Download Treatment Options for Clozapine-Induced Enuresis: A

TITLE: Treatment Options for Clozapine-Induced Enuresis: A Review of Clinical
Effectiveness
DATE: 27 September 2010
CONTEXT AND POLICY ISSUES:
Clozapine is an atypical antipsychotic indicated in the management of treatment-resistant
schizophrenia.1 Clozapine binds dopamine receptors as well as exerting potent anticholinergic,
adrenolytic, antihistaminic, and antiserotoninergic activity.1 It has been shown to be efficacious in
treating both the positive (e.g., hallucinations) and negative symptoms (e.g., social withdrawal)
associated with schizophrenia.
Patients treated with clozapine may experience adverse effects ranging in severity from relatively
benign to serious and potentially life-threatening conditions such as seizures and
agranulocytosis.1,2 One potential adverse effect is enuresis, or an inability to control urination,
which can cause emotional stress and poor compliance among the affected patients.3 The true
prevalence of clozapine-induced enuresis has yet to be determined as published estimates range
from 0.23% to 44%.4,5 The reasons for this lack of consistency is are unclear and may be related
to differences in dosage,6 ethnicity,7 and treatment setting.3
The mechanism for clozapine-induced enuresis has not been fully elucidated; however, a leading
hypothesis involves blockade of the α-adrenergic receptors resulting in a decrease in internal
bladder sphincter tone.7 A number of treatments are available for the management of enuresis
including desmopressin,8 tricyclic antidepressants,9 anticholinergics,10 and alarms.11 However,
there is currently no universally accepted approach to addressing clozapine-induced enuresis.2,6
This report reviews the safety and effectiveness of the various treatment strategies for clozapineinduced enuresis.
RESEARCH QUESTIONS:
1.
What treatments are available in Canada to treat clozapine-induced enuresis?
2.
What are the potential adverse effects of treatments for clozapine-induced enuresis?
METHODS:
A limited literature search was conducted on key health technology assessment resources,
including Ovid MEDLINE (1950 to August Week 3 2010), Ovid EMBASE (1996 to 2010 Week 34),
PubMed, The Cochrane Library (Issue 8, 2010), University of York Centre for Reviews and
Dissemination (CRD) databases, ECRI (Health Devices Gold), EuroScan, international health
technology agencies, and a focused Internet search. The search was limited to English language,
with no time limit for articles’ publication dates. No filters were applied to limit the retrieval by
study type.
SUMMARY OF FINDINGS:
The literature search identified one prospective cohort study,6 and 13 case reports.4,12-23 There
were no health technology assessments, systematic reviews, meta-analyses, randomized
controlled clinical trials, uncontrolled clinical trials, or case control studies. Results from individual
studies are summarized in Appendix 1 and the treatment strategies identified are listed in
Appendix 2.
Non-randomized studies
Desmopressin
There were six reports involving a total of ten patients that received desmopressin spray to treat
their clozapine-induced nocturnal enuresis.4,15-19 The patients consisted of nine adults and one
adolescent, ranging in age from 16 to 47 years. Five studies reported that the desmopressin was
effective.4,16-19 One of these reports involved a patient who had received initial, unsuccessful
treatment with tolterodine.19 The one case with negative results involved a patient that developed
severe hyponatremia following two doses of desmopressin which required hospitalization in an
intensive care unit. Hyponatremia is an important adverse event associated with treatment using
desmopressin and the manufacturers recommend careful medical supervision when using this
product. Furthermore, the patient that developed hyponatremia had a previously documented
hyponatremic episode. The product monograph clearly indicates that desmopressin is
contraindicated in patients with known hyponatremia.8 Two articles17,18 reported that no adverse
events occurred with desmopressin treatment and three failed to report this information.4,16,19 The
most common dosage was 10 μg/day in each nostril which is consistent with the average daily
doses reported in the product monograph for desmopressin spray.8 Two case reports16,19 failed to
provide the exact dosage used by the patients and only one reported the time to resolution.19
Anticholinergic agents
There were two case series (n = 10) where patients were given the anticholinergic agent
oxybutynin (5-15 mg/day) for nocturnal enuresis.16,17 Both articles stated that the treatment was
effective; however, neither reported the time to resolution. The dosage was consistent with
recommendations in the product monograph for oxybutynin.10 Frankenburg et al (1996)17 reported
that no adverse events occurred with oxybutynin treatment and Lurie et al (1997)16 did not report
the occurrence of adverse events in their study.16 Trihexiphenidyl, another anticholinergic agent,
was reported to be effective at doses of 5 mg/day and 6 mg/day (n = 3).20,21 Poyurovsky et al
(1996)20 stated that the nocturnal enuresis had resolved within five days of trihexiphenidyl
treatment; however, Aggarwal et al (2009)21 did not report the time to onset for the therapeutic
effect. Similar to oxybutynin, there were no adverse events in one study21 and other failed to
provide this information.20 All patients in these case reports were adults; however, those receiving
trihexiphenidyl were younger (range: 21-24 years) than those who received oxybutynin (range:
26-43 years).
