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A review of the treatment options for clozapine-induced hypersalivation

Maudsley Hospital, Denmark Hill, London SE5 8AF

	Abstract

Top Abstract Introduction Proposed mechanisms of action... Therapeutic options for the... Antimuscarinic agents Adrenoceptor agonists Adrenoceptor antagonists Other strategies References

 
AIMS AND METHOD

To develop and introduce an evidence-based drug treatment protocol for clozapine-induced hypersalivation, a review of published literature relating to clozapine-induced hypersalivation and its treatment was undertaken in March 2000. The databases searched were Medline, EMBASE and PsychLit, from 1966 to the present.

RESULTS

This paper reviews the evidence of the benefit of using antimuscarinic agents, adrenergic antagonists and adrenergic agonists. There is a lack of good-quality controlled-trials, with most papers reporting a series of uncontrolled cases dependent on subjective measures of improvement reported by the patients. However, the published literature suggests a benefit for all of the drug categories reviewed. The most effective treatment may be a combination of terazosin and benzhexol.

CLINICAL IMPLICATIONS

Clozapine-induced hypersalivation is not only an embarrassing problem, but can be difficult to treat. An evidence-based prescribing protocol will encourge the use of those drugs found to be the most effective in treating this problem. It will also offer alternatives if a certain treatment is ineffective or intolerable.

	Introduction

Top Abstract Introduction Proposed mechanisms of action... Therapeutic options for the... Antimuscarinic agents Adrenoceptor agonists Adrenoceptor antagonists Other strategies References

 
Hypersalivation is a common side-effect experienced early in clozapine treatment. It is a socially stigmatising condition that may cause poor compliance among those with schizophrenia who are unresponsive to other neuroleptic medications. However, clinical evidence evaluating the various proposed treatment strategies is sparse, with an absence of any randomised controlled trials. Prescribing guidelines for treatment of this troublesome side-effect are suggested.

Clozapine is an atypical antipsychotic with superior clinical efficacy and minimal motor adverse affects. The primary indication for clozapine is in the treatment of schizophrenia in those patients who are unresponsive to other neuroleptics. Hypersalivation is a common and distressing side-effect of clozapine treatment. It affects approximately 31% of patients, usually developing early in the course of treatment, and is more prominent at night (Safferman et al, 1991). Clozapine-induced hypersalivation can be most troublesome during sleep and may be voluminous, causing disturbed sleep and respiratory problems secondary to aspiration of saliva. Clozapine-induced hypersalivation can also cause painful swelling of the salivary glands and is socially stigmatising. It may therefore lead to poor compliance early on in treatment, despite dramatic improvement in patients' psychiatric condition.

	Proposed mechanisms of action of clozapine-induced hypersalivation

Top Abstract Introduction Proposed mechanisms of action... Therapeutic options for the... Antimuscarinic agents Adrenoceptor agonists Adrenoceptor antagonists Other strategies References

 
Clozapine has a complex pharmacology. It has antagonistic activity at the D₁, D₂, D₃ and D₄ dopamine receptors, ₁ and ₂ adrenergic, 5-HT₂ serotonin, H₁ histamine and M₁, M₂, M₃ and M₅ receptors, with agonist activity at the M₄ muscarinic receptor (Zorn et al, 1994). Hypersalivation is a paradoxical side-effect because clozapine has marked anticholinergic properties. Parasympathetic stimulation causes high salivary flow rates and sympathetic stimulation leads to high protein levels (Baum, 1993). The agonist effect of clozapine on the muscarinic M₄ receptor has been put forward to explain in part the paradoxical hypersalivation. Another proposed mechanism is clozapine's antagonist activity at the ₂ adrenoceptor. While muscarinic blockade leads to diminished salivary secretion, ₂ antagonists can increase salivation (Berlan et al, 1992).

Attempts have been made to measure the flow of saliva in patients with clozapine induced hypersalivation and compare it to the rate in a set of controls (Ben-Aryeh et al, 1996; Rabinowitz et al, 1996). These studies found no significant difference in either the composition of saliva or saliva flow rate between both groups. Possible explanations for the subjective reporting of hypersalivation by patients may lie with either interference with normal deglutition through oesophageal dysfunction (McCarthy & Terkelsen, 1994), or a disturbance in the normal circadian pattern of salivary flow, which is usually high during the day and low at night. However, there is a methodological weakness to both these studies because they measured salivary flow during the day and not when it is most problematical, that is, at night.

It is likely that the true explanation for hypersalivation lies in a combination of the above mechanisms. This is supported by the limited clinical and experimental evidence available on pharmacological treatment strategies for clozapine-induced hypersalivation.

	Therapeutic options for the alleviation of clozapine-induced hypersalivation

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The main targets for pharmacological intervention of clozapine-induced hypersalivation are the muscarinic and adrenergic receptors. Several studies suggest that different receptors located on the salivary glands themselves, including and ß adrenergic and muscarinic receptors can alter salivary flow (Mandel et al, 1975; Ukai et al, 1989). A potential site of action for therapeutic intervention may be alteration in peripheral adrenergic tone to override the central muscarinic effects of clozapine.

