Skip to main content

255 - References

References

260 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 References

  1. Man WH, et al. Reporting patterns of sialorrhea comparing users of clozapine to users of other antipsychotics: a disproportionality analysis using VigiBase. J Clin Psychopharmacol 2020; 40:283–286.
  2. Subramanian S, et al. Clozapine dose for schizophrenia. Cochrane Database Syst Rev 2017; 6:CD009555.
  3. Schoretsanitis G, et  al. Elevated clozapine concentrations in clozapine-­treated patients with hypersalivation. Clin Pharmacokinet 2021; 60:329–335.
  4. Sanagustin D, et  al. Prevalence of clozapine-­induced sialorrhea and its effect on quality of life. Psychopharmacology (Berl) 2023; 240:203–211.
  5. Grover S, et al. Patient and caregivers perspective about clozapine: a systematic review. Schizophr Res 2024; 268:223–232.
  6. Hinkes R, et al. Aspiration pneumonia possibly secondary to clozapine-­induced sialorrhea. J Clin Psychopharmacol 1996; 16:462–463.
  7. Saenger RC, et al. Aspiration pneumonia due to clozapine-­induced sialorrhea. Clin Schizophr Relat Psychoses 2016; 9:170–172.
  8. Gurrera RJ, et al. Aspiration pneumonia: an underappreciated risk of clozapine treatment. J Clin Psychopharmacol 2016; 36:174–176.
  9. Kaplan J, et  al. Clozapine-­associated aspiration pneumonia: case series and review of the literature. Psychosomatics 2017; 58:199–203.
  10. Cicala G, et al. A comprehensive review of swallowing difficulties and dysphagia associated with antipsychotics in adults. Expert Rev Clin Pharmacol 2019; 12:219–234.
  11. Praharaj SK, et  al. Clozapine-­induced sialorrhea: pathophysiology and management strategies. Psychopharmacology (Berl) 2006; 185:265–273.
  12. Davydov L, et al. Clozapine-­induced hypersalivation. Ann Pharmacother 2000; 34:662–665.
  13. Rogers DP, et al. Therapeutic options in the treatment of clozapine-­induced sialorrhea. Pharmacotherapy 2000; 20:1092–1095.
  14. Rabinowitz T, et al. The effect of clozapine on saliva flow rate: a pilot study. Biol Psychiatry 1996; 40:1132–1134.
  15. Ben Aryeh H, et al. Salivary flow-­rate and composition in schizophrenic patients on clozapine: subjective reports and laboratory data. Biol Psychiatry 1996; 39:946–949.
  16. Praharaj SK, et al. Salivary flow rate in patients with schizophrenia on clozapine. Clin Neuropharmacol 2010; 33:176–178.
  17. Sockalingam S, et al. Review: insufficient evidence to guide use of drugs for clozapine induced hypersalivation. Evid Based Ment Health 2009; 12:12. Table 1.57  (Continued) Treatment Comments Metoclopramide Starting dose of 10mg/day20,70,71 Double-­blind, RCT trial found metoclopramide was associated with a significant reduction in nocturnal hypersalivation and drooling. Described as an ‘effective and tolerated’ treatment in cases in clinical practice.72 Moclobemide 150–300mg/day45 Effective in 9 of 14 patients treated in one open study. Appears to be as effective as amisulpride (see above). N–acetylcysteine73 An antioxidant that also modulates glutamatergic, neurotrophic and inflammatory pathways. Small case series reported with significant decrease in sialorrhea. Oxybutynin 5mg up to twice daily74 Single case report Pirenzepine 50–150mg/day75–77 Selective M1, M4 antagonist. Extensive clinical experience suggests efficacy in some but only randomised trial suggested no effect. Still widely used. Does not have a UK or US licence for any indication. May cause constipation. Propantheline 7.5mg at night19,20 Peripheral anticholinergic. No central effects. Meta-­analyses of relevant trials have found that propantheline outperforms placebo for the treatment of antipsychotic-­induced sialorrhoea.18–20 May worsen constipation. Quetiapine51 May reduce hypersalivation by allowing lower doses of clozapine to be used Sofpironium bromide 5% gel23 A small RCT reported a 40% reduction in saliva flow at 4 weeks. Very limited availability – Japan only. Sulpiride 150–300mg/day20,78–80 Supported by one, small positive RCT and a Cochrane review of clozapine augmentation with sulpiride (at higher sulpiride doses). May allow dose reduction of clozapine.