Antidepressants
There was one case report where amitriptyline (25 mg/day), a tricyclic antidepressant, was
provided to one patient (35 years of age) with clozapine-induced enuresis.12 The authors reported
Treatment Options for Clozapine-Induced Enuresis
2
that after four days of amitriptyline therapy the enuresis had effectively resolved and that
nocturnal and day-time sialorrhea were also improved. It was not reported if the patient
experienced any adverse events due to the addition of amitriptyline to his/her therapeutic
regimen.
Antipsychotics
Aripiprazole was used to treat three patients with clozapine-induced nocturnal enuresis at doses
of 10-15 mg/day.13,14 The authors of these cases reported that the treatment was effective within 1
to 3 months. Rocha et al (2006)13 reported that no adverse events occurred after initiating
treatment with aripiprazole and Lee and Kim (2010) did not report whether or not the patients
experienced any adverse events.14 Another case involved ceasing treatment with clozapine and
commencing therapy with olanzapine.23 The authors reported that the nocturnal enuresis remitted
following this change in pharmacotherapy. The dosage of olanzapine was not reported nor was it
reported if the patient experienced any adverse events from switching antipsychotics. The
patients were all adults ranging in age from 27 years to 52 years.
Adrenergic agonists
Fuller et al (1996)6 conducted a small, prospective cohort study involving 16 patients with
clozapine-induced urinary incontinence. The authors gave the patients ephedrine (25-150
mg/day) and reported improvement in symptoms of urinary incontinence in 15 patients within 24
hours of maximal dosing. There were no adverse events reported for these patients. The patients
in this study were heterogeneous with regard to the dosages of clozapine (range: 200-700
mg/day); concomitant use of medications; and age (range: 32-69 years).
Other approaches
Frankenburg et al (1996)17 reported that the clozapine-induced enuresis was resolved in one
patient by using an alarm clock set to wake the patient in the middle night. Once woken the
patient could voluntarily empty his/her bladder. Pojurovsky et al (1995)22 used 40-80 mg/day of
verapamil, an L-type calcium channel blocker, to treat two patients with clozapine-induced
enuresis.22 The authors noted that the 80 mg/day treatment was effective and that the enuresis
had resolved after one day. The patient experienced bradycardia (reduction of 11-22 beats/min)
for five days after the first dose of 40 mg/day verapamil and for 4 days following the first dose of
80 mg/day verapamil. Kho et al (2001)23 also reported individual cases where clozapine-induced
nocturnal enuresis was resolved following initiation of valproic acid (1500 mg/day) to control
seizures (n = 1) and with the initiation of insulin to control diabetes (n = 1). The duration between
initiating these therapies and resolution of the enuresis was not reported by the study authors.
