

    Guillaume Fond & Laurent Boyer

  13. Fondation FondaMental Fondation de Coopération Scientifique en Santé Mentale, Université Paris Est, Créteil, France

    Guillaume Fond & Laurent Boyer

  14. Innovation in Mental and Physical Health and Clinical Treatment (IMPACT) Strategic Research Centre, School of Medicine, Barwon Health, Deakin University, Geelong, VIC, Australia

    Andre Fèrrer Carvalho

  15. Pain and Rehabilitation Center, Department of Medicine and Health Sciences, Linköping University, Linköping, Sweden

    Elena Dragioti

  16. Department of Psychiatry, University of Ottawa, Ottawa, ON, Canada

    Jess G. FIEDOROWICZ & Marco Solmi

  17. Department of Mental Health, The Ottawa Hospital, Ottawa, ON, Canada

    Jess G. FIEDOROWICZ & Marco Solmi

  18. Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada

    Jess G. FIEDOROWICZ & Marco Solmi

  19. Department of Psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, NY, USA

    Christoph U. Correll

  20. Department of Psychiatry and Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA

    Christoph U. Correll

  21. Center for Psychiatric Neuroscience, Feinstein Institute for Medical Research, Manhasset, NY, USA

    Christoph U. Correll

  22. Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin, Berlin, Germany

    Christoph U. Correll & Marco Solmi

Authors
  1. Michele Fornaro
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  2. Claudio Caiazza
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  3. Martina Billeci
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Contributions

MF and MB conceived the study, which MF and CaC coordinated. CaC, NS, MDP, MS, and CUC assisted in the statistical analysis and critical interpretation of the results. MF and CaC wrote the manuscript, which all authors read and approved.

Corresponding author

Correspondence to Michele Fornaro.

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Competing interests

MF received honoraria for his speaker activity from the American Society of Clinical Psychopharmacology (ASCP) and served as a consultant for Angelini, Otsuka, Lundbeck, Sanofi-Aventis, and Boehringer Ingelheim. WM has previously received university grants/fellowships from La Trobe University, Deakin University, University of Queensland, and Bond University. WM has received funding and/or has attended events funded by Cobram Estate Pty. Ltd and Bega Dairy and Drinks Pty Ltd. WM has received travel funding from the Nutrition Society of Australia. WM has received consultancy funding from Nutrition Research Australia and ParachuteBH. MS has received honoraria/has been a consultant for AbbVie, Angelini, Lundbeck, and Otsuka. VBM received honoraria from Angelini, unrelated to the present work. CUC has been a consultant and/or advisor to or has received honoraria from: AbbVie, Acadia, Adock Ingram, Alkermes, Allergan, Angelini, Aristo, Biogen, Boehringer-Ingelheim, Bristol-Meyers Squibb, Car dio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Delpor, Denovo, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Jamjoom Pharma, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Neurelis, Newron, Noven, Novo Nordisk, Otsuka, Pharmabrain, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Sage, Seqirus, SK Life Science, Sumitomo Pharma America, Sunovion, Sun Pharma, Supernus, Tabuk, Takeda, Teva, Tolmar, Vertex, and Viatris. He provided expert testimony for Janssen and Otsuka. He served on a Data Safety Monitoring Board for Compass Pathways, Denovo, Lundbeck, Relmada, Reviva, Rovi, Supernus, and Teva. He has received grant support from Janssen and Takeda. He received royalties from UpToDate and is also a stock option holder of Cardio Diagnostics, Kuleon Biosciences, LB Pharma, Mindpax, and Quantic. All other authors declare no conflicts of interest relevant to this work.

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Fornaro, M., Caiazza, C., Billeci, M. et al. Nutraceuticals and phytoceuticals in the treatment of schizophrenia: a systematic review and network meta-analysis “Nutra NMA SCZ”. Mol Psychiatry 30, 168–187 (2025). https://doi.org/10.1038/s41380-024-02645-y

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