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Psychopharmacology

, Volume 185, Issue 3, pp 265–273 | Cite as

Clozapine-induced sialorrhea: pathophysiology and management strategies

  • Samir Kumar PraharajEmail author
  • Manu Arora
  • Sachin Gandotra
Review

Abstract

Rationale

Clozapine is an atypical antipsychotic agent with proven efficacy in refractory schizophrenia, but its widespread use is limited by adverse effects such as agranulocytosis, seizures, sedation, weight gain, and sialorrhea. Clozapine-induced sialorrhea (CIS) is bothersome and has socially stigmatizing adverse effects, which result in poor treatment compliance. The pathophysiology of this condition is poorly understood and the treatment options available are based mostly on case reports and open-label studies.

Objective

To review the available studies on CIS.

Method

All relevant studies available through PUBMED search supplemented with manual search were undertaken.

Result

The clinical features, complications, assessment, pathophysiology, and management of CIS are discussed.

Conclusion

Although the studies evaluating the therapeutic options has limitations and no drug has been found to be superior, judicious use of pharmacological agents along with behavioral methods will reduce this troublesome side effect and enhance compliance.

Keywords

Clozapine Sialorrhea Hypersalivation 

References

  1. Ahlner BH, Lind MG (1983) A swab technique for sialometry. Normal range. Acta Otolaryngol 95(1–2):173–182PubMedGoogle Scholar
  2. Antonello C, Tessier P (1999) Clozapine and sialorrhea: a new intervention for this bothersome and potentially dangerous side effect. J Psychiatry Neurosci 24:250PubMedGoogle Scholar
  3. Bai YM, Lin CC, Chen JY, Liu WC (2001) Therapeutic effect of pirenzepine for clozapine-induced hypersalivation: a randomized, double-blind, placebo-controlled, cross-over study. J Clin Psychopharmacol 21(6):608–611CrossRefPubMedGoogle Scholar
  4. Baldessarini RJ, Huston-Lyons D, Campbell A, Marsh E, Cohen BM (1992) Do central antiadrenergic actions contribute to the atypical properties of clozapine? Br J Psychiatry 160:12–16PubMedGoogle Scholar
  5. Ben-Areyh H, Jungeman T, Szargel R, Klein E, Laufer D (1996) Salivary flow-rate and composition in schizophrenic patients on clozapine: subjective reports and laboratory data. Biol Psychiatry 39:946–949CrossRefPubMedGoogle Scholar
  6. Berlan M, Montrstruc J, Lafontan M (1992) Pharmacological prospects for alpha 2 adrenoceptor antagonist therapy. Trends Pharmacol Sci 13:277–282CrossRefPubMedGoogle Scholar
  7. Bothwell JE, Clarke K, Dooley JM et al (2002) Botulinum toxin A as a treatment for excessive drooling in children. Pediatr Neurol 27:18–22CrossRefPubMedGoogle Scholar
  8. Bourgeois JA, Drexler KG, Hall MJ (1991) Hypersalivation and clozapine. Hosp Community Psychiatry 42(11):1174PubMedGoogle Scholar
  9. Boyce HW, Bakheet MR (2005) Sialorrhea: a review of a vexing, often unrecognized sign of oropharyngeal and esophageal disease. J Clin Gastroenterol 39(2):89–97PubMedGoogle Scholar
  10. Brodkin ES, Pelton GH, Price LH (1996) Treatment of clozapine-induced parotid gland swelling. Am J Psychiatry 153:445Google Scholar