Limitations
There were no randomized controlled trials, uncontrolled clinical trials, larger cohort studies, or
case control studies identified. The evidence identified in this review consists of case reports4,12-23
and one small (16 patients), prospective cohort study.6 These study designs are typically
considered poor for accurately assessing the effectiveness of interventions and may carry a high
risk of bias. Planning and conducting a controlled clinical trial could be difficult in this population
as the true prevalence of clozapine-induced enuresis has yet to be determined.
Treatment Options for Clozapine-Induced Enuresis
3
Among the included studies, six failed to provide a clear indication of the time required to resolve
the enuresis following treatment.4,16-18,20,23 The dosage of clozapine was heterogeneous between
the various patients described in the case reports (range: 150-900 mg/day); however, no one
exceed the maximum recommended dose of 900 mg/day and most were within the expected
therapeutic range of 300-600 mg/day.1 The dose of the interventions used for treating the
enuresis were within the ranges specified in the product monographs,8,10,24-28 but three of the case
reports neglected to provide this information.16,19,23 Seven case reports failed to state whether or
not the patients experienced any adverse events related to the treatment of their clozapineinduced enuresis.4,12,14,16,19,20,23 This is a key limitation of the available evidence as it cannot be
assumed that the absence of reporting is an indication of an absence of events.
CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING:
This rapid review identified reports of twelve different treatment strategies used to control
clozapine-induced enuresis. Desmopressin was the most commonly reported effective treatment
in case reports. Ephedrine was also shown to be an effective and well-tolerated treatment with a
relatively rapid onset of action. The anticholinergic agents oxybutynin and trihexiphenidyl were
also reported to be effective and well-tolerated in patients. The addition of aripiprazole, another
atypical antipsychotic, was effective in two case reports. There were single case reports stating
that verapamil, amitriptyline, valproic acid, and the use of an alarm clock all effectively resolved
clozapine-induced enuresis. The only published report of an agent that failed to improve the
enuresis involved a single patient receiving tolterodine.
Some case reports neglected to address the occurrence of any adverse events associated with
the treatment of clozapine-induced enuresis. Others reported that no adverse events occurred
with treatment. There was one report of a patient developing severe hyponatremia after receiving
desmopressin; however, the treatment should have been contraindicated in this patient due to a
previous hyponatremic episode. In another study, the initiation of verapamil was associated with
an immediate reduction in pulse rate; however, there were insufficient details concerning the
magnitude of the bradycardiac effect and whether or not it was associated with any symptoms.
Overall, the available evidence is limited and larger controlled studies with be required in order to
properly assess the safety and effectiveness of treatment strategies for clozapine-induced
enuresis.
PREPARED BY:
Health Technology Inquiry Service
Email: [email protected]
Tel: 1-866-898-8439
Treatment Options for Clozapine-Induced Enuresis
4
REFERENCES:
1.
Novartis Pharmaceuticals Canada,Inc. PrCLOZARIL*: (Clozapine Tablets). 2010 Jul 16
[cited 2010 Sep 9]. In: Health Canada. Drug Product Database [Internet]. Ottawa (ON):
Health Canada; c2005 - . Available from: http://webprod.hc-sc.gc.ca/dpd-bdpp/indexeng.jsp.
2.
Iqbal MM, Aneja A, Rahman A, Megna JL, Yasmin L, Schwartz TL, et al. Therapeutic
options in the treatment of Clozapine-induced adverse effects. J Pharm Technol.
2004;20(3):155-64.
3.
Jeong SH, Kim JH, Ahn YM, Lee KY, Kim SW, Jung DC, et al. A 2-year prospective followup study of lower urinary tract symptoms in patients treated with clozapine. J Clin
Psychopharmacol. 2008 Dec;28(6):618-24.
4.
Aronowitz JS, Safferman AZ, Lieberman JA. Management of clozapine-induced enuresis.
Am J Psychiatry. 1995 Mar;152(3):472.
5.
Lin CC, Bai YM, Chen JY, Lin CY, Lan TH. A retrospective study of clozapine and urinary
incontinence in Chinese in-patients. Acta Psychiatr Scand. 1999 Aug;100(2):158-61.
