Advertisement

CNS Drugs

pp 1–14 | Cite as

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

Abstract

Background

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.

Methods

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.

Results

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).

Conclusion

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.

Notes

Compliance with Ethical Standards

Funding

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

40263_2019_612_MOESM1_ESM.docx (789 kb)
Supplementary material 1 (DOCX 788 kb)
40263_2019_612_MOESM2_ESM.docx (13 kb)
Supplementary material 2 (DOCX 12 kb)
40263_2019_612_MOESM3_ESM.docx (28 kb)
Supplementary material 3 (DOCX 28 kb)
40263_2019_612_MOESM4_ESM.docx (28 kb)
Supplementary material 4 (DOCX 28 kb)
40263_2019_612_MOESM5_ESM.docx (17 kb)
Supplementary material 5 (DOCX 17 kb)
40263_2019_612_MOESM6_ESM.docx (19 kb)
Supplementary material 6 (DOCX 19 kb)

References

  1. 1.
    Saha S, Chant D, Welham J, McGrath J. A systematic review of the prevalence of schizophrenia. PLoS Med. 2005;2(5):e141.Google Scholar
  2. 2.
    Howes OD, McCutcheon R, Agid O, De Bartolomeis A, Van Beveren NJ, Birnbaum ML, et al. Treatment-resistant schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) working group consensus guidelines on diagnosis and terminology. Am J Psychiatry. 2016;174(3):216–29.Google Scholar
  3. 3.
    Siskind D, McCartney L, Goldschlager R, Kisely S. Clozapine v. first-and second-generation antipsychotics in treatment-refractory schizophrenia: systematic review and meta-analysis. Br J Psychiatry. 2016;209(5):385–92.Google Scholar
  4. 4.
    Land R, Siskind D, Mcardle P, Kisely S, Winckel K, Hollingworth SA. The impact of clozapine on hospital use: a systematic review and meta-analysis. Acta Psychiatr Scand. 2017;135(4):296–309.Google Scholar
  5. 5.
    Myles N, Myles H, Xia S, Large M, Kisely S, Galletly C, et al. Meta-analysis examining the epidemiology of clozapine-associated neutropenia. Acta Psychiatr Scand. 2018;138(2):101–9.Google Scholar
  6. 6.
    Rohde C, Polcwiartek C, Kragholm K, Ebdrup B, Siskind D, Nielsen J. Adverse cardiac events in out-patients initiating clozapine treatment: a nationwide register-based study. Acta Psychiatrica Scandinavica. 2018;137(1):47–53.Google Scholar
  7. 7.
    Maher S, Cunningham A, O’Callaghan N, Byrne F, Mc Donald C, McInerney S, et al. Clozapine-induced hypersalivation: an estimate of prevalence, severity and impact on quality of life. Ther Adv Psychopharmacol. 2016;6(3):178–84.  https://doi.org/10.1177/2045125316641019.Google Scholar
  8. 8.
    Bird AM, Smith TL, Walton AE. Current treatment strategies for clozapine-induced sialorrhea. Ann Pharmacother. 2011;45(5):667–75.  https://doi.org/10.1345/aph.1P761.Google Scholar
  9. 9.
    Citrome L, McEvoy JP, Saklad SR. A guide to the management of clozapine-related tolerability and safety concerns. Clin Schizophr Relat Psychoses. 2016.  https://doi.org/10.3371/csrp.saci.070816.Google Scholar
  10. 10.
    Liang C-S, Ho P-S, Shen L-J, Lee W-K, Yang F-W, Chiang K-T. Comparison of the efficacy and impact on cognition of glycopyrrolate and biperiden for clozapine-induced sialorrhea in schizophrenic patients: a randomized, double-blind, crossover study. Schizophr Res. 2010;119(1–3):138–44.  https://doi.org/10.1016/j.schres.2010.02.1060.Google Scholar
