Pharmacological treatment of clozapine-induced sialorrhoea

Clozapine (Clopine^®, Clozaril^®) is a novel atypical antipsychotic agent. It is an effective second-line option for treatment-resistant schizophrenia. Approximately 30% to 60% of all patients with schizophrenia that fails to respond to typical antipsychotics are likely to respond to clozapine.

Clozapine exhibits dopamine blocking activity as well as potent noradrenergic, anticholinergic, antihistaminic, and muscarinic effects. Clozapine is an attractive alternative to other antipsychotics due to its low incidence of extrapyramidal symptoms (EPS) and prolactin effects.

Reluctance to prescribe clozapine is associated with the potentially fatal adverse effect of agranulocytosis. Access to clozapine follows a strict protocol that requires patients to have regular blood tests, the results of which are entered into a database. Confirmation that white blood cell and neutrophil counts fall within the acceptable range must then occur before the medication can be supplied.

A less serious, yet bothersome side effect is sialorrhoea. Sialorrhoea, or excessive drooling, is estimated to affect between 30% and 80% of patients treated with clozapine. Sialorrhoea is often most troublesome during the night where it may cause sleep disturbances. During the day, sialorrhoea can lead to complications such as social awkwardness, speech difficulties, perioral infections, and maceration. In extreme situations, choking and aspiration can occur. Pharmacological treatment of sialorrhoea is, therefore, important to ensure compliance and improve the quality of life.

Due to the marked anticholinergic properties of clozapine, sialorrhoea is considered a paradoxical side effect. The aetiology of clozapine-induced sialorrhoea may relate to blockade of alpha2-adrenergic receptors and activation of muscarinic M4 receptors that leads to increased saliva production. However, there is also a theory that clozapine-induced sialorrhoea is related to reduced swallowing which leads to pooling of saliva in the mouth.

Some medicines have been trialled for the management of sialorrhoea. Oral agents like amitriptyline and benztropine have been utilised for their anticholinergic effects, and clonidine has been used for its alpha2-adrenergic effect. However, the use of these agents is limited by the prevalence of systemic side effects that can reduce tolerability and compliance. Due to the absence of specific medications to treat sialorrhoea, sublingual administration of products intended to be used by a different route have been trialled. Intranasal preparations of ipratropium bromide and ophthalmic formulations of atropine have been administered sublingually with varying efficacy. Ipratropium demonstrates moderate efficacy in the treatment of sialorrhoea. Systemic side effects are not often observed due to poor absorption. However, sublingual administration can cause an uncomfortably dry mouth. Atropine is used more frequently and demonstrates high efficacy and tolerable side effects.

Although not formally indicated as a treatment for sialorrhoea, Atropt^® (atropine sulfate 1%) eye drops are prescribed off-label for this indication by some psychiatrists. A dose of one to two drops sublingually every four to six hours as required is most commonly used. Patients should be advised to swish the drops to increase surface area contact with the oral mucosa. The effects of this treatment are long lasting, with some patients experiencing relief that lasts throughout the night. Minimal systemic and local adverse effects have been reported with the use of this therapy.