CNS Drugs

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Treatment Strategies for Clozapine-Induced Sialorrhea: A Systematic Review and Meta-analysis

  • Shih-Yu Chen
  • Gopi Ravindran
  • Qichen Zhang
  • Steve Kisely
  • Dan SiskindEmail author
Systematic Review



Clozapine is the most effective medication for treatment-refractory schizophrenia. However, it has a high burden of adverse events, including common adverse events such as sialorrhea. Sialorrhea can lead to severe physical complications such as aspiration pneumonia, as well as psychological complications including embarrassment and low self-esteem. Compromised adherence and treatment discontinuation can occur due to intolerability. There have been no meta-analyses examining strategies to mitigate clozapine-induced sialorrhea.


We systematically searched Chinese and Western research databases for randomised controlled trials examining agents for clozapine-induced sialorrhea. No limit to language or date were applied to the search. Where sufficient data for individual agents was available, pairwise meta-analyses were conducted. Results were provided as risk ratios and number needed to treat. Sensitivity analysis was conducted by study quality. Adverse events were provided as number needed to harm.


19 studies provided data for use in the meta-analysis. Improvement in clozapine-induced sialorrhea was seen in meta-analyses of propantheline (studies = 6, risk ratio [RR] 2.38, 95% confidence interval [CI] 1.52–3.73; number needed to treat [NNT] 3, 95% CI 1.9–2.7), diphenhydramine (studies = 5, RR 3.09, 95% CI 2.36–4.03; NNT 2, 95% CI 1.5–2.0), chlorpheniramine (studies = 2, RR 2.37, 95% CI 1.59–3.55; NNT 3, 95% CI 1.6–3.5), and benzamide derivatives (odds ratio [OR] 6.93, 95% CI 3.03–15.86). When meta-analyses were limited to high-quality studies, all these results remained significant. Single studies of benzhexol, cyproheptadine, doxepin and Kongyan Tang showed promise. Propantheline increased rates of constipation with a number needed to harm (NNH) of 9 (95% CI 4.2–204.1).


Clozapine-induced sialorrhea is a potentially serious adverse event. Included studies in this meta-analysis were limited by poor study quality. Diphenhydramine, chlorpheniramine and benzamide derivatives appear to have the best supporting evidence and lowest reported adverse events. Caution should be exercised when using propantheline given its increased risk of constipation.


Compliance with Ethical Standards


Dan Siskind is supported in part by an NHMRC ECF APP1111136. The authors have no other funding to disclose.

Conflict of interest

Shih-Yu Chen, Gopi Ravindran, Qichen Zhang, Steve Kisely and Dan Siskind declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Supplementary material

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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Metro South Addiction and Mental Health Service, Level 2 Mental Health, Woolloongabba Community Health CentreBrisbaneAustralia
  2. 2.School of MedicineUniversity of QueenslandBrisbaneAustralia

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