  11. 11.
    Sagya R, Weizman A, Katz N. Pharmacological and behavioral management of some often-overlooked clozapine-induced side effects. Int Clin Psychopharmacol. 2014;29(6):313–7.  https://doi.org/10.1097/YIC.0000000000000044.Google Scholar
  12. 12.
    Sockalingam S, Shammi C, Remington G. Treatment of clozapine-induced hypersalivation with ipratropium bromide: a randomized, double-blind, placebo-controlled crossover study. J Clin Psychiatry. 2009;70(8):1114–9.  https://doi.org/10.4088/JCP.08m04495.Google Scholar
  13. 13.
    Ekström J, Godoy T, Loy F, Riva A. Parasympathetic vasoactive intestinal peptide (VIP): a likely contributor to clozapine-induced sialorrhoea. Oral Dis. 2014;20(3):e90–6.  https://doi.org/10.1111/odi.12139.Google Scholar
  14. 14.
    Ignjatović Ristić D, Cohen D, Obradović A, Nikić-Đuričić K, Drašković M, Hinić D. The Glasgow antipsychotic side-effects scale for clozapine in inpatients and outpatients with schizophrenia or schizoaffective disorder. Nord J Psychiatry. 2018;72(2):124–9.  https://doi.org/10.1080/08039488.2017.1400097.Google Scholar
  15. 15.
    Villa A, Wolff A, Narayana N, Dawes C, Aframian D, Lynge Pedersen A, et al. World Workshop on Oral Medicine VI: a systematic review of medication-induced salivary gland dysfunction. Oral Dis. 2016;22(5):365–82.  https://doi.org/10.1111/odi.12402.Google Scholar
  16. 16.
    Reinstein MJ, Sirotovskaya LA, Chasanov MA, Jones LE, Mohan S. Comparative efficacy and tolerability of benzatropine and terazosin in the treatment of hypersalivation secondary to clozapine. Clin Drug Investig. 1999;17(2):97–102.Google Scholar
  17. 17.
    Syed R, Au K, Cahill C, Duggan L, He Y, Udu V, et al. Pharmacological interventions for clozapine-induced hypersalivation. Cochrane Database Syst Rev. 2008;3:Cd005579.  https://doi.org/10.1002/14651858.cd005579.pub2.Google Scholar
  18. 18.
    Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev. 2015;4:1.  https://doi.org/10.1186/2046-4053-4-1.Google Scholar
  19. 19.
    Higgins J, Green S. Cochrane handbook for systematic reviews of interventions. The Cochrane Collaboration; 2011. http://handbook.cochrane.org.
  20. 20.
    Barendregt JJ, Doi SA. MetaXL user guide version 5.3. EpiGear International Pty Ltd; 2016.Google Scholar
  21. 21.
    Kreinin A, Novitski D, Weizman A. Amisulpride treatment of clozapine-induced hypersalivation in schizophrenia patients: a randomized, double-blind, placebo-controlled cross-over study. Int Clin Psychopharmacol. 2006;21(2):99–103.Google Scholar
  22. 22.
    Kreinin A, Miodownik C, Mirkin V, Gaiduk Y, Yankovsky Y, Bersudsky Y, et al. Double-blind, randomized, placebo-controlled trial of metoclopramide for hypersalivation associated with clozapine. J Clin Psychopharmacol. 2016.  https://doi.org/10.1097/jcp.0000000000000493.Google Scholar
  23. 23.
    Man W, Colen-de KJ, Schulte P, Cahn W, Haelst I, Doodeman H, et al. The effect of glycopyrrolate on nocturnal sialorrhea in patients using clozapine: a randomized, crossover, double-blind, placebo-controlled trial. J Clin Psychopharmacol. 2017.  https://doi.org/10.1097/jcp.0000000000000657.Google Scholar
  24. 24.