6.
Fuller MA, Borovicka MC, Jaskiw GE, Simon MR, Kwon K, Konicki PE. Clozapine-induced
urinary incontinence: incidence and treatment with ephedrine. J Clin Psychiatry. 1996
Nov;57(11):514-8.
7.
Hsu JW, Wang YC, Lin CC, Bai YM, Chen JY, Chiu HJ, et al. No evidence for association of
alpha 1a adrenoceptor gene polymorphism and clozapine-induced urinary incontinence.
Neuropsychobiology. 2000;42(2):62-5.
8.
Ferring, Inc. PrDDAVPr Spray: Desmopressin Acetate nasal spray. 2008 Jun 19 [cited 2010
Sep 9]. In: Health Canada. Drug Product Database [Internet]. Ottawa (ON): Health Canada;
c2005 - . Available from: http://webprod.hc-sc.gc.ca/dpd-bdpp/index-eng.jsp.
9.
Glazener CM, Evans JH, Cheuk DK. Complementary and miscellaneous interventions for
nocturnal enuresis in children. Cochrane Database Syst Rev [Internet]. 2005 Apr 18 [cited
2010 Sep 2];(2):CD005230. Available from:
http://www.thecochranelibrary.com/view/0/index.html Subscription required.
10.
Janssen-Ortho Inc. PrDITROPAN XL*: oxybutynin chloride: extended-release tablets, USP.
2009 Mar 3 [cited 2010 Sep 9]. In: Health Canada. Drug Product Database [Internet].
Ottawa (ON): Health Canada; c2005 - . Available from: http://webprod.hc-sc.gc.ca/dpdbdpp/index-eng.jsp.
11.
Glazener CM, Evans JH, Peto RE. Alarm interventions for nocturnal enuresis in children.
Cochrane Database Syst Rev [Internet]. 2005 Apr 18 [cited 2010 Sep 2];(2):CD002911.
Available from: http://www.thecochranelibrary.com/view/0/index.html Subscription required.
12.
Praharaj SK, Arora M. Amitriptyline for clozapine-induced nocturnal enuresis and
sialorrhoea [letter]. Br J Clin Pharmacol [Internet]. 2007 Jan [cited 2010 Sep 2];63(1):128-9.
Treatment Options for Clozapine-Induced Enuresis
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Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2000705/pdf/bcp00630128.pdf
13.
Rocha FL, Hara C. Benefits of combining aripiprazole to clozapine: three case reports. Prog
Neuropsychopharmacol Biol Psychiatry. 2006;30(6):1167-9.
14.
Lee MJ, Kim CE. Use of aripiprazole in clozapine induced enuresis: report of two cases. J
Korean Med Sci [Internet]. 2010 Feb [cited 2010 Sep 1];25(2):333-5. Available from:
http://jkms.org/Synapse/Data/PDFData/0063JKMS/jkms-25-333.pdf
15.
Sarma S, Ward W, O'Brien J, Frost AD. Severe hyponatraemia associated with
desmopressin nasal spray to treat clozapine-induced nocturnal enuresis. Aust N Z J
Psychiatry. 2005 Oct;39(10):949.
16.
Lurie SN, Hosmer C. Oxybutynin and intranasal desmopressin for clozapine-induced urinary
incontinence. J Clin Psychiatry. 1997 Sep;58(9):404.
17.
Frankenburg FR, Kando JC, Centorrino F, Gilbert JM. Bladder dysfunction associated with
clozapine therapy [letter]. J Clin Psychiatry. 1996 Jan;57(1):39-40.
18.
Steingard S. Use of desmopressin to treat clozapine-induced nocturnal enuresis [letter]. J
Clin Psychiatry. 1994 Jul;55(7):315-6.
19.
English BA, Still DJ, Harper J, Saklad SR. Failure of tolterodine to treat clozapine-induced
nocturnal enuresis. Ann Pharmacother. 2001 Jul;35(7-8):867-9.
20.