  11. Calderon J, Robin E, Sobota WL (2000) Potential use of ipratropium bromide for the treatment of clozapine induced hypersalivation: a preliminary report. Int Clin Psychopharmacol 15:49–52PubMedGoogle Scholar
  12. Carlson GW (2000) The salivary glands. Embryology, anatomy, and surgical applications. Surg Clin North Am 80:261–273CrossRefPubMedGoogle Scholar
  13. Chatelut E, Rispail Y, Berlan M et al (1989) Yohimbine increases human salivary secretion. Br J Clin Pharmacol 28:366–368PubMedGoogle Scholar
  14. Comley C, Galletly C, Ash D (2000) Use of atropine eye drops for clozapine induced hypersalivation. Aust N Z J Psychiatry 34(6):1033–1034CrossRefPubMedGoogle Scholar
  15. Copp PJ, Lament R, Tennent TG (1991) Amitriptyline in clozapine-induced sialorrhea. Br J Psychiatry 159:166Google Scholar
  16. Corrigan FM, MacDonald S (1995) Clozapine-induced hypersalivation and the alpha 2 adrenoceptor. Br J Psychiatry 167:412Google Scholar
  17. Cree A, Mir S, Fahy T (2001) A review of the treatment options for clozapine-induced hypersalivation. Psychiatr Bull 25:114–116CrossRefGoogle Scholar
  18. Croissant B, Hermann D, Olbrich R (2005) Reduction of side effects by combining clozapine with amisulpride: case report and short review of clozapine-induced hypersalivation. Pharmacopsychiatry 38:38–39CrossRefPubMedGoogle Scholar
  19. Davydov L, Botts SR (2000) Clozapine-induced hypersalivation. Ann Pharmacother 34(5):662–665CrossRefPubMedGoogle Scholar
  20. Disse B, Reichl R, Speck G et al (1993) Ba 679 BR, a novel long-acting anticholinergic bronchodilator. Life Sci 52:537–544CrossRefPubMedGoogle Scholar
  21. Frankenburg AE (1991) Clozapine update. Tufts University School of Medicine, Ninth Annual Psychopharmacology Update, BostonGoogle Scholar
  22. Freudenreich O, Beebe M, Goff DC (2004) Clozapine-induced sialorrhea treated with sublingual ipratropium spray: a case series. J Clin Psychopharmacol 24(1):98–100CrossRefPubMedGoogle Scholar
  23. Fritze J, Elliger T (1995) Pirenzepine for clozapine-induced hypersalivation. Lancet 346:1034CrossRefGoogle Scholar
  24. Gaftanyuk O, Trestman RL (2004) Scolpolamine patch for clozapine-induced sialorrhea. Psychiatr Serv 55(3):318CrossRefGoogle Scholar
  25. Grabowski J (1992) Clonidine treatment of clozapine-induced hypersalivation. J Clin Psychopharmacol 12(1):69–70PubMedGoogle Scholar
  26. Gross NJ (1988) Ipratropium bromide. N Engl J Med 319:486–494PubMedGoogle Scholar
  27. Gross NJ (2004) Tiotropium bromide. Chest 126:1946–1953CrossRefPubMedGoogle Scholar
  28. Harris MM, Dignam PF (1980) A nonsurgical method of reducing drooling in cerebral-palsied children. Dev Med Child Neurol 22(3):293–299PubMedGoogle Scholar
  29. Hinkes R, Quesada TV, Currier MB, Gonzalez-Blanco M (1996) Aspiration pneumonia secondary to clozapine-induced sialorrhea. Br J Psychiatry 169(3):390–391Google Scholar
  30. Hyson HC, Johnson AM, Jog MS (2002) Sublingual atropine for sialorrhea secondary to parkinsonism: a pilot study. Mov Disord 17(6):1318–1320CrossRefPubMedGoogle Scholar
  31. Ichikawa J, Dai J, O’Laughlin IA et al (2002) Atypical, but not typical, antipsychotic drugs increase cortical acetylcholine release without an effect in the nucleus accumbens or striatum. Neuropsychopharmacology 26:325–339CrossRefPubMedGoogle Scholar
