Amitriptyline for clozapine‐induced nocturnal enuresis and sialorrhoea

Abstract

Clozapine is an atypical antipsychotic of the dibenzodiazepine class which is useful in treating resistant schizophrenia. Besides agranulocytosis, which is potentially life-threatening, there are other disabling adverse effects of clozapine such as seizures, hypotension, sialorrhoea, constipation, nocturnal enuresis and weight gain. Clozapine-induced sialorrhoea occurs at a rate of approximately 30%, although it varies from 10 to 80% in the literature [1]. Nocturnal enuresis is a less frequently reported side-effect and incidence varies from 0.23%[2] to 41%[3]. It is possible that the occurrence of sialorrhoea and enuresis contributes to poor medication compliance. The patient, a 35-year-old man with a diagnosis of paranoid schizophrenia for the past 10 years, was initiated on clozapine as he was treatment resistant (i.e. did not respond to an adequate trial of one typical and one atypical antipsychotic agent). Over a period of 4 weeks clozapine was gradually titrated to 400 mg per day−1 in two divided doses. At this dose the patient complained of new-onset nocturnal enuresis. Bed-wetting that occurred daily was distressing for the patient. At this time he also developed troublesome sialorrhoea, which occurred during both night and day. To control both symptoms, amitriptyline 25 mg at bedtime was started. Rapid and complete resolution of enuresis was seen after 4 days. There was also marked reduction of nocturnal sialorrhoea, with disappearance of daytime sialorrhoea. Amitriptyline is a tertiary amine tricyclic antidepressant which blocks serotonin and norepinephrine transporters and thereby inhibits their neuronal uptake. It also acts as an antagonist at muscarinic, histaminic and adrenergic receptors. Amitriptyline has previously been found to be useful in clozapine-induced sialorrhoea; however, the doses used were higher, at 87–100 mg per day−1[4]. Amitriptyline has also been found to be effective in the treatment of nocturnal enuresis in children, acting through anticholinergic action on bladder tone [5]. Multiple mechanisms may be responsible for clozapine-induced sialorrhoea, including α2-adrenoreceptor antagonism, M4-muscarinic receptor agonism and decreased laryngeal peristalsis [1]. The pathophysiological mechanism of clozapine-induced enuresis is also likely to be multifactorial. It has been suggested that sedation due to clozapine prevents patients from waking up during sleep to empty their bladder, which is exacerbated when used in combination with other sedative drugs [6]. However, in our patient this was not the case as, despite amitriptyline’s potential to cause sedation, the patient’s nocturnal enuresis improved. Similarly, the suggestion that the potent anticholinergic action of clozapine can lead to urinary retention and subsequent overflow incontinence [2] also does not explain enuresis in our case, as this mechanism would also be aggravated by amitriptyline. Drugs found to be useful in clozapine-induced sialorrhoea include pirenzepine, clonidine and other anticholinergic agents such as transdermal hyoscine, atropine solution, etc. [1]. In clozapine-induced enuresis, drugs such as desmopressin, oxybutynin and trihexiphenidyl have been helpful [7]. Caution should be observed if amitriptyline is administered with clozapine, as there may be an increase in anticholinergic effects, hypotension, sedation or lowering of the seizure threshold. Nevertheless, when enuresis and sialorrhoea due to clozapine coexist, low-dose amitriptyline may be another option in the therapeutic armamentarium.