Poyurovsky M, Modai I, Weizman A. Trihexyphenidyl as a possible therapeutic option in
clozapine-induced nocturnal enuresis. Int Clin Psychopharmacol. 1996 Mar;11(1):61-3.
21.
Aggarwal A, Garg A, Jiloha RC. Trihexyphenidyl (benzhexol) in clozapine-induced nocturnal
enuresis and sialorrhea [letter]. Indian J Med Sci. 2009 Oct;63(10):470-1.
22.
Pojurovsky M, Schneidman M, Mark M, Weizman A. Verapamil treatment in clozapineinduced sleep-related enuresis: a case report. Eur Psychiatry. 1995;10(8):413-5.
23.
Kho KH, Nielsen O. Clozapine-induced nocturnal enuresis: diagnostic and treatment issues.
Psychiatr Bull R Coll Psychiatr [Internet]. 2001 [cited 2010 Sep 2];25(6):232-3. Available
from: http://pb.rcpsych.org/cgi/reprint/25/6/232
24.
Pfizer Canada Inc. PrDETROL*: (tolterodine L-tartrate). 2010 Feb 10 [cited 2010 Sep 9]. In:
Health Canada. Drug Product Database [Internet]. Ottawa (ON): Health Canada; c2005 - .
Available from: http://webprod.hc-sc.gc.ca/dpd-bdpp/index-eng.jsp.
25.
Bristol-Myers Squibb Canada. PrABILIFY*: Aripiprazole tablets. 2010 Aug 18 [cited 2010
Sep 9]. In: Health Canada. Drug Product Database [Internet]. Ottawa (ON): Health Canada;
c2005 - . Available from: http://webprod.hc-sc.gc.ca/dpd-bdpp/index-eng.jsp.
26.
Pfizer Canada Inc. PrCOVERA-HS*: (verapamil hydrochloride) controlled-onset extended
release tablets. 2006 Sep 8 [cited 2010 Sep 9]. In: Health Canada. Drug Product Database
Treatment Options for Clozapine-Induced Enuresis
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[Internet]. Ottawa (ON): Health Canada; c2005 - . Available from: http://webprod.hcsc.gc.ca/dpd-bdpp/index-eng.jsp.
27.
Canadian Pharmacists' Association. Trihexyphenidyl: trihexyphenidyl HCl: antiparkinsonian
agent. 2005 Nov [cited 2010 Sep 10]. In: e-CPS [Internet]. Ottawa (ON): Canadian
Pharmacists' Association; 2009 - . Available from: https://www.e-therapeutics.ca
Subscription required.
28.
Canadian Pharmacists' Association. Amitriptyline: amitriptyline HCl antidepressantanalgesic. 2009 Nov [cited 2010 Sep 10]. In: e-CPS [Internet]. Ottawa (ON): Canadian
Pharmacists' Association; 2009 - . Available from: https://www.e-therapeutics.ca
Subscription required.