    Xu H, Dong A, Zhang T, Shu W. Diphenhydramine for clozapine -induced salivation at various dosage levels. New Drugs Clin Rem. 1997;16(04):14–6.Google Scholar
  25. 25.
    Yang S, Shundi X, Yin Y. A double-blinded placebo-controlled trial on the use of cyproheptadine in clozapine-induced sialorrhoea. Chin J Neuropsychiatr Disord. 1996;08(01):12–3.Google Scholar
  26. 26.
    Lin H. A double-blinded placebo-controlled trial on the use of propantheline in clozapine-induced sialorrhoea. Chin J Neuropsychiatr Dis. 1999;25(05):316–7.Google Scholar
  27. 27.
    Yang H, Huang S, Feng C, Chen J. A study on the treatments for clozapine-induced sialorrhoea. J Binzhou Med Coll. 1999;22(05):451.Google Scholar
  28. 28.
    Gong G, Yuan L, Qin D, Li H, Zhao L, Hu C, et al. A double-blinded placebo-controlled randomized trial on the use of diphenhydramine, propantheline and astemizole in clozapine-induced sialorrhoea. Chin J Psychiatry. 1998;31(03):10.Google Scholar
  29. 29.
    Tao J, Yin X, Liu J. A randomized controlled trial on the use of sulpiride in clozapine-induced sialorrhoea. Neurol Disord Ment Health. 2007;07(02):141–3.Google Scholar
  30. 30.
    Qin J, Cui C, Ge F. A comparison of treatments for clozapine-induced sialorrahoea. Chin J Clin Psychiatry. 1999;09(04):225–6.Google Scholar
  31. 31.
    Fan Z, Zheng C, Li S. A placebo-controlled trial on the use of propantheline in clozapine-induced sialorrhoea. Strait Pharm J. 1996;08(02):33–4.Google Scholar
  32. 32.
    Cheng J, Jiang S. A study on the use of benzhexol in clozapine-induced sialorrhoea. J Mod Chin Integr Med. 2005;14(16):2135–6.Google Scholar
  33. 33.
    Zhao Z, Chen H, Xie B, Sun S, Wu H, Ma Q, et al. A controlled trial on the use of Zhiyan capsule in clozapine-induced sialorrhoea. Med J Chin Civ Admin. 2000;12(02):34–5.Google Scholar
  34. 34.
    Lu X, Xue S, Yang M. The use of diphehydramine in clozapine-induced sialorrhoea. Sichuan J Ment Health. 1998;11(01):38–40.Google Scholar
  35. 35.
    Lu L, Liu G, Zhao J, Liu A, Liu S, Liu L, et al. A double-blinded placebo-controlled trial on the use of chlorpheniramine in clozapine-induced sialorrhoea. Chin J Neuropsychiatr Dis. 1994;27(04):252–3.Google Scholar
  36. 36.
    Li Z, Song Z, Cheng P, Li C, Xiang X, Shi H. A double-blinded controlled trial on the use of astemizole in clozapine-induced sialorrhoea. Chin J Clin Psychiatry. 1993;03(01):34–5.Google Scholar
  37. 37.
    Mao Z, Yang Y, Wang Y, Ma J, Cheng J. A controlled trial on the use of traditional chinese medication Kongyan Decoction in clozapine-induced sialorrhoea. In: The 12th national academic conference on integrated traditional Chinese medicine and western medicine in Psychiatry. Lanzhou, Gansu, China. 2013.Google Scholar
  38. 38.
    Qian Q, Gao Z. The use of topical Wu Dan San on acupuncture points inclozapine-induced sialorrhoea. Shanghai Arch Psychiatry. 1996;08(02):103.Google Scholar
  39. 39.
    Ekström J, Godoy T, Riva A. Clozapine: agonistic and antagonistic salivary secretory actions. J Dent Res. 2010;89(3):276–80.  https://doi.org/10.1177/0022034509356055.Google Scholar
  40. 40.
    Rabinowitz T, Frankenburg FR, Centorrino F, Kando J. The effect of clozapine on saliva flow rate: a pilot study. Biol Psychiatry. 1996;40(11):1132–4.  https://doi.org/10.1016/s0006-3223(96)89255-9.Google Scholar
