Nutraceuticals and phytoceuticals in the treatment of schizophrenia: a systematic review and network meta-analysis

Michele Fornaro; Claudio Caiazza; Martina Billeci; Michael Berk; Wolfgang Marx; Vicent Balanzá-Martínez; Michele De Prisco; Rosanna Pezone; Giuseppe De Simone; Niccolo' Solini; Felice Iasevoli; Fabrice Berna; Guillaume Fond; Laurent Boyer; Andre F Carvalho; Elena Dragioti; Jess Fiedorowicz; Andrea de Bartolomeis; Christoph Correll; Marco Solmi

doi:10.21203/rs.3.rs-3787917/v1

Nutraceuticals and phytoceuticals in the treatment of schizophrenia: a systematic review and network meta-analysis

Res Sq [Preprint]. 2024 Jan 12:rs.3.rs-3787917. doi: 10.21203/rs.3.rs-3787917/v1.

Authors

Michele Fornaro¹, Claudio Caiazza², Martina Billeci², Michael Berk³, Wolfgang Marx⁴, Vicent Balanzá-Martínez⁵, Michele De Prisco², Rosanna Pezone², Giuseppe De Simone², Niccolo' Solini⁶, Felice Iasevoli⁶, Fabrice Berna⁶, Guillaume Fond⁶, Laurent Boyer⁷, Andre F Carvalho⁷, Elena Dragioti⁸, Jess Fiedorowicz⁸, Andrea de Bartolomeis⁸, Christoph Correll⁸, Marco Solmi⁹

Affiliations

¹ Federico II University of Naples.
² University of Naples Federico II.
³ Deakin University, Australia.
⁴ Deakin University.
⁵ University of Valencia.
⁶ APHM.
⁷ Innovation in Mental and Physical Health and Clinical Treatment (IMPACT) Strategic Research Centre, School of Medicine, Barwon Health, Deakin University, Geelong, VIC, Australia.
⁸ Donald and Barbara Zucker School of Medicine at Hofstra/Northwell.
⁹ uOttawa.

Abstract

Background: Sub-optimal response in schizophrenia is frequent, warranting augmentation strategies over treatment-as-usual (TAU).

Methods: 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.

Results: The systematic review included 49 records documenting 50 studies (n=2,384) documenting 22 interventions. Citicoline (SMD=-1.05,95%CI=-1.85; -.24), L-lysine (SMD=-1.04,95%CI=-1.84;-.25), N-acetylcysteine (SMD=-.87,95%CI=-1.27;-.47) and sarcosine (SMD=-.5,95%CI=-.87-.13) outperformed placebo for total symptomatology. High heterogeneity (tau²=.10, I²=55.9%) and global inconsistency (Q=40.79, df=18, p=.002) emerged without publication bias (Egger's test, p=.42). Sarcosine improved negative symptoms (SMD=-.65, 95%CI=-1.10; -.19). N-acetylcysteine improved negative symptoms (SMD=-.90, 95%CI=-1.42; -.39)/general psychopathology (SMD=-.76, 95%CI=-1.39; -.13). No compound improved total symptomatology within acute phase studies (k=7, n=422). Sarcosine (SMD=-1.26,95%CI=-1.91; -.60), citicoline (SMD=-1.05,95%CI=-1.65;-.44), and N-acetylcysteine (SMD=-.55,95%CI=-.92,-.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,-.45), L-lysine (SMD=-1.05,95%CI=-1.55,-.19), omega-3 fatty acids (SMD=-.83,95%CI=-1.31,-.34) and withania somnifera (SMD=-.71,95%CI=-1.21,-.22). Citicoline (SMD=-1.05,95%CI=-1.86,-.23), L-lysine (SMD=-1.04,95%CI=-1.84,-.24), N-acetylcysteine (SMD=-.89,95%CI=-1.35,-.43) and sarcosine (SMD=-.61,95%CI=-1.02,-.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.

Conclusions: 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.

Keywords: Nutraceuticals; network meta-analysis; nutritional psychiatry; phytoceuticals; psychiatry; psychosis; schizophrenia; systematic review; treatment-resistance.

Publication types

Preprint