	Antimuscarinic agents

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Amitriptyline
Amitriptyline is a tricyclic antidepressant that, among other actions, is an antagonist of muscarinic receptors both centrally and peripherally. The evidence for its efficacy in treating clozapine-induced hypersalivation comes from a letter in the British Journal of Psychiatry (Copp et al, 1991). Four patients with clozapine-induced hypersalivation were given 87-100 mg amitriptyline for an unspecified length of time and this resulted in either an improvement in the hypersalivation or a complete cessation.

Pirenzepine
Pirenzepine is a muscarinic receptor antagonist that shows its highest binding affinity for M₁ receptors and its main application is for the treatment of benign gastric ulcers. It shows little or no affinity for receptors, and has poor central nervous system (CNS) penetration. More common side-effects include dry mouth and blurred vision. Evidence for its clinical efficacy comes from a letter in Lancet (Fritz & Tilmann, 1995), reporting 120 patients who had their clozapine induced hypersalivation treated with daily doses of 25-100 mg of pirenzepine. They report that pirenzepine was successful in the treatment of the hypersalivation but did not use objective measures of salivation. The only reported side-effect was mild diarrhoea.

Benzhexol (trihexyphenidyl)
Benzhexol is a competitive antagonist of acetylcholine at muscarinic receptors and has good penetration of the CNS. It is most commonly used in the adjunctive therapy of Parkinson's disease. Common side-effects include dry mouth, blurred vision and occasionally confusion. The evidence for its efficacy as a treatment for clozapine-induced hypersalivation comes from one study (Spivak et al, 1997). Fourteen patients with chronic schizophrenia, who exhibited nocturnal hypersalivation during clozapine treatment, were administered 5-15 mg benzhexol at night for 15 days. Response was measured using a subjective rating scale and a 44% improvement was found.

Benzatropine
Benzatropine is a non-selective competitive antagonist of acetylcholine at muscarinic receptors; like benzhexol, its main application is as an adjunct in the treatment of Parkinson's disease. It is well-tolerated, although the usual anticholinergic side-effects of blurred vision, dry mouth and confusion may occur. The evidence for its efficacy in the treatment of clozapine-induced hypersalivation is also from a single study (Reinstein et al, 1999). Fifteen patients with chronic schizophrenia, and clozapine-induced hypersalivation, were treated with benzatropine 1 mg twice daily for 12 weeks and using subjective reporting found a satisfactory decrease in their hypersalivation had occurred in 66% of patients. The main criticism of both this and the benzhexol study is that they were not randomised control trials and treated only a small number of subjects.

Atropine
Atropine is a non-selective competitive antagonist of acetylcholine at muscarinic receptors. Common side-effects are dry mouth and blurred vision. Antonello (1999) described three patients who were treated with atropine for clozapine-induced hypersalivation. The patients were given one drop of 1% atropine solution sublingually at bedtime, and, if required, could have a further drop in a bedside glass of water to use as a ‘top up’. They reported immediate relief from the hypersalivation, which was both instantaneous and lasted throughout the night.

Hyoscine hydrobromide
Hyoscine is a competitive antagonist of acetylcholine at postganglionic parasympathetic nerve endings. Its main use is in the treatment of motion sickness and as a premedication. There are no publications supporting its efficacy in the treatment of clozapine-induced hypersalivation.

Ipratropium bromide
This is a non-selective muscarinic antagonist, most commonly used as a bronchodilator in the treatment of asthma and chronic obstructive airways disease. A single study used intranasal ipratropium bromide on 10 patients with clozapine-induced hypersalivation who had failed to respond to benzatropine or clonidine (Calderon et al, 2000). By using an intranasal route they hoped to minimise anticholinergic systemic absorption and therefore, side-effects. This was a non-comparative trial with no control group. Using a five-point subjective hypersalivation rating scale they found initially that eight patients reported an initial improvement with minimal side-effects. However, after 6 months two patients dropped out of the study and two reported no sustained improvement. The other six patients reported a statistically significant improvement had been maintained.

	Adrenoceptor agonists

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Clonidine
Clonidine is a partial agonist at adrenoceptors both within the CNS and the periphery. It is more specific for ₂ receptors than ₁. Its main use is as a centrally acting hypotensive agent. Though uncommon with doses less than 1 mg a day, there is a withdrawal syndrome associated with cessation of clonidine treatment with a rapid rebound hypertension. More common side-effects are sedation, dry mouth, bradycardia and contact dermatitis. A 0.1 mg once-a-week clonidine patch was administered to four patients with clozapine induced hypersalivation (Grabowski, 1992). The author reports a sustained improvement in two patients, a limited and short-lived improvement in another and no improvement in the fourth. Clonidine patches are not available in the UK.

Lofexidine
Lofexidine is an ₂ agonist that is only licensed in the UK for the short-term treatment of opiate withdrawal symptoms. A single case was reported where a patient with clozapine-induced hypersalivation was given 0.2 mg twice daily lofexidine over an unspecified time period. The patient showed significant improvement in his hypersalivation (Corrigan & MacDonald, 1995). However, lofexidine could not be used long-term without running the risk of depression or exacerbation of psychosis.

