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  • Systematic Review
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Pharmacological interventions for antipsychotic-related sialorrhea: a systematic review and network meta-analysis of randomized trials

Molecular Psychiatry volume 28, pages 3648–3660 (2023)Cite this article

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Abstract

Antipsychotic-induced sialorrhea carries a significant burden, but evidence-based treatment guidance is incomplete, warranting network meta-analysis (NMA) of pharmacological interventions for antipsychotic-related sialorrhea. PubMed Central/PsycInfo/Cochrane Central database/Clinicaltrials.gov/WHO-ICTRP and the Chinese Electronic Journal Database (Qikan.cqvip.com) were searched for published/unpublished RCTs of antipsychotic-induced sialorrhea (any definition) in adults, up to 06/12/2023. We assessed global/local inconsistencies, publication bias, risk of bias (RoB2), and confidence in the evidence, conducting subgroup/sensitivity analyses. Co-primary efficacy outcomes were changes in saliva production (standardized mean difference/SMD) and study-defined response (risk ratios/RRs). The acceptability outcome was all-cause discontinuation (RR). Primary nodes were molecules; the mechanism of action (MoA) was secondary. Thirty-four RCTs entered a systematic review, 33 NMA (n = 1958). All interventions were for clozapine-induced sialorrhea in subjects with mental disorders. Regarding individual agents and response, metoclopramide (RR = 3.11, 95% C.I. = 1.39–6.98), cyproheptadine, (RR = 2.76, 95% C.I. = 2.00–3.82), sulpiride (RR = 2.49, 95% C.I. = 1.65–3.77), propantheline (RR = 2.39, 95% C.I. = 1.97–2.90), diphenhydramine (RR = 2.32, 95% C.I. = 1.88–2.86), benzhexol (RR = 2.32, 95% C.I. = 1.59–3.38), doxepin (RR = 2.30, 95% C.I. = 1.85–2.88), amisulpride (RR = 2.23, 95% C.I. = 1.30–3.81), chlorpheniramine (RR = 2.20, 95% C.I. = 1.67–2.89), amitriptyline (RR = 2.09, 95% C.I. = 1.34–3.26), atropine, (RR = 2.03, 95% C.I. = 1.22–3.38), and astemizole, (RR = 1.70, 95% C.I. = 1.28–2.26) outperformed placebo, but not glycopyrrolate or ipratropium. Across secondary nodes (k = 28, n = 1821), antimuscarinics (RR = 2.26, 95% C.I. = 1.91–2.68), benzamides (RR = 2.23, 95% C.I. = 1.75–3.10), TCAs (RR = 2.23, 95% C.I. = 1.83–2.72), and antihistamines (RR = 2.18, 95% C.I. = 1.83–2.59) outperformed placebo. In head-to-head comparisons, astemizole and ipratropium were outperformed by several interventions. All secondary nodes, except benzamides, outperformed the placebo on the continuous efficacy outcome. For nocturnal sialorrhea, neither benzamides nor atropine outperformed the placebo. Active interventions did not differ significantly from placebo regarding constipation or sleepiness/drowsiness. Low-confidence findings prompt caution in the interpretation of the results. Considering primary nodes’ co-primary efficacy outcomes and head-to-head comparisons, efficacy for sialorrhea is most consistent for the following agents, decreasing from metoclopramide through cyproheptadine, sulpiride, propantheline, diphenhydramine, benzhexol, doxepin, amisulpride, chlorpheniramine, to amitriptyline, and atropine (the latter not for nocturnal sialorrhea). Shared decision-making with the patient should guide treatment decisions regarding clozapine-related sialorrhea.

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Fig. 1
Fig. 2: Network and forest plot of co-primary efficacy and acceptability outcomes for primary nodes and sialorrhea reduction for secondary nodes.

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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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Acknowledgements

The authors sincerely acknowledge Dr. Giulia Chock, MD, for her assistance in the appraisal of the Chinese language evidence at review.