  32. Jongerius PH, van Limbeek J, Rotteveel JJ (2004) Assessment of salivary flow rate: biologic variation and measure error. Laryngoscope 114:1801–1804CrossRefPubMedGoogle Scholar
  33. Kahl KG, Hagenah J, Zapf S, Trillenberg P, Klein C, Lencer R (2004) Botulinum toxin as an effective treatment of clozapine-induced hypersalivation. Psychopharmacology (Berl) 173(1–2):229–230CrossRefGoogle Scholar
  34. Kane J, Honigfeld G, Singer J, Meltzer H (1988) Clozapine for the treatment-resistant schizophrenic: a double-blind comparison versus chlorpromazine. Arch Gen Psychiatry 45:789–796PubMedGoogle Scholar
  35. Lieberman JA, Safferman AZ (1992) Clinical profile of clozapine: adverse reactions and agranulocytosis. Psychiatr Q 63(1):51–70CrossRefPubMedGoogle Scholar
  36. Lipp A, Trottenberg T, Schink T, Kupsch A, Arnold G (2003) A randomized trial of botulinum toxin A for treatment of drooling. Neurology 61(9):1279–1281PubMedGoogle Scholar
  37. Mancini F, Zangaglia R, Cristina S, Sommaruga MG, Martignoni E, Nappi G et al (2003) Double-blind, placebo-controlled study to evaluate the efficacy and safety of botulinum toxin type A in the treatment of drooling in parkinsonism. Mov Disord 18(6):685–688CrossRefPubMedGoogle Scholar
  38. Mandel ID, Zengo A, Katz R, Wotman S (1975) Effect of adrenergic agents on salivary composition. J Dent Res 54:B27–B33PubMedGoogle Scholar
  39. Marinkovic D, Timotijevic I, Babinski T et al (1994) The side effects of clozapine: a four year follow-up study. Prog Neuropsychopharmacol Biol Psychiatry 18:537–544CrossRefPubMedGoogle Scholar
  40. McCarthy R, Terkelsen K (1994) Oesophageal dysfunction in two patients after clozapine treatment. J Clin Psychopharmacol 14:281–283PubMedGoogle Scholar
  41. McKane JP, Hall C, Akram G (2001) Hyoscine patches in clozapine induced hypersalivation. Psychiatr Bull 25:277CrossRefGoogle Scholar
  42. Michal P, Lysikova M, El-Fakahany EE, Tucek S (1999) Clozapine interaction with the M2 and M4 subtypes of muscarinic receptors. Eur J Pharmacol 376(1–2):119–125CrossRefPubMedGoogle Scholar
  43. Mier RJ, Bachrach SJ, Lakin RC, Barker T, Childs J, Moran M (2000) Treatment of sialorrhea with glycopyrrolate: a double-blind, dose-ranging study. Arch Pediatr Adolesc Med 154:1214–1218PubMedGoogle Scholar
  44. Navazesh M, Christensen CM (1982) A comparison of whole mouth resting and stimulated salivary measurement procedures. J Dent Res 61:1158–1162PubMedGoogle Scholar
  45. Nemeroff CB, Putnam JS (2005) α2-Adrenergic receptor agonists: clonidine and guanfacine. In: Sadock BJ, Sadock VA (eds) Kaplan & Sadock’s comprehensive textbook of psychiatry, vol. 2. Lippincot Williams & Wilkins, Philadelphia, pp 2718–2722Google Scholar
  46. Newall AR, Orser R, Hunt M (1996) The control of oral secretions in bulbar ALS/MND. J Neurol Sci 139(suppl):43–44CrossRefPubMedGoogle Scholar
  47. Ogura C, Kishimoto A, Mizukawa R (1987) Comparative study of the effects of 9 antidepressants on several physiological parameters in healthy volunteers. Neuropsychobiology 17:139–144PubMedGoogle Scholar