Schizophrenia and related psychoses CHAPTER 1 18. Fornaro M, et al. Pharmacological interventions for antipsychotic-­related sialorrhea: a systematic review and network meta-­analysis of ­randomized trials. Mol Psychiatry 2023; 28:3648–3660. 19. Syed R, et al. Pharmacological interventions for clozapine-­induced hypersalivation. Cochrane Database Syst Rev 2008; (3):CD005579. 20. Chen SY, et  al. Treatment strategies for clozapine-­induced sialorrhea: a systematic review and meta-­analysis. CNS Drugs 2019; 33:225–238. 21. Palmer SE, et  al. Life-­threatening clozapine-­induced gastrointestinal hypomotility: an analysis of 102 cases. J Clin Psychiatry 2008; 69:759–768. 22. West S, et al. Clozapine induced gastrointestinal hypomotility: a potentially life threatening adverse event: a review of the literature. Gen Hosp Psychiatry 2017; 46:32–37. 23. Amano Y, et al. Efficacy of sofpironium bromide gel on clozapine-­induced hypersalivation in patients with treatment-­resistant schizophrenia: double-­blind, controlled crossover study. BJPsych Open 2023; 9:e14. 24. Mohammad-­Gholizad F, et al. Evaluation and comparison of the effectiveness of atropine eye drops, ipratropium bromide nasal spray, and amitriptyline tablet in the management of clozapine-­associated sialorrhea in patients with refractory schizophrenia: a randomized clinical trial. J Clin Psychopharmacol 2024; 44:9–15. 25. Miodownik C, et  al. Treatment of clozapine-­associated sialorrhea: the role of benzamide derivatives. J Clin Psychopharmacol 2023; 43:171–177. 26. Kreinin A, et al. Amisulpride treatment of clozapine-­induced hypersalivation in schizophrenia patients: a randomized, double-­blind, placebo-­ controlled cross-­over study. Int Clin Psychopharmacol 2006; 21:99–103. 27. Kreinin A, et al. Amisulpride versus moclobemide in treatment of clozapine-­induced hypersalivation. World J Biol Psychiatry 2010; 12:620–626. 28. Praharaj SK, et al. Amisulpride treatment for clozapine-­induced sialorrhea. J Clin Psychopharmacol 2009; 29:189–190. 29. Aggarwal A, et al. Amisulpride for clozapine induced sialorrhea. Psychopharmacol Bull 2009; 42:69–71. 30. Croissant B, et al. Reduction of side effects by combining clozapine with amisulpride: case report and short review of clozapine-­induced hypersalivation—a case report. Pharmacopsychiatry 2005; 38:38–39. 31. Praharaj SK, et al. Amisulpride improved debilitating clozapine-­induced sialorrhea. Am J Ther 2011; 18:e84–e85. 32. Kulkarni RR. Low-­dose amisulpride for debilitating clozapine-­induced sialorrhea: case series and review of literature. Indian J Psychol Med 2015; 37:446–448. 33. Copp P, et al. Amitriptyline in clozapine-­induced sialorrhoea. Br J Psychiatry 1991; 159:166. 34. Praharaj SK, et al. Amitriptyline for clozapine-­induced nocturnal enuresis and sialorrhoea. Br J Clin Pharmacol 2007; 63:128–129. 35. Sinha S, et al. Very low dose amitriptyline for clozapine-­associated sialorrhea. Curr Drug Saf 2016; 11:262–263. 