Clozapine has been shown to be a superior antipsychotic (Reference Kane, Honigfeld and SingerKane et al, 1988). Owing to its potential for causing severe side-effects, it is usually reserved for the management of treatment-refractory psychiatric illnesses. Apart from the risk of agranulocytosis in 0.8% of the patients within a year of initiation (Reference Alvir, Lieberman and SaffermanAlvir et al, 1993), clozapine has been known to cause seizures, hypotension, tachycardia, weight gain and sialorrhoea. Nocturnal enuresis is a less known side-effect; reports estimate that it occurs in 0.23% (Reference Aronowitz, Safferman and LiebermanAronowitz et al, 1995) to 27% (Reference Centorrino, Baldessarini and KandoCentorrino et al, 1994) of patients using clozapine. Patients are sometimes embarrassed to report this side-effect, leading to an underestimation of its incidence (Reference Warner, Harvey and BarnesWarner et al, 1994). It is possible that the occurrence of enuresis contributes to non-compliance of taking medication.
The pathophysiological mechanism of clozapine-induced enuresis remains unclear. It is suggested that sedation prevents the patients from waking up during sleep to empty the bladder, especially if combined with other sedative medication (Reference SteingardSteingard, 1994). Others suggest that clozapine is a potent anticholinergic antagonist, which can lead to urinary retention and subsequent overflow incontinence (Reference Aronowitz, Safferman and LiebermanAronowitz et al, 1995).
Warner et al (Reference Warner, Harvey and Barnes1994) report the occurrence of clozapine-induced enuresis in five out of 12 patients in the first 3 months of treatment resolving spontaneously in all cases. Centorrino et al (Reference Centorrino, Baldessarini and Kando1994), however, report enuresis as a late side-effect, which is not correlated to the plasma level of the drug.
In these case reports we suggest a systematic treatment approach, as the pathophysiology of this side-effect appears to be diverse.
Case reports
Patient A, a female suffering from schizophrenia, complained of being unable to wake up to empty her bladder because of a very deep and long sleep. She had no complaints other than frequent bedwetting. There were no signs or symptoms of epilepsy. The patient was on 200 mg clozapine twice daily with a plasma level of 0.48 mg/l, which is well above the minimal recommended therapeutic level of 0.35 mg/l (Reference Kronig, Munne and SzymanskiKronig et al, 1995) and clorazepate 10 mg three times a day. After clozapine was replaced by olanzapine, the nocturnal enuresis remitted. She experienced no relapse after the switch of the medication.
Patient B, a 27-year-old male suffering from schizophrenia, was seen for complaints of bedwetting. He was also known to have lost consciousness twice in the day time, without tongue biting or incontinence. The patient was on clozapine 400 mg once daily and lactulose 30 ml once daily. The electroencephalogram recording showed signs of a generalised epilepsy. After clozapine was replaced by olanzapine the patient experienced a relapse of his psychosis. Because his psychosis was known to be resistant to classic neuroleptic medication, clozapine 400 mg once daily was restarted, with a plasma level of 0.59 mg/l, and the olanzapine stopped. Valproic acid 500 mg three times a day was added to prevent a recurrence of seizures. His psychosis remitted and he had no further episodes of enuresis or seizures.
Patient C, a 29-year-old male suffering from schizophrenia, was seen for nocturnal enuresis. At previous investigations serum glucose levels were within the normal range. He was on clozapine 200 mg twice daily (unknown plasma level), fluvoxamine 50 mg twice daily and oxazepam 25 mg twice daily. When he was seen for his nocturnal enuresis the urine sample taken was positive for glucose, with serum glucose levels of 23.4 and 23.8 mmol/l and a glycosolated haemoglobin of 8.4%. After insulin therapy was started the nocturnal enuresis remitted. High doses of insulin were necessary to control the diabetes. Two years later clozapine was stopped owing to high fever and an infiltration in the left middle lung. Zuclopenthixol was initiated. After the switch of the antipsychotic medication the dose of insulin was decreased and after a few months it was stopped as the diabetes remitted.
Discussion
These case reports show the need for further investigations before treatment for clozapine-induced enuresis can be started. The occurrence of enuresis can be explained by several pathophysiological mechanisms.
Patients can have a recurrence of enuresis with a history of prior enuresis (Reference BerriosBerrios, 1986). Enuresis occurring after initiation of clozapine can be attributed to the medication. Reducing sedative co-medication as well as clozapine prevents the patient from sleeping through his or her urge to void the bladder in his or her sleep, as seen in case A.
A spontaneous remission of this side-effect is possible (Reference Warner, Harvey and BarnesWarner et al, 1994). Epileptic seizures can present as nocturnal enuresis as shown in case B. During the first 6 months after marketing, 71 out of 5629 patients (1.3%) using clozapine were shown to have had generalised tonic—clonic seizures (Reference Pacia and DevinskyPacia & Devinsky, 1994). Patients with a history of seizures or epilepsy were more likely to have seizures soon after initiation of therapy. Seizures tended to occur at low doses (300 mg/day) during the titration phase and at high doses (600 mg/day) during the maintenance phase. The majority of patients who had seizures were able to continue the medication with dose reduction and more gradual dose titrating, or with the addition of anticonvulsive medication.
Recently, clozapine has been associated with the occurrence of diabetes mellitus (Reference Wirshing, Spellberg and ErhartWirshing et al, 1998). Fifteen cases have so far been described (Reference Brugman, Cohen and De VRIESBrugman et al, 2000). A positive family history of diabetes and a personal history of impaired glucose tolerance may increase the risk of developing this side-effect. Treatment of the diabetes can alleviate this indirectly caused clozapine-induced enuresis, as shown in case C.
Treatment with desmopressin (a synthetic analogue of the antidiuretic hormone vasopressin), 10 μg in each nostril at bedtime, has been suggested (Reference SteingardSteingard, 1994; Reference Aronowitz, Safferman and LiebermanAronowitz et al, 1995; Frankenbur et al, 1996). It decreases the formation of urine by increasing water reabsorption by the renal collecting ducts. Others have suggested the use of oxybutynin (Reference Frankenburg, Kando and CentorrinoFrankenburg et al, 1996) and trihexyphenidyl (Reference Poyurovski, Modai and WeizmanPoyurovski et al, 1996) to treat clozapine-induced enuresis.
Conclusion
Enuresis is a side-effect of clozapine that is probably underreported if not specifically asked about. The underlying pathophysiological mechanisms are varied, which necessitates further investigations prior to commencing treatment of this side-effect.
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