1114 | Use of Desipramine for the Treatment of Overactive Bladder Refractory to Antimuscarinic Therapy Joel H. Hillelsohn, Soroush Rais-Bahrami, Neeti Bagadiya, Mahyar Kashan, Gary H. Weiss Corresponding author: Joel H Hillelsohn, BA The Arthur Smith Institute for Urology, Hofstra North Shore-LIJ School of Medicine, 450 Lakeville Rd, Suite M-41, New Hyde Park, NY 11040, USA. Tel: +1 516 734 8500 Fax: +1 516 734 8537 E-mail: Jhillelsohn@gmail.com Received September 2012 Accepted January 2013 Hofstra North Shore-LIJ School of Medicine, The Arthur Smith Institute for Urology, New Hyde Park, NY, 11042, USA. MISCELLANEOUS Purpose: To evaluate the use of desipramine in the treatment of overactive bladder (OAB). Materials and Methods: We retrospectively evaluated 43 patients who were treated with desipramine for OAB refractory to antimuscarinic therapy. These OAB patients were strati- fied by the presence or absence of bladder pain. Results: Forty-three patients were evaluated with a mean follow up time of 12.2 ± 4.6 months. The mean age of the patients was 71 ± 16 years. Twelve patients (28%) discontinued desip- ramine, 9 due to perceived lack of efficacy, 2 due to central anticholinergic side effects, and 1 due to the development of oropharyngeal sores. Patients were stratified into two subgroups based upon treatment with desipramine for OAB alone (n = 29) or OAB and bladder pain (n = 14). There was no difference between the groups in regard to sex (P = .34), prior history of radiation (P = .19), side effects (P = .16), and specifically evaluated central anti-cholinergic side effects (P = .66). There was no statistical difference in the self-reported success rate of the medication (P = .48). In the OAB plus bladder pain subgroup, 71% of patients reported improvement in their pain. Overall, 13 (30%) patients had history of prior pelvic radiation and 10 of those (77%) reported improvement with desipramine. Conclusion: Desipramine is a potential useful treatment for patients with OAB. In addition, it can be used in patients with OAB and bladder pain and patients with complex OAB such as OAB caused by pelvic radiation. Keywords: urinary incontinence, urge; cholinergic antagonists; drug therapy; antidepressive agents, tricyclic; treatment outcome. Miscellaneous 1115Vol. 10 | No. 4 | Autumn 2013 |U R O LO G Y J O U R N A L INTRODUCTION Overactive bladder (OAB) is a condition character-ized by increased urinary urgency, with or without incontinence.(1) Its prevalence has been estimated to range between 11.8% and 14%, slightly lower in men than in women.(2,3) This symptom profile has been shown in several studies to increase with age.(2,4,5) The incidence in- creases from 10.5% for patients aged 18-24, up to 21.9% for those aged greater than 65 years.(3) In elderly patients who fail conservative treatments for OAB, pharmacologic man- agement can be challenging.(6) Traditionally, anticholinergic agents such as oxybutynin are used as a first-line pharma- cologic treatment.(7) If the patient symptoms are refractory to treatment with traditional first-line anticholinergic agents, tricyclic antidepressants (TCAs) such as amitriptyline and imipramine can be prescribed. However, a limitation of all anticholinergic agents on the market is their lack of specific- ity for muscarinic receptors of the bladder. As a result, cen- tral anticholinergic side-effects including memory defects, fatigue, and impaired balance can often be experienced.(6) Furthermore; elderly patients are particularly vulnerable to these side-effects associated with the central anticholinergic effects of TCAs. This is due in part to an increased anticho- linergic load, polypharmacy, a natural age-related decline in cholinergic function, and declining function of the blood brain barrier.(6) Desipramine is an active metabolite of imipramine. It is dis- tinguished by the presence of only one n-methyl group on its side chain.(7) It has been shown in several studies to have less central nervous system (CNS) side effects than other TCA agents including imipramine and amitriptyline.(7-9) No published study has evaluated the use of desipramine as a treatment for OAB. Herein, we report on our experience with desipramine for the primary treatment of symptomatic OAB with the goal of minimizing CNS-related side-effects. MATERIALS AND METHODS Data Collection Data was prospectively collected on patients that were pre- scribed desipramine by a single physician (GHW) for the second-line treatment of OAB over a two year period span- ning between 2010 and 2011. Diagnosis of OAB was based upon established AUA guidelines.