36. Cereda G, et al. Amitriptyline for clozapine-­induced hypersalivation: a case series. Schizophr Res 2022; 243:110–111. 37. Antonello C, et al. Clozapine and sialorrhea: a new intervention for this bothersome and potentially dangerous side effect. J Psychiatry Neurosci 1999; 24:250. 38. Mustafa FA, et al. Sublingual atropine for the treatment of severe and hyoscine-­resistant clozapine-­induced sialorrhea. Afr J Psychiatry 2013; 16:242. 39. Matos Santana TE, et al. Sublingual atropine in the treatment of clozapine-­induced sialorrhea. Schizophr Res 2017; 182:144–145. 40. Mubaslat O, et  al. The effect of sublingual atropine sulfate on clozapine-­induced hypersalivation: a multicentre, randomised placebo-­ controlled trial. Psychopharmacology (Berl) 2020; 237:2905–­2915. 41. Van der Poorten T, et al. The sublingual use of atropine in the treatment of clozapine-­induced sialorrhea: a systematic review. Clin Case Rep 2019; 7:2108–2113. 42. Mutlu E, et al. A systematic chart review of pharmacological interventions in patients with clozapine-­induced hypersalivation. Schizophr Res 2024; 268:138–144. 43. Leung JG, et al. Potential problems surrounding the use of sublingually administered ophthalmic atropine for sialorrhea. Schizophr Res 2017; 185:202–203. 44. Spivak B, et al. Trihexyphenidyl treatment of clozapine-­induced hypersalivation. Int Clin Psychopharmacol 1997; 12:213–215. 45. Praharaj SK, et  al. Complete resolution of clozapine-­induced sialorrhea with low dose trihexyphenidyl. Psychopharmacol Bull 2010; 43:73–75. 46. Reinstein M, et al. Comparative efficacy and tolerability of benzatropine and terazosin in the treatment of hypersalivation secondary to clozapine. Clin Drug Investig 1999; 17:97–102. 47. Kahl KG, et  al. Botulinum toxin as an effective treatment of clozapine-­induced hypersalivation. Psychopharmacology (Berl) 2004; 173:229–230. 48. Steinlechner S, et al. Botulinum toxin B as an effective and safe treatment for neuroleptic-­induced sialorrhea. Psychopharmacology (Berl) 2010; 207:593–597. 49. Kahl KG, et al. [Pharmacological strategies for clozapine-­induced hypersalivation: treatment with botulinum toxin B in one patient and review of the literature]. Nervenarzt 2005; 76:205–208. 50. Verma R, et al. Botulinum toxin: a novel therapy for clozapine-­induced sialorrhoea. Psychopharmacology (Berl) 2018; 235:369–371. 51. Stern RG, et al. Clozapine-­induced sialorrhea alleviated by bupropion: a case report. Prog Neuropsychopharmacol Biol Psychiatry 2009; 33:1578–1580. 52. Grabowski J. Clonidine treatment of clozapine-­induced hypersalivation. J Clin Psychopharmacol 1992; 12:69–70. 53. Praharaj SK, et al. Is clonidine useful for treatment of clozapine-­induced sialorrhea? J Psychopharmacol 2005; 19:426–428. 54. Duggal HS. Glycopyrrolate for clozapine-­induced sialorrhea. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31:1546–1547. 55. Robb AS, et al. Glycopyrrolate for treatment of clozapine-­induced sialorrhea in three adolescents. J Child Adolesc Psychopharmacol 2008; 18:99–107.

