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Effects of antidepressant therapy on voiding chart data andnocturnal urine production in children with enuresis – a randomized controlled study
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. (Pediatrisk inflammations- och metabolismforskning samt barnhälsa)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
Division of Child and Adolescent Psychiatry, Department of Clinical Sciences, Umeå University, SE- 901 87 Umeå, Sweden.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. (Pediatrisk inflammations- och metabolismforskning samt barnhälsa)ORCID iD: 0000-0002-4590-4957
(English)Manuscript (preprint) (Other academic)
Abstract [en]

 

Introduction:

Since a substantial minority of enuretic children does not respond to either first- or second-line treatment, there is still need for antidepressants in therapy-resistant enuresis. We recently published the results of a placebo-controlled study of the noradrenergic antidepressant reboxetine in this patient group. The drug was found to have a modest but statistically significant antienuretic effect.

 

Aim:To determine whether reboxetine exerts its antienuretic effect via modulation of either bladder function or nocturnal urine production, as reflected by the voiding chart.

Patients and Methods:The study had a randomized, double-blind cross-over design, with three treatment periods of four weeks each. The therapies given were 1) placebo, 2) reboxetine 4 mg + placebo and 3) reboxetine 4 mg + desmopressin 0.4 mg, all drugs given orally in the evening. During the last two weeks of each treatment period, the families were asked to complete a voiding chart in which day-time voiding frequency and voided volumes were documented during 48 hours. Nocturnal urine production was assessed via weighing of diapers.

 

Results:No clear and consistent reboxetine effects were seen on either voiding parameters or nocturnal urine production. Neither did we find any significant difference in the voiding chart data of responders to active treatment, compared to that of non-responders.

Discussion:This observation may have several different, non-exclusive explanations, one of which is that the anti-enuretic action of reboxetine is explained by the drug’s noradrenergic effects on arousal. It may also be the case that the voiding chart is too blunt an instrument to detect nocturnal, or indeed daytime, detrusor overactivity. It is thus not ascertained that the lack of reboxetine influence on the bladder variables actually precludes that the drug can affect detrusor function. The lack of difference in nocturnal urine production between treatment  periods with and without desmopressin may indicate that nocturnal polyuria is of minor importance in therapy-resistant enuresis.

Finally, it may obviously be the case that the number of patients was too small, since the power calculations underlying the determination of sample size in this study were made based on treatment response, not voiding chart variables.

Conclusion:In this randomized, placebo-controlled study we found no effect on daytime voiding parameters or nocturnal urine production that can explain the antienuretic effect of reboxetine. This may indicate that the drug exerts its beneficial effects via noradrenergic modulation of arousal.

Keywords [en]
Nocturnal enuresis, voiding chart, reboxetine, antidepressants, desmopressin
National Category
Medical and Health Sciences
Research subject
Pediatrics
Identifiers
URN: urn:nbn:se:uu:diva-389833OAI: oai:DiVA.org:uu-389833DiVA, id: diva2:1339386
Available from: 2019-07-29 Created: 2019-07-29 Last updated: 2019-08-15Bibliographically approved
In thesis
1. Therapy-resistant enuresis: In search of new therapies and prognostic markers
Open this publication in new window or tab >>Therapy-resistant enuresis: In search of new therapies and prognostic markers
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

A large minority of children with enuresis do not respond to treatment with either desmopressin or the enuresis alarm. Anticholinergics have not proven as successful as expected. The fourth evidence-based treatment of enuresis, the tricyclic antidepressant imipramine, is cardiotoxic when overdosed, which has led to diminished use. Since the long-term consequences of enuresis are potentially grave it is important that effective treatments of therapy-resistant enuresis are found.

When investigating the enuretic child a full voiding-chart - in addition to the case history - is the method of choice. However, there is no robust evidence that daytime voiding chart data actually do predict nocturnal detrusor function.

The aim of this thesis was to determine whether there is a role for the noradrenergic antidepressant reboxetine in the treatment of therapy-resistant enuresis, and whether anamnestic data and the voiding chart provides prognostic information regarding response to treatment with anticholinergics and antidepressants respectively in therapy-resistant patients.

In a retrospective evaluation of 61 children who for humanitarian purposes had been treated with reboxetine 32(52%) responded to this treatment, 21 of them after desmopressin had been added. We then proceeded with a randomized placebo-controlled study with 18 patients, in which the reduction of wet nights was much better with either reboxetine in monotherapy or in combination with desmopressin than during the placebo period (p=0.002). However, no patient achieved complete dryness. No prognostic markers for therapy-response were found in either of these studies.

In the randomized study we also sought to investigate whether reboxetine had any statistically significant effect on voiding-chart data. No such effect was found, but in respect to this secondary aim the sample size was too small. Nonetheless , this led to the speculation whether reboxetine exerts its antienuretic effect via modulation of arousal mechanisms.

Prognostic markers were sought in a retrospective evaluation of 154 patients treated with anticholinergics or antidepressants, but few and inconsistent differences were found between the groups responding or not responding to the various treatment regimens, and this was true both for anamnestic and voiding chart data.

In conclusion reboxetine seems to be an alternative in the treatment of enuretic children who have not responded to standard treatment, but further trials with higher doses and larger study populations are needed. The internationally recommended assessment of children with therapy-resistant enuresis does not seem to give the prognostic information intended.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2019. p. 60
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1584
Keywords
Nocturnal enuresis, Reboxetine, Antidepressants, Desmopressin, Voiding chart
National Category
Medical and Health Sciences
Research subject
Pediatrics
Identifiers
urn:nbn:se:uu:diva-389838 (URN)978-91-513-0701-5 (ISBN)
Public defence
2019-10-04, Enghoff-salen, Akademiska Sjukhuset, Ing 50 bv, Uppsala, 13:15 (Swedish)
Opponent
Supervisors
Available from: 2019-09-12 Created: 2019-07-29 Last updated: 2019-10-15

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Lundmark, ElisabetStenberg, ArneNevéus, Tryggve

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