(10) Patients were informed about the off-label use of desipramine for this purpose. An inclusion criterion was OAB refractory to prior anticholin- ergic treatment. Patient demographics, clinical characteris- tics, and patient-reported outcomes, and side-effect profiles while taking desipramine were retrospectively reviewed. Pa- tients were followed serially at monthly visits to assess the therapeutic effects as well as side effects of the medication regimen. Data collection and analysis for this study was ap- proved by the Institutional Review Board (IRB) and all pa- tient data was stored in a secure patient de-identified database in accordance with the IRB approval. Statistical Analyses All statistical analyses were conducted on Microsoft Excel 2007 platform. Continuous and categorical variables were analyzed using Mann-Whitney U test and Chi-Squared test, respectively. RESULTS Forty-three patients were evaluated who were prescribed desipramine after failing treatment with at least one anti- muscarinic agent. Failure from an antimuscarinic agent was determined through chart review. The initial dosing of all pa- tients was 10 mg. The range of final dosing was 10 mg to 75 mg. Two patients (5%) dosages were raised to 25 mg, 3 (7%) to 50 mg and 1 (2%) to 75 mg. Their dosages were raised based on clinical evaluation of patient self-reported symptom benefit and side effects. The mean age of the patients was 71 ± 16 years (Table 1). Twenty-three patients (53%) were male and 20 (47%) were female. Overall, 13 (30%) patients had history of prior pelvic radiation and 10 of those (77%) re- ported improvement with desipramine. Thirty-one (72%) of the original 43 patients continue to take desipramine as pre- scribed at a mean follow up of 12.2 ± 4.6 months, reporting clinical benefit and improvement of their OAB symptoms. Twelve patients (28%) discontinued desipramine, 9 (75%) due to perceived lack of efficacy, 2 (17%) due to central an- ticholinergic side effects, and 1 (8%) due to the development of oropharyngeal sores. The average duration of compliant use of the medication in these patients who discontinued use was calculated at 6 ± 3.4 months. Overall, 12 patients Use of Desipramine for Overactive Bladder | Hillelsohn et al 1116 | reported side effects from the medication, the most common being dry mouth (n = 5, 42%), constipation (n = 2, 17%), and fatigue (n = 3, 25%). Furthermore, patients were stratified into two subgroups based upon desipramine treatment for OAB alone (n = 29) or OAB combined with bladder pain (n = 14) (Table 2). There was no difference noted between the groups in regard to sex (P = .34), prior history of pelvic radiation (P = .19), side ef- fects (P = .16), and specifically assessed central anticholin- ergic side effects (P = .66). However, the OAB plus bladder pain group was significantly older (P = .05). There was no statistical difference in the self-reported success rate of the medication (P = .48). In the OAB plus bladder pain group 10 (71%) patients reported improvement in their pain in addi- tion to OAB symptoms. DISCUSSION CNS side effects from treatment with anti-muscarinic agents include headache, fatigue, dizziness, cognitive impairment, confusion, and insomnia.(11) TCAs have similar side-effects due to their adjunct anticholinergic properties.(11-13) More el- derly patients are more likely to suffer from OAB and are also more likely to experience anticholinergic side-effects from the medications used to treat their symptoms.(12) This increased risk is commonly attributed, at least in part, to polypharmacy which is more prevalent in this population with more comorbidity. Gardner and colleagues estimated that between 21% and 32% of nursing home residents are simultaneously prescribed two or more medications with an- ticholinergic activity.(3,13) In addition, the elderly may have diminished efficiency of drug metabolism and elimination, leading to an increased anticholinergic “load” effectively.(14) Delirium can be caused by blockage of brain muscarinic re- ceptors and drugs with anticholinergic activity are the most common cause of drug-induced delirium.(15,16) Among the TCA agents, desipramine has been noted to have the least anticholinergic affect.(15) In initial clinical trials, it was noted to have less CNS side effects when compared to imipramine.(9) These findings were corroborated in two sub- sequent studies.(7,11) A randomized control trial of 20 patients comparing imipramine and desipramine use for the treatment of major depression, found that although desipramine was not superior to imipramine in its treatment of depression symptoms, it is less likely to produce central anticholinergic side effects such as headache, tremors, and dizziness.(10) Di Mascio and colleagues enrolled 7 blinded subjects who were given either a dose of imipramine (50 mg, 100 mg or 200 mg) desipramine (50 mg, 100 mg, and 200 mg) or a placebo. Subjects were then tested performing various cognitive and visou- motor tasks such as typing, aiming and performing calculations. They found that imipramine produced marked impairment in intellectual and visuo-motor function in com- parison to desipramine.