Treatment Options for Clozapine-Induced Enuresis
7
APPENDIX 1: Summary of results from individual studies of treatment for clozapine
induced enuresis
Author
Fuller et al6
Patients
16
Treatment
Ephedrine
(25-150 mg/day)
Clozapine Dosage
Range: 200-700 mg/day
Mean: 440 mg/day
Praharaj et
12
al
Rocha et
al13
1
Amitriptyline (25
mg HS)
Aripiprazole
(15 mg/day)
400 mg/day
Lee et al14
2
Aripiprazole
(10 mg/day)
Range: 200-425 mg/day
Aronowitz et
al4
Sarma et
15
al
Lurie et al16
1
150 mg/day
Frankenburg
17
et al
4
Desmopressin
(10 μg/nostril)
Desmopressin
(10 μg/day)
Desmopressin
(dose not
reported)
Desmopressin
(10 μg/nostril)
Steingard18
1
Desmopressin
(10 μg/nostril)
300 mg/day
English et
al19
1
Range: 250-300 mg/day
Lurie et al16
5
Tolterodine
(2 mg/week);
Desmopressin
(dose not
reported)
Oxybutynin
(5-15 mg/day)
Frankenburg
et al17
5
Oxybutynin
(5-15 mg/day)
Mean: 402 ± 244 mg/day
Poyurovsky
et al20
2
Trihexiphenidyl
(5 mg/day)
Range: 300-400 mg/day
Aggarwal et
al21
Pojurovsky
22
et al
1
Trihexiphenidyl
(6 mg/day)
Verapamil
(80 mg/day)
350 mg/day
Kho et al23
1
Switch to
olanzapine
(dose not
reported)
400 mg/day
1
1
2
1
Treatment Options for Clozapine-Induced Enuresis
Range: 300-400 mg/day
700 mg/day
Range: 300-900 mg/day
Mean: 402 ± 244 mg/day
Range: 300-900 mg/day
150 mg/day
 Results
 Effective with improvement in 15/16
patients within 24 hours of maximal
dose
 No adverse events were reported
 Effective with resolution after 4 days
 Adverse events were not reported
 Effective with improvement after 2
months
 No adverse events were reported
 Effective with resolution after 1-3
months
 No adverse events reported
 Effective with “rapid” resolution
 Adverse events were not reported
 Patient developed severe
hyponatraemia
 Effective; time to resolution not
reported
 Adverse events were not reported
 Effective; time to resolution not
reported
 No adverse events were reported
 Effective; time to resolution not
reported
 No adverse events were reported
 Tolterodine was ineffective
 Desmopressin was effective with
resolution after 2 days
 Adverse events were not reported
 Effective; time to resolution not
reported
 Adverse events were not reported
 Effective; time to resolution not
reported
 No adverse events were reported
 Effective; time to resolution not
reported
 Adverse events were not reported
 Effective with resolution after 5 days
 No adverse events were reported
 Effective with resolution after 1 day
 Patient experienced bradycardia
(reduction of 11-22 beats/min) for 5
days after the first dose of 40 mg/day
verapamil and for 4 days following the
first dose of 80 mg/day verapamil
 Effective; time to resolution not
reported
 Adverse events were not reported
8
Author
Frankenburg
17
et al
Patients
1
Treatment
Alarm clock
Treatment Options for Clozapine-Induced Enuresis
Clozapine Dosage
Mean: 402 ± 244 mg/day
 Results
 Effective; time to resolution not
reported
 Adverse events were not reported
9
APPENDIX 2: Drugs used in the treatment of clozapine-induced enuresis
The information below was summarized from the Health Canada approved product monographs
for the agents identified in the literature review.8,10,24-28
Generic Name
Desmopressin
Trade name
DDAVP
Spray
Dosage
10-40 μg/day
Oxybutynin
Ditropan
5-30 mg
Tolterodine
Detrol
2-4 mg
Aripiprazole
Abilify
10-30 mg
Verapamil
Covera-HS
180-480 mg/day
Trihexiphenidyl
Generics sold
in Canada
5-15 mg/day
Amitriptyline
Generics sold
in Canada
25-300 mg/day
Treatment Options for Clozapine-Induced Enuresis
Approved Indications
 Management of vasopressin sensitive central
diabetes insipidus and for the control of temporary
polyuria and polydipsia following head trauma,
hypophysectomy or surgery in the pituitary region.8
 Indicated for the relief of the symptoms of urge
incontinence, urgency and frequency in patients
with overactive bladder.10
 Symptomatic management of patients with an
overactive bladder with symptoms of urinary
frequency, urgency, or urge incontinence, or any
combination of these symptoms.24
 Treatment of schizophrenia and related psychotic
disorders.25
 Acute treatment of manic or mixed episodes in
bipolar I disorder.25
 Treatment of mild to moderate essential
hypertension.26
 Treatment of chronic stable angina pectoris.26
 Adjunctive therapy in the symptomatic treatment of
Parkinsonism and drug-induced parkinsonian
symptoms.27
 Pharmacologic management of depressive
illness.28
10