  48. Pearlman C (1994) Clozapine, nocturnal sialorrhea, and choking. J Clin Psychopharmacol 14(4):283PubMedGoogle Scholar
  49. Pitcher JL (1971) Safety and effectiveness of the modified Sengstaken–Blakemore tube: a prospective study. Gastroenterology 61:291–298PubMedGoogle Scholar
  50. Praharaj SK, Verma P, Roy D, Singh A (2005) Is clonidine useful for treatment of clozapine-induced sialorrhea? J Psychopharmacol 19(4):426–428CrossRefPubMedGoogle Scholar
  51. Rabinowitz T, Frankenburg FR, Centorrino F, Kando J (1996) The effect of clozapine on saliva flow rate: a pilot study. Biol Psychiatry 40:1132–1134CrossRefPubMedGoogle Scholar
  52. Rapp D (1980) Drool control: long-term follow-up. Dev Med Child Neurol 22:448–453PubMedGoogle Scholar
  53. Reddihough D, Johnson H, Ferguson E (1992) The role of a saliva control clinic in the management of drooling. J Paediatr Child Health 28:395–397PubMedGoogle Scholar
  54. Reinstein MJ, Sirotovskaya LA, Chasanov MA, Jones LE (1999) Comparative efficacy and tolerability of benztropine and terazosin in the treatment of hypersalivation secondary to clozapine. Clin Drug Investig 17(2):97–102CrossRefGoogle Scholar
  55. Richardson C, Kelly DL, Conley RR (2001) Biperiden for excessive sweating from clozapine. Am J Psychiatry 158:1329–1330CrossRefGoogle Scholar
  56. Richelson E, Nelson A (1984) Antagonism by neuroleptics of neurotransmitter of normal brain in vitro. Eur J Pharmacol 103:197–204CrossRefPubMedGoogle Scholar
  57. Robinson D, Fenn H, Yesavage J (1995) Possible association of parotitis with clozapine. Am J Psychiatry 152(2):297–298PubMedGoogle Scholar
  58. Rogers D, Shramko J (2000) Therapeutic options in the treatment of clozapine-induced sialorrhoea. Pharmacotherapy 20(9):1092–1095CrossRefPubMedGoogle Scholar
  59. Rotteveel LJC, Jongerius PH, van Limbeek J, van den Hoogen FJA (2004) Salivation in healthy school children. Int J Pediatr Otorhinolaryngol 68(6):767–774CrossRefPubMedGoogle Scholar
  60. Safferman A, Liberman J, Kane M et al (1991) Update on the clinical efficacy and side effects of clozapine. Schizophr Bull 17:247–261PubMedGoogle Scholar
  61. Sanchez C, Lembol HL (1994) The involvement of muscarinic receptor subtypes in the mediation of hypothermia, tremor, and salivation in male mice. Pharmacol Toxicol 74(1):35–39PubMedGoogle Scholar
  62. Schneider B, Weigmann H, Hiemke C, Weber B, Fritze J (2004) Reduction of clozapine-induced hypersalivation by pirenzepine is safe. Pharmacopsychiatry 37(2):43–45CrossRefPubMedGoogle Scholar
  63. Senner JE, Logemann J, Zecker S, Gaebler-Spira D (2004) Drooling, saliva production, and swallowing in cerebral palsy. Dev Med Child Neurol 46(12):801–806CrossRefPubMedGoogle Scholar
  64. Sochaniwskyj AE (1982) Drool quantification: noninvasive technique. Arch Phys Med Rehabil 63:605–607PubMedGoogle Scholar
  65. Spivak B, Adlersberg S, Rosen L, Gonen N, Mester R, Weizman A (1996) Trihexyphenidyl treatment of clozapine-induced hypersalivation. J Clin Psychopharmacol 16:462–463CrossRefPubMedGoogle Scholar
  66. Spivak B, Adlersberg S, Rosen L, Gonen N, Mester R, Weizman A (1997) Trihexyphenidyl treatment of clozapine-induced hypersalivation. Int Clin Psychopharmacol 12(4):213–215PubMedGoogle Scholar