	Adrenoceptor antagonists

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Terazosin
Terazosin is an ₁ receptor antagonist. Its main application is in the treatment of mild to moderate essential hypertension. The main side-effect associated with terazosin is first dose hypotension. There is one study measuring the efficacy of terazosin (Reinstein et al, 1999). This was a non-randomised trial comparing terazosin and benzatropine and both combined. There were 15 patients in each of the groups. The terazosin only group received 2 mg at night for 12 weeks. It was found that at 12 weeks 93% of patients reported discontinuation of their hypersalivation. In contrast, the benzatropine group reported only a 66% discontinuation. In the combined group where subjects received 2 mg terazosin and 1 mg twice daily benzatropine, there was a 100% discontinuation of hypersalivation.

	Other strategies

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The lowering of the clozapine dose and the use of sugarless candy or gum to increase swallowing has also been employed ‘in practice’ to help alleviate hypersalivation. The avoidance of rapid titration when starting clozapine may reduce the chances of experiencing hypersalivation. Although these strategies may be useful adjuncts to the above pharmacological interventions, they are unlikely to prove sufficient on their own.

	References

Top Abstract Introduction Proposed mechanisms of action... Therapeutic options for the... Antimuscarinic agents Adrenoceptor agonists Adrenoceptor antagonists Other strategies References

 
ANTONELLO, C. (1999) Clozapine and sialorrhea: a new intervention for this bothersome and potentially dangerous side effect (letter). Journal of Psychiatry and Neuroscience, 24, 250.[Medline]

BAUM, B. (1993) Principles of saliva secretion in saliva as a novel diagnostic fluid. Annals of the New York Academy of Science, 694, 17-23.[Medline]

BEN-ARYEH, H., JUNGERMAN, T., SZARGEL, R., et al (1996) Salivary flow-rate and composition in schizophrenic patients on clozapine: subjective reports and laboratory data. Biological Psychiatry, 39, 946-949.[CrossRef][Medline]

BERLAN, M., MONTRSTRUC, J. & LAFONTAN, M. (1992) Pharmacological prospects for alpha 2 adrenoceptor antagonist therapy. Trends in Pharmacological Science, 13, 277-282.[CrossRef][Medline]

CALDERON, J., ROBIN, E. & SOBOTA, W. L. (2000) Potential use of ipatropium bromide for the treatment of clozapine-induced hypersalivation: a preliminary report. International Clinical Psychopharmacology, 15, 49-52.[Medline]

COPP, P. J., LAMENT, R. & TENNENT, T. G. (1991) Amitriptyline in clozapine-induced sialorrhoea (letter). British Journal of Psychiatry, 159, 166.

CORRIGAN, F. M. & MACDONALD, S. (1995) Clozapine-induced hypersalivation and the alpha 2 adrenoceptor (letter). British Journal of Psychiatry, 167, 412.

FRITZ, J. & TILMANN, E. (1995) Pirenzepine for clozapine-induced hypersalivation (letter). Lancet, 346, 1034.[Medline]

GRABOWSKI, J. (1992) Clonidine treatment of clozapine-induced hypersalivation (letter). Journal of Clinical Psychopharmacology, 12, 69-70.[Medline]

MANDEL, J., ZENGO, A., KATZ, R., et al (1975) Effects of adrenergic agents on salivary composition. Journal of Dental Research, 54, B27-B33.

MCCARTHY, R. & TERKELSEN, K. (1994) Oesophageal dysfunction in two patients after clozapine treatment. Journal of Clinical Psychopharmacology, 14, 281-283.[Medline]

RABINOWITZ, T., FRANKENBERG, F., CENTORRINO, F., et al (1996) The effect of clozapine on saliva flow rate: a pilot study. Biological Psychiatry, 40, 1132-1134.[CrossRef][Medline]

REINSTEIN, M., SIROTOVSKYA, L., CHASONOV, M., et al (1999) Comparative efficacy and tolerability of benzatropine and terazosin in the treatment of hypersalivation secondary to clozapine. Clinical Drug Investigation, 17, 97-102.

SAFFERMAN, A., LIBERMAN, J., KANE, M., et al (1991) Update on the clinical efficacy and side effects of clozapine. Schizophrenia Bulletin, 17, 247-261.

SPIVAK, B., ADLERSBERG, S., ROSEN, L., et al (1997) Trihexyphenidyl treatment of clozapine induced hypersalivation. International Clinical Psychopharmacology, 12, 213-215.[Medline]

UKAI, Y., TANIGUCHI, T. & KIMURA, K. (1989) Muscarinic supersensitivity and subsensitivity induced by chronic treatment with atropine and disopylfluorophosphate in rat submaxillary glands. Archives of International Pharmacodynamic Therapy, 6, 148-157.

ZORN, S., JONES, S., WARD, K., et al (1994) Clozapine is a potent and selective muscarinic M4 receptor agonist. European Journal of Pharmacology, 269, R1-R2.[CrossRef][Medline]

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