Clozapine induced Hypersalivation

• Many antipsychotics can cause hypersalivation, but it affects around 30% of patients taking clozapine (reported range 10-80%) (1,2,3). 
• It usually develops early in treatment, is often more prominent at night, and may reduce compliance (1,2,3,4).  
• The exact mechanism of clozapine-induced hypersalivation is unknown (2,3,5).  

Management

• If clozapine dose reduction (in appropriate patients) has not alleviated symptoms and an alternative antipsychotic is not an option, various pharmacological interventions have been used to manage hypersalivation (see Table 1 for treatment options). 
• Non-pharmacological strategies (e.g. sugarless chewing gum) have been recommended first-line but they are often ineffective (2,6,7).  
• A Cochrane Review to determine the clinical effects of pharmacological interventions (including traditional Chinese medicines) for clozapine-induced hypersalivation identified 15 trials. The authors concluded that “There are currently insufficient data to confidently inform clinical practice” 

Intervention Summary

• There is very limited comparative efficacy data to support the choice of one treatment for clozapine-induced hypersalivation over another.  In practice the potential risks and benefits of each option should be considered on an individual basis.   Some options have specific risks:
• Some agents may have additive hypotensive effects with clozapine (e.g. amitriptyline, terazosin, clonidine, lofexidine). Blood pressure should be monitored in these patients.
• Some may cause drowsiness (e.g. hyoscine, benzatropine, amitriptyline).
• Some may cause psychiatric side effects (e.g. depression with clonidine, agitation with trihexyphenidyl).
• Antimuscarinic agents will have additive side effects with clozapine. Cognitive function may also be impaired. Pirenzepine, glycopyrronium and ipratropium are believed to have little CNS penetration. Peripherally, anticholinergics can impair the gag reflex, compromising swallowing and increasing the risk of aspiration (23).
• Amitriptyline with clozapine may increase the risk of convulsions.
• Amisulpride with clozapine may cause hyperprolactinaemia.

Intervention Dosing and Outcomes:

Intervention	Report Descriptions [ref]	Dose of Intervention	Outcome and notes when used in clozapine patients
Antimuscarinics
Amitriptyline oral	(a) Case reports (n=4) [9] (b) Case report [10]	(a) 75-100mg per day. (b) 25mg at night.	Marked improvement.
			Beware additive side effects (e.g. fits, hypotension) [10,11].
Atropine eye drops 1% sublingually	(a) Case report [12] (b) Case reports (n=3) [6] (c) Case report [13]	(a) 1-2 drops in the morning. (b) 1 drop at night (plus top-up overnight dose of 1 drop in water prn (n=1)). (c) 2 drops bd.	(a) Resolution. (b) “Immediate relief”. (c) Resolution.
			Fast relief [6] but may not be sustained [14]; dropper can be hard to use with risk of accidental overdose [14]. Beware additive anticholinergic side effects [13] and bitter taste [15].
Hyoscine hydrobromide patch/oral	(a) Case reports (n=4) [15] (b) Case report [23] (c) Anecdotal [3,4]	(a) Patch (dose not given). (b) Patch 1.5mg every 72hrs. (c) 300 microgram tablet nocte increased to tds if necessary, sucked & swallowed.	(a) Improvement, including pts failing other treatments. (b) Persistent improvement. (c) Widely used in practice (e.g. KwellsÒ). Beware cognitive impairment, drowsiness.
Trihexyphenidyl (benzhexol) hydrochloride oral	(a) Non-comparative study (n=14) for 15 days [30] (b) Case report with 3 month follow-up [31]	(a) 5mg nocte, gradually increasing to maximum of 15mg nocte. (b) 6mg per day in divided doses.	(a) 11 pts improved; 3 pts did not. (b) Marked reduction in nocturnal hypersalivation and disappearance of daytime hypersalivation.
			May impair cognitive function [4].
Adrenoceptor Antagonists
Terazosin oral	Retrospective chart review (n=60) [16]	See benzatropine above.
			Beware additive hypotension [34].
Miscellaneous
Amisulpride oral	(a) Randomised, double-blind, placebo-controlled, cross-over study (n=20). 3 wks active treatment [38] (b) Open-label crossover trial vs. moclobemide (n=53) [39] (c) Case report; patient also on pirenzepine throughout [40] (d) Case report with 3 month follow-up [41] (e) Case report	(a) Amisulpride 100mg/day titrated up to 400mg/day over 1 week. b) Amisulpride 400mg/day vs. moclobemide 300mg/day. (c) Amisulpride up to 600mg daily with clozapine dose reduction. (d) Amisulpride 50mg/day. (e) Amisulpride 50mg/day increased over 2 weeks to 150mg/day.	(a) Statistically significant improvement. Prolactin levels rose in most patients and may need monitoring. (b) At 2 weeks, 39 improved, 1 worsened and 13 unchanged. Less effective than moclobemide. (c) Enabled reduced pirenzepine dose. Hyper-salivation markedly improved. (d) Significant improvement in hypersalivation. (e)  Marked improvement in daytime hypersalivation but night-time hypersalivation still present. Constipation and tachycardia reported.

References:

1. Medicines Information (UKMi) pharmacists for NHS healthcare professionals
2. Lexicomp