  67. Suskind DL, Tilton A (2002) Clinical study of Botulinum-A toxin in the treatment of sialorrhea with children with cerebral palsy. Laryngoscope 112:73–81CrossRefPubMedGoogle Scholar
  68. Szabadi E (1996) Clozapine-induced hypersalivation and the alpha-2 adrenoceptor. Br J Psychiatry 169(3):380–381Google Scholar
  69. Szabo B (2002) Imidazoline antihypertensive drugs: critical review on their mechanism of action. Pharmacol Ther 93:1–35CrossRefPubMedGoogle Scholar
  70. Taylor D, Paton C, Kerwin R (2003) The South London and Maudsley NHS Trust 2003 prescribing guidelines. Martin Dunitz, LondonGoogle Scholar
  71. Terry R, Frances RF, Franca C, Judith K (1996) The effect of clozapine on saliva flow rate: a pilot study. Biol Psychiatry 40:1132–1134CrossRefPubMedGoogle Scholar
  72. Tessier P, Antonello C (2001) Clozapine and sialorrhea: update. J Psychiatry Neurosci 26(3):253Google Scholar
  73. Thomas-Stonell N, Greenberg J (1988) Three treatment approaches and clinical factors in the reduction of drooling. Dysphagia 3:73–78PubMedGoogle Scholar
  74. Thorburn JR, James MF, Feldman C, Moyes DG, Du Toit PS (1986) Comparison of the effects of atropine and glycopyrrolate on pulmonary mechanics in patients undergoing fibreoptic bronchoscopy. Anesth Analg 65:1285–1289PubMedGoogle Scholar
  75. Tscheng DZ (2002) Sialorrhea—therapeutic drug options. Ann Pharmacother 36(11):1785–1790CrossRefPubMedGoogle Scholar
  76. Van Kammen DP, Marder SR (2005) Serotonin–dopamine antagonists (atypical or second generation antipsychotics). In: Sadock BJ, Sadock VA (eds) Kaplan & Sadock’s comprehensive textbook of psychiatry, vol. 2. Lippincot Williams & Wilkins, Philadelphia, pp 2914–2938Google Scholar
  77. Vasile JS, Steingard S (1995) Clozapine and the development of salivary gland swelling: a case study. J Clin Psychiatry 56(11):511–513PubMedGoogle Scholar
  78. Wagstaff AJ, Bryson HM (1995) Clozapine: a review of its pharmacological properties and a therapeutic use in patients with schizophrenia who are unresponsive to or intolerant of classical antipsychotic agents. CNS Drugs 1:370–400Google Scholar
  79. Wagstaff A, Perry C (2003) Clozapine: in prevention of suicide in patients with schizophrenia or schizo-affective disorder. CNS Drugs 17(4):273–280 (discussion 281–283)CrossRefPubMedGoogle Scholar
  80. Webber MA, Szwast SJ, Steadman TM, Frazer A, Malloy FW, Lightfoot JD et al (2004) Guanfacine treatment of clozapine-induced sialorrhea. J Clin Psychopharmacol 24(6):675–676CrossRefPubMedGoogle Scholar
  81. Young CR, Bowers MB, Mazure CM (1998) Management of the adverse effects of clozapine. Schizophr Bull 24:381–390PubMedGoogle Scholar
  82. Zeppetella G (1999) Nebulized scopolamine in the management of oral dribbling: three case reports. J Pain Symptom Manage 17(4):293–295CrossRefPubMedGoogle Scholar
  83. Zorn SH, Jones SB, Ward KM, Liston DR (1994) Clozapine is a potent and selective muscarinic M4 receptor agonist. Eur J Pharmacol 269:R1–R2CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Samir Kumar Praharaj
    • 1
    Email author
  • Manu Arora
    • 1
  • Sachin Gandotra
    • 1
  1. 1.Central Institute of PsychiatryRanchiIndia

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