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Author notes

  1. These authors jointly supervised this work: Michele Fornaro, Claudio Caiazza.

Authors and Affiliations

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

    Michele Fornaro, Claudio Caiazza, Niccolò Solini, Martina Billeci, Martina Vannini, Annarita Barone & Andrea de Bartolomeis

  2. Bipolar and Depressive Disorders Unit, IDIBAPS, CIBERSAM, Hospital Clinic, Barcelona, Catalonia, Spain

    Michele De Prisco

  3. The Ottawa Hospital, Ontario, Canada

    Risa Shorr

  4. Department of Neuroscience, University of Padova, Padua, Italy

    Stefano Caiolo, Marialaura Lussignoli & Fabio Sambataro

  5. Metro South Addiction and Mental Health Service, Brisbane, QLD, Australia; School of Medicine, University of Queensland, Brisbane, QLD, Australia

    Dan Siskind

  6. Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia

    Dan Siskind

  7. Azienda Ospedale Università Padova, Padua University-Hospital, Padua, Italy

    Giorgio Pigato

  8. Staff UNESCO Chair for Health Education and Sustainable Development at Federico II University of Naples, Naples, Italy

    Andrea de Bartolomeis

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

    Christoph U. Correll

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

    Christoph U. Correll

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

    Christoph U. Correll & Marco Solmi

  12. The Ottawa Hospital, Mental Health Department, Ottawa, ON, Canada

    Marco Solmi

  13. Ottawa Hospital Research Institute (OHRI) Clinical Epidemiology Program University of Ottawa, Ottawa, ON, Canada

    Marco Solmi

  14. School of Epidemiology and Public Health, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada

    Marco Solmi

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Contributions

MF, CC, and MS conceived the study. CUC and AdB coordinated the study. NS, MDP, MB, MB, RS, SC, ML, DS, GP, AB and FS assisted in data extraction, analysis, and interpretation. MF and CC wrote the manuscript. All authors read and approved the final version of the manuscript.

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Correspondence to Michele Fornaro.

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Competing interests

CUC reported receiving personal fees from Alkermes plc, Allergan plc, Angelini Pharma, Gedeon Richter, Gerson Lehrman Group, Intra-Cellular Therapies, Inc, Janssen Pharmaceutica/Johnson&Johnson, LB Pharma International BV,H Lundbeck A/S, MedAvante-ProPhase, Medscape, Neurocrine Biosciences, Noven Pharmaceuticals, Inc, Otsuka Pharmaceutical Co, Inc, Pfizer, Inc, Recordati, Rovi, Sumitomo Dainippon Pharma, Sunovion Pharmaceuticals, Inc, Supernus Pharmaceuticals, Inc, Takeda Pharmaceutical Company Limited, Teva Pharmaceuticals, Acadia Pharmaceuticals, Inc, Axsome Therapeutics, Inc, Indivior, Merck&Co, Mylan NV, MedInCell, and Karuna Therapeutics and grants from Janssen Pharmaceutica, Takeda Pharmaceutical Company Limited, Berlin Institute of Health, the National Institute of Mental Health, Patient Centered Outcomes Research Institute, and the Thrasher Foundation outside the submitted work; receiving royalties from UpToDate; and holding stock options in LB Pharma. No other disclosures were reported. AdB has received research support from Janssen, Lundbeck, and Otsuka and lecture fees for educational meeting from Chiesi, Lundbeck, Roche, Sunovion, Viatris, Recordati, Angelini and Takeda; he has served on advisory boards for Eli Lilly, Jansen, Lundbeck, Otsuka, Roche, and Takeda, Chiesi, Recordati, Angelini, Vitria. MS has received honoraria/has been a consultant for Angelini, Lundbeck, and Otsuka. MF received honoraria from the American Society of Clinical Psychopharmacology (ASCP), Angelini, Lundbeck, Bristol Meyer Squibb, and Boehringer-Ingelheim for his speaker activities. GP has received research grants and/or has been a consultant for, and/or has been a speaker for: Angelini, Lundbeck, Janssen, Otsuka, Pfizer, Roche, Eisai. DS is funded in part by an NHMRC EL2 Fellowship GNT1194635. FS has received honoraria/has been a consultant for Janssen (past five years). The other authors report no conflict of interest.

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Fornaro, M., Caiazza, C., Solini, N. et al. Pharmacological interventions for antipsychotic-related sialorrhea: a systematic review and network meta-analysis of randomized trials. Mol Psychiatry 28, 3648–3660 (2023). https://doi.org/10.1038/s41380-023-02266-x

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  • DOI: https://doi.org/10.1038/s41380-023-02266-x

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