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Home , Clozapine, Enuresis, Nocturnal enuresis

TITLE: Treatment Options for Clozapine-Induced : A Review of Clinical Effectiveness

DATE: 27 September 2010

CONTEXT AND POLICY ISSUES:

Clozapine is an atypical indicated in the management of treatment-resistant .1 Clozapine binds receptors as well as exerting potent , adrenolytic, antihistaminic, and antiserotoninergic activity.1 It has been shown to be efficacious in treating both the positive (e.g., ) 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 and .1,2 One potential adverse effect is enuresis, or an inability to control , which can cause emotional 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- receptors resulting in a decrease in internal bladder sphincter tone.7 A number of treatments are available for the management of enuresis including ,8 ,9 ,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 clozapine- induced 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 .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 .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 (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 (25 mg/day), a tricyclic , 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 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 .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 . The patients were all adults ranging in age from 27 years to 52 years.

Adrenergic

Fuller et al (1996)6 conducted a small, prospective cohort study involving 16 patients with clozapine-induced . The authors gave the patients (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 , an L-type calcium , 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 (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 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 clozapine- induced 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 , 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. 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/index- eng.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 follow- up 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 . 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/dpd- bdpp/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 5

Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2000705/pdf/bcp0063- 0128.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. 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 clozapine- induced -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

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[Internet]. Ottawa (ON): Health Canada; c2005 - . Available from: http://webprod.hc- sc.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 antidepressant- analgesic. 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.

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APPENDIX 1: Summary of results from individual studies of treatment for clozapine induced enuresis

Author Patients Treatment Clozapine Dosage  Results Fuller et al6 16 Ephedrine Range: 200-700 mg/day  Effective with improvement in 15/16 (25-150 mg/day) Mean: 440 mg/day patients within 24 hours of maximal dose  No adverse events were reported Praharaj et 1 Amitriptyline (25 400 mg/day  Effective with resolution after 4 days 12 al mg HS)  Adverse events were not reported Rocha et 1 Aripiprazole Range: 300-400 mg/day  Effective with improvement after 2 al13 (15 mg/day) months  No adverse events were reported Lee et al14 2 Aripiprazole Range: 200-425 mg/day  Effective with resolution after 1-3 (10 mg/day) months  No adverse events reported Aronowitz et 1 Desmopressin 150 mg/day  Effective with “rapid” resolution 4 al (10 μg/nostril)  Adverse events were not reported Sarma et 1 Desmopressin 700 mg/day  Patient developed severe al15 (10 μg/day) hyponatraemia Lurie et al16 2 Desmopressin Range: 300-900 mg/day  Effective; time to resolution not (dose not reported reported)  Adverse events were not reported Frankenburg 4 Desmopressin Mean: 402 ± 244 mg/day  Effective; time to resolution not et al17 (10 μg/nostril) reported  No adverse events were reported Steingard18 1 Desmopressin 300 mg/day  Effective; time to resolution not (10 μg/nostril) reported  No adverse events were reported English et 1 Tolterodine Range: 250-300 mg/day  Tolterodine was ineffective 19 al (2 mg/week);  Desmopressin was effective with Desmopressin resolution after 2 days (dose not  Adverse events were not reported reported) Lurie et al16 5 Oxybutynin Range: 300-900 mg/day  Effective; time to resolution not (5-15 mg/day) reported  Adverse events were not reported Frankenburg 5 Oxybutynin Mean: 402 ± 244 mg/day  Effective; time to resolution not et al17 (5-15 mg/day) reported  No adverse events were reported Poyurovsky 2 Trihexiphenidyl Range: 300-400 mg/day  Effective; time to resolution not et al20 (5 mg/day) reported  Adverse events were not reported Aggarwal et 1 Trihexiphenidyl 350 mg/day  Effective with resolution after 5 days 21 al (6 mg/day)  No adverse events were reported Pojurovsky 1 Verapamil 150 mg/day  Effective with resolution after 1 day 22 et al (80 mg/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 Kho et al23 1 Switch to 400 mg/day  Effective; time to resolution not olanzapine reported (dose not  Adverse events were not reported reported)

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Author Patients Treatment Clozapine Dosage  Results Frankenburg 1 Alarm clock Mean: 402 ± 244 mg/day  Effective; time to resolution not et al17 reported  Adverse events were not reported

Treatment Options for Clozapine-Induced Enuresis 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 Trade name Dosage Approved Indications Desmopressin DDAVP 10-40 μg/day  Management of sensitive central Spray diabetes insipidus and for the control of temporary and polydipsia following head trauma, hypophysectomy or surgery in the pituitary region.8 Oxybutynin Ditropan 5-30 mg  Indicated for the relief of the symptoms of urge incontinence, urgency and frequency in patients with .10 Tolterodine Detrol 2-4 mg  Symptomatic management of patients with an overactive bladder with symptoms of urinary frequency, urgency, or urge incontinence, or any combination of these symptoms.24 Aripiprazole Abilify 10-30 mg  Treatment of schizophrenia and related psychotic disorders.25  Acute treatment of manic or mixed episodes in .25 Verapamil Covera-HS 180-480 mg/day  Treatment of mild to moderate essential hypertension.26  Treatment of chronic stable angina pectoris.26 Trihexiphenidyl Generics sold 5-15 mg/day  Adjunctive therapy in the symptomatic treatment of in Canada Parkinsonism and drug-induced parkinsonian symptoms.27 Amitriptyline Generics sold 25-300 mg/day  Pharmacologic management of depressive in Canada illness.28

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