262 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 56. Liang CS, et al. 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; 119:138–144. 57. Man WH, 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; 37:155–161. 58. Praharaj SK, et al. Low-­dose glycopyrrolate for clozapine-­associated sialorrhea. J Clin Psychopharmacol 2014; 34:392. 59. Qurashi I, et al. Glycopyrrolate in comparison to hyoscine hydrobromide and placebo in the treatment of hypersalivation induced by cloza­ pine (GOTHIC1): a feasibility study. Pilot Feasibility Stud 2019; 5:79. 60. Webber MA, et al. Guanfacine treatment of clozapine-­induced sialorrhea. J Clin Psychopharmacol 2004; 24:675–676. 61. McKane JP, et al. Hyoscine patches in clozapine-­induced hypersalivation. Psychiatr Bull 2001; 25:277. 62. Gaftanyuk O, et al. Scolpolamine patch for clozapine-­induced sialorrhea. Psychiatr Serv 2004; 55:318. 63. Segev A, et al. Hyoscine for clozapine-­induced hypersalivation: a double-­blind, randomized, placebo-­controlled cross-­over trial. Int Clin Psychopharmacol 2019; 34:101–107. 64. Takeuchi I, et al. Effect of scopolamine butylbromide on clozapine-­induced hypersalivation in schizophrenic patients: a case series. Clin Psychopharmacol Neurosci 2015; 13:109–112. 65. British National Formulary JFC. Hyoscine hydrobromide – unlicensed use. 2023 (last accessed December 2023); https://bnf.nice.org.uk/ drugs/hyoscine-­hydrobromide/#unlicensed-­use. 66. Calderon J, et al. Potential use of ipatropium bromide for the treatment of clozapine-­induced hypersalivation: a preliminary report. Int Clin Psychopharmacol 2000; 15:49–52. 67. Freudenreich O, et al. Clozapine-­induced sialorrhea treated with sublingual ipratropium spray: a case series. J Clin Psychopharmacol 2004; 24:98–100. 68. Sockalingam S, et  al. Treatment of clozapine-­induced hypersalivation with ipratropium bromide: a randomized, double-­blind, placebo-­ controlled crossover study. J Clin Psychiatry 2009; 70:1114–1119. 69. Corrigan FM, et al. Clozapine-­induced hypersalivation and the alpha 2 adrenoceptor. Br J Psychiatry 1995; 167:412. 70. Kreinin A, et al. Double-­blind, randomized, placebo-­controlled trial of metoclopramide for hypersalivation associated with clozapine. J Clin Psychopharmacol 2016; 36:200–205. 71. Hallahan B. Metoclopramide may be effective for clozapine-­induced hypersalivation. Evid Based Ment Health 2016; 19:124. 72. Livermore C, et al. A retrospective case notes review of the effectiveness and tolerability of metoclopramide in the treatment of clozapine-­ induced hypersalivation (CIH). BMC Psychiatry 2022; 22:277. 73. Uzun Ö, et al. Effect of N-­acetylcysteine on clozapine-­induced sialorrhea in schizophrenic patients: a case series. Int Clin Psychopharmacol 2020; 35:229–231. 74. Leung JG, et al. Immediate-­release oxybutynin for the treatment of clozapine-­induced sialorrhea. Ann Pharmacother 2011; 45:e45. 75. Fritze J, et al. Pirenzepine for clozapine-­induced hypersalivation. Lancet 1995; 346:1034. 76. Bai YM, et al. Therapeutic effect of pirenzepine for clozapine-­induced hypersalivation: a randomized, double-­blind, placebo-­controlled, cross-­ over study. J Clin Psychopharmacol 2001; 21:608–611. 77. Schneider B, et al. Reduction of clozapine-­induced hypersalivation by pirenzepine is safe. Pharmacopsychiatry 2004; 37:43–45. 78. Kreinin A, et al. Sulpiride addition for the treatment of clozapine-­induced hypersalivation: preliminary study. Isr J Psychiatry Relat Sci 2005; 42:61–63. 79. Wang J, et al. Sulpiride augmentation for schizophrenia. Cochrane Database Syst Rev 2010; (1):CD008125. 80. Prljača E, et al. Clozapine-­induced hypersalivation treated with sulpiride: is it a solution? Psychiatr Danub 2021; 33:1230–1232.