  41. 41.
    Webber MA, Szwast SJ, Steadman TM, Frazer A, Malloy FW, Lightfoot JD, et al. Guanfacine treatment of clozapine-induced sialorrhea. J Clin Psychopharmacol. 2004;24(6):675–6.Google Scholar
  42. 42.
    BenAryeh H, Jungerman T, Szargel R, Klein E, Laufer D. Salivary flow-rate and composition in schizophrenic patients on clozapine, subjective reports and laboratory data. Biol Psychiatry. 1996;39(11):946–9.  https://doi.org/10.1016/0006-3223(95)00296-0.Google Scholar
  43. 43.
    Antonello C, Tessier P. Clozapine and sialorrhea: a new intervention for this bothersome and potentiallydangerous side effect. J Psychiatry Neurosci. 1999;24(31):250.Google Scholar
  44. 44.
    Sharma A, Ramaswamy S, Dahl E, Dewan V. Intraoral application of atropine sulfate ophthalmic solution for clozapine-induced sialorrhea. Ann Pharmacother. 2004;38(9):1538.Google Scholar
  45. 45.
    Comley C, Galletly C, Ash D. Use of atropine eye drops for clozapine induced hypersalivation. Aust N Z J Psychiatry. 2000;34(6):1033–4.Google Scholar
  46. 46.
    Gaftanyuk O, Trestman R. Scopolamine patch for clozapine-induced sialorrhea. Psychiatr Serv. 2004;55(3):318.Google Scholar
  47. 47.
    McKane J, Hall C, Akram G. Hyoscine patches in clozapine-induced hypersalivation. Psychiatr Bull. 2001;25(7):277.Google Scholar
  48. 48.
    Canaday BR, Stanford RH. Propantheline bromide in the management of hyperhidrosis associated with spinal cord injury. Ann Pharmacother. 1995;29(5):489–92.  https://doi.org/10.1177/106002809502900507.Google Scholar
  49. 49.
    Duggal H. Glycopyrrolate for clozapine-induced sialorrhea. Prog Neuro Psychopharmacol Biol Psychiatry. 2007;31:1546–7.Google Scholar
  50. 50.
    MIMS. MIMS online. Crows Nest, N.S.W: monthly index of medical specialities Australia; 1996.Google Scholar
  51. 51.
    Parfitt K, Martindale W. Martindale: the complete drug reference. London: Pharmaceutical Press; 1999.Google Scholar
  52. 52.
    Matsumoto S, Yamazoe Y. Involvement of multiple human cytochromes P450 in the liver microsomal metabolism of astemizole and a comparison with terfenadine. Br J Clin Pharmacol. 2001;51(2):133–42.Google Scholar
  53. 53.
    WHO. Astemizole: voluntary withdrawal: Janssen, USA. WHO Pharmaceuticals Newsletter. 1999.Google Scholar
  54. 54.
    Caldara R, Masci E, Cambielli M, Tittobello A, Piepoli V, Barbieri C. Effect of sulpiride isomers on gastric acid and gastrin secretion in healthy man. Eur J Clin Pharmacol. 1983;25(3):319–22.Google Scholar
  55. 55.
    Sockalingam S, Shammi C, Remington G. Clozapine-induced hypersalivation: a review of treatment strategies. Can J Psychiatry. 2007;52(6):377–84.  https://doi.org/10.1177/070674370705200607.Google Scholar
  56. 56.
    Siskind DJ, Lee M, Ravindran A, Zhang Q, Ma E, Motamarri B, Kisely S. Augmentation strategies for clozapine refractory schizophrenia: a systematic review and meta-analysis. Aust N Z J Psychiatry. 2018;52:751–67.Google Scholar
  57. 57.
    Cohen JF, Korevaar DA, Wang J, Spijker R, Bossuyt PM. Should we search Chinese biomedical databases when performing systematic reviews? Syst Rev. 2015;4:23.  https://doi.org/10.1186/s13643-015-0017-3.Google Scholar

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

Personalised recommendations