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Reducing clozapine-induced hypersalivation

Antimuscarinic medications and chewing gum can help prevent excess saliva from disrupting a patient’s life

Vol. 10, No. 10 / October 2011

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Hypersalivation is a well-documented side effect of clozapine that may affect nearly 30% of patients who take this medication.1 Because clozapine has anticholinergic properties that are expected to reduce secretions, hypersalivation is considered a paradoxical effect. This paradox can be explained by examining clozapine’s actions at the molecular level.

Clozapine has antagonistic activity at many types of receptors, including D1 to D5 dopaminergic, α1 and α2 adrenergic, serotonergic, histaminergic, and M1, M2, M3, and M5 cholinergic.2 By contrast, clozapine’s activity at M4 cholinergic receptors is agonistic. The combination of clozapine’s antagonist activity at α2 adrenergic receptors and agonist activity at muscarinic M4 receptors results in hypersalivation.3 Clozapine also increases pooling of saliva in the mouth by diminishing esophageal motility, which gives the appearance of hypersalivation as a result of reduced saliva clearance through normal swallowing.4

Practical lifestyle changes

Excessive saliva secretion and pooling can be reduced by practical behavioral and/or pharmacologic interventions. Patients who chew gum during the day will increase their swallowing unconsciously5; recommend sugarless gum to help avoid tooth decay and gum disease. If hypersalivation is particularly bothersome at night, patients may find it useful to cover their pillows with an absorbent towel.

Pharmacologic treatments

Pharmacologic interventions rely on counteracting clozapine’s secretion-inducing effects by opposing M4 agonism, α2 antagonism, or both. Antimuscarinic medications such as benztropine, trihexyphenidyl, amitriptyline, or pirenzepine often are used to reduce hypersalivation,6 although 1 systematic review concluded further evidence is needed to support the effectiveness of this approach.7 The α2 antagonism can be opposed by using the α2 agonist clonidine, which can be administered as a weekly transdermal patch of 0.1 to 0.2 mg.8 In 1 retrospective study, the cholinergic and adrenergic mechanisms of hypersalivation were addressed by combining benztropine (2 mg/d in a divided dose) with the α1 antagonist terazosin (2 mg/d). This combination reduced hypersalivation significantly in all patients after 12 weeks, exceeding the efficacy of either benztropine or terazosin administered alone.9

Hypersalivation is an inconvenient, potentially embarrassing aspect of clozapine treatment that can cause avoidable distress. One or more of these suggestions may help control an adverse effect that could diminish patient satisfaction and undermine treatment compliance.


The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.


1. Safferman A, Lieberman JA, Kane JM, et al. Update on the clinical efficacy and side effects of clozapine. Schizophr Bull. 1991;17(2):247-261.

2. Zorn SH, Jones SB, Ward KM, et al. Clozapine is a potent and selective muscarinic M4 receptor agonist. Eur J Pharmacol. 1994;269(3):R1-R2.

3. Berlan M, Montastruc JL, Lafontan M. Pharmacological prospects for alpha 2-adrenoceptor antagonist therapy. Trends Pharmacol Sci. 1992;13(7):277-282.

4. Sadock BJ, Sadock VA. Kaplan and Sadock’s comprehensive textbook of psychiatry. 7th ed. Philadelphia PA: Lippincott Williams & Wilkins; 2000.

5. Bourgeois JA, Drexler KG, Hall MJ. Hypersalivation and clozapine. Hosp Community Psychiatry. 1991;42(11):1174.-

6. Cree A, Mir S, Fahy T. A review of the treatment options for clozapine-induced hypersalivation. The Psychiatrist. 2001;25:114-116.

7. Syed R, Au K, Cahill C, et al. Pharmacological interventions for clozapine-induced hypersalivation. Cochrane Database Syst Rev. 2008;(3):CD005579.-

8. Grabowski J. Clonidine treatment of clozapine-induced hypersalivation. J Clin Psychopharmacol. 1992;12(1):69-70.

9. Reinstein MJ, Sirotovskaya LA, Chasanov MA, et al. Comparative efficacy and tolerability of benztropine and terazosin in the treatment of hypersalivation secondary to clozapine. Clin Drug Investig. 1999;17(2):97-102.

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