(7) Desipramine has also been compared to amitriptyline in head- to-head investigation. In a double blinded crossover study by Blackwell and colleagues, nine healthy female volunteers Table 1. Baseline characteristics of patients prescribed desipramine for overactive bladder. Patients Number 43 Male 23 Female 20 Age ± SD, years 71 ± 16 Side effects, n (%) 12 (28) Central anticholinergic side effects, n (%) 7 (16) Prior pelvic radiation, n (%) 13 (30) Patients doing well on medication, n (%) 31 (72) Key: SD, standard deviation. Table 2. Comparison of patients prescribed desipramine for overactive bladder only and for overactive bladder plus bladder pain. OAB Only OAB and Bladder Pain P Number 29 14 - Male 18 5 .19 Female 11 9 Age ± SD, years 68.4 ± 18.0 76.7 ± 8.5 .05 Side effects, n (%) 6 (21%) 6 (43) .16 Central anticholinergic side ef- fects, n (%) 4 (14) 3 (21) .66 With prior pelvic radiation, n (%) 9 (31.0) 4 (28.6) .34 Patients doing well on medica- tion, n (%) 22 (75.8) 9 (64.3) .48 Key: SD, standard deviation; OAB, overactive bladder. Miscellaneous 1117Vol. 10 | No. 4 | Autumn 2013 |U R O LO G Y J O U R N A L Use of Desipramine for Overactive Bladder | Hillelsohn et al were given three different doses of desipramine (25 mg, 50 mg, and 100 mg), three different doses of amitriptyline (25 mg, 50 mg, and 100 mg) and placebo. The patients then were asked to rate their sedation on Clyde Mood Scale. Amitrip- tyline was noted to produce more sedation at all levels and was clinically significant at 50 mg (P < .01).(8) In a study of pigeons by Vaillant, the central anticholinergic effects of desipramine, amitriptyline and imipramine were assessed by measuring their ability to mask the central muscarinic ef- fects of physostigmine.(17) Desipramine was found to be the least effective in CNS function of the TCAs tested, requir- ing the highest dose to reverse the central muscarinic activity of physostigmine. Furthermore, in a study by Abernethy and colleagues, metabolic clearance of desipramine was found to be less affected by increasing age than that of imipramine.(18) In consideration of its decreased central anticholinergic ac- tivity, we sought to report on the use of desipramine for pa- tients with OAB refractory to treatment with first-line anti- muscarinic agents. To our knowledge this is the first study reporting on the use of desipramine for OAB. Our results indicate that it is well tolerated in a population of patient’s refractory to antimuscarinic therapy. Also significant was that 77% of patients with prior history of pelvic radiation reported improved symptoms following desipramine treatment, as this population can be difficult to treat.(21) Furthermore, only two patients discontinued the medication due to central anticho- linergic side-effects and the vast majority (72%) reported im- provement on the prescribed therapy with desipramine. Patients with bladder pain and OAB can be difficult to man- age, since many of them can fall into the Interstitial Cystitis/ Bladder Pain Syndrome (IC/BPS) spectrum.(19) For IC/BPS patients’ amitriptyline has been the most extensively TCA agent studied. In a large double blinded randomized control trial by Foster and colleagues comparing behavior modifica- tion and education with and without amitriptyline, they found that patients who could tolerate a low dosing (25 mg) had sig- nificant benefit from the drug.(20) Desipramine has also been studied in the setting of IC/PBS. Renshaw reported on the successful use of desipramine in a single patient.(21) In our study we reported 71% of patients subjectively reported an improvement in their bladder pain. Our study is limited by its retrospective nature and single- arm design which cannot fully access the comparative effi- cacy of desipramine as a single-agent treatment modality for OAB. Future, prospective randomized studies are needed on this topic to fully elucidate the utility and side-effect profile of desipramine over other agents as a treatment option for OAB. CONCLUSION Our experience to date has demonstrated desipramine as a useful potential treatment for patients with OAB refractory to first-line antimuscarinic therapy, possibly providing an alter- native treatment modality with a mechanistically minimized risk of CNS side-effects compared to other TCAs. CONFLICT OF INTEREST None declared. REFERENCES 1. Van Kerrebroeck P, Abrams P, Chaikin D, et al. The standardi- zation of terminology in nocturia: report from the stand- ardization subcommittee of the International Continence Society. BJU Int. 2002;90:11-5. 2. Irwin DE, Milsom I, Hunskaar S, et al. Population-based sur- vey of urinary incontinence, overactive bladder, and other lower urinary tract symptoms in five countries: results of the EPIC study. Eur Urol. 2006;50:1306-14. 3. Herschorn S, Gajewski J, Schulz J, Corcos J. A population- based study of urinary symptoms and incontinence: the Ca- nadian Urinary Bladder Survey. BJU Int. 2008;101:52-8. 4. 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