Bladder dysfunction and behavioural disorders in children are commonly concomitant; hence, it is difficult to treat each in isolation. Pharmacotherapy is common treatment for behavioural disorders, and these medications may have intended or unintended positive or negative bladder sequelae. This review identifies the literature regarding the effects of behavioural pharmacotherapy on bladder functioning and possible bladder management strategies in children with concomitant behaviour and bladder disorders to enable clinicians to better manage both conditions. A PROSPERO registered PRISMA-guided review of three major databases was performed. After an initial scoping study revealed significant heterogeneity, a narrative approach was undertaken to discuss the results of all relevant cases relating to children being treated with pharmacotherapy for behaviour disorders and outcomes related to bladder function. Studies were screened to identify those that described effects of commonly prescribed medications in children with behavioural disorders such as stimulants, alpha 2 agonists, tricyclic antidepressants (TCA), serotonin and noradrenergic reuptake inhibitors (SNRI), selective serotonin reuptake inhibitors (SSRI) and antipsychotics, and the findings and implications were summarised. The review identified 46 studies relevant to behavioural pharmacotherapy and bladder function (stimulants (n = 9), alpha 2 agonists (n = 2), TCAs (n = 7), SNRIs (n = 8), SSRIs (n = 8) and antipsychotics (n = 6). Six studies focused specifically on bladder management in children with behavioural disorders with concurrent behavioural pharmacotherapy. This review identifies useful factors that may assist clinicians with predicting unintended bladder effects following initiation of behavioural pharmacotherapy to facilitate the best approach to the treatment of bladder dysfunction in children with behavioural disorders. With this evidence, we have provided a useful decision-making algorithm to aide clinicians in the management of these dual pathologies.
Behavioural disorders are highly prevalent and are one of the most commonly treated conditions of childhood [1, 2], and include Attention-deficit hyperactivity disorder (ADHD), Autism spectrum disorder (ASD), Oppositional defiance disorder (ODD) and Anxiety. Children with behavioural disorders, particularly autism, often experience delay in reaching developmental milestones, including difficulty in achieving day and night continence [3, 4]. Children with behavioural disorders are known to have increased incidence of urinary symptoms due to bladder dysfunction [5, 6]. It is estimated that 2–7% of school-aged children are diagnosed with ADHD  with lesser percentages for other disorders such as ASD, ODD and non-psychiatric anxiety-related disorders. In 2014, it was estimated that 314,000 (14%) children in Australia were affected by behavioural or mental health conditions .
Patients with a diagnosed behavioural disorder often have other disorders related to global development. Hence, there are a disproportionate number of children with behavioural disorders who also experience urinary incontinence [6, 8,9,10,11,12] in addition to other developmental problems such as faecal incontinence and learning delays. There is limited literature to clarify whether there is a cause–effect relationship between behavioural disorders and bladder dysfunction in children. Depending on the severity of their behavioural symptoms, children may require medications to manage the behavioural disorder. While the nature of the correlation between behavioural disorders and bladder dysfunction is unclear, it may be that they share a central cause with the effect of inattention or lack of focus and thus intentional behavioural disruption; leading to the theory that appropriate treatment of the behavioural disorder will assist in management of bladder dysfunction . A wide range of medications, particularly those used for behavioural management, are known to have effects on the urinary bladder and urinary symptoms . In ADHD management, it is estimated that 6.1% of children are prescribed medications and this number is 30.3% in Autism . Often children will require multiple medications to manage their behaviours, in addition to non-pharmacological treatments. There is paucity of high-quality data on the impact of behavioural disorders and their associated medical therapies on bladder function and management and the efficacy of treatment of bladder dysfunction in children with comorbid behavioural disorders . Therefore, in this wide-scoped, sensitive search enabled narrative review, we sought to identify pertinent literature related to the effects of behavioural pharmacotherapy on bladder functioning specifically and effective management strategies for bladder dysfunction in children with behavioural disorders.
We performed a review using PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines. The review protocol has been registered with PROSPERO (CRD42018094062). Relevant studies included in this review were case reports, case series, cohort studies, case-controlled studies, randomised controlled trials and quasi-randomised studies. An initial scoping search suggested that the available studies were too heterogenous to perform a conventional systematic review; hence, a narrative approach was undertaken.
Eligible studies had participants that were children aged 5–18 years with an identified behavioural disorder that affects functioning as per DSM Axis II disorders (i.e., pervasive behavioural disorders), including Autism Spectrum Disorder (ASD), Attention-deficit/hyperactivity disorder (ADHD), Oppositional Defiance Disorder (ODD), Conduct disorder and Anxiety-related disorders (without Depressive symptoms) that are often highly comorbid with other behavioural disorders. For eligibility, children had to be treated with a medication for management of their behavioural disorder. Comparison groups included children who do not take medication or children as cross-over comparison (pre or post medical treatment of behaviour), children taking placebo or children taking other medications. Systematic reviews were excluded from this analysis.
An electronic search using the EMBASE (1996–2018), MEDLINE (1996–2018), PUBMED and PSYCHINFO (2002–2018) databases to identify studies using appropriately selected search terms was performed (see appendix 1).
The search identified 2239 studies with 46 found to be eligible for full-text review (see appendix 2 for PRISMA search flowchart). The majority of studies were case reports (n = 15) and cohort studies (n = 15) with some case series (n = 8) and randomised controlled trials (n = 8).
Nine studies looked at the effect of stimulants on bladder dysfunction. Two studies looked at the use of alpha agonists. Seven studies examined the use of tricyclic antidepressants (TCAs) in bladder and behaviour. Eight studies have looked at Serotonin and noradrenergic reuptake inhibitors (SNRIs) for bladder treatment, four for nocturnal enuresis and four for stress incontinence. Eight studies looked at selective serotonin reuptake inhibitors (SSRIs) and bladder effects. Six studies looked at the effects of antipsychotics. The remaining six studies look at varied strategies for managing comorbid behaviour and bladder disorders.
Medications and known bladder effects
Pharmacological agents are not without unintended side-effects and of particular interest to us is the effect of these agents (intended and unintended) on bladder function in children (see Table 1). We posed a series of clinically relevant questions to frame the discussion regarding the effects of these agents on bladder function.
Is there evidence that pharmacotherapy to primarily treat behavioural disorders may show benefit in aspects of bladder dysfunction?
Stimulants and effects on bladder function
Stimulants include such medications as methylphenidate, lisdexamfetamine, guanfacine and dextroamphetamine, with predominant use as a first-line medical therapy in ADHD. Two case series [18, 19] looked at the use of stimulants and resolution of nocturnal enuresis (NE) in children with ADHD. Williamson  reported on 3 children aged 9, 11 and 15 treated with 3 different stimulants and nocturnal enuresis resolved immediately after starting stimulants. In one child, symptoms recurred when stimulant treatment was ceased.  The hypothesis proposed by these authors was that stimulants might decrease sleep arousal threshold allowing children to awaken and exert continence control. Ferrara  also found nocturnal enuresis was adequately treated in six out of nine children with concurrent ADHD and nocturnal enuresis once methylphenidate was started or the dosage was increased. Bahali  reported a case of a 7-year-old girl where nocturnal enuresis resolved with stimulant treatment though atomoxetine, a noradrenaline reuptake inhibitor, prescribed to help moderate her ADHD symptoms.
In slightly contrary findings, Ferrara et al.  reported that nine children with ADHD and nocturnal enuresis responded well to increasing doses of methylphenidate alone to treat both disorders, while desmopressin was not effective in treating those children who were not medically treated for ADHD.
In summary, the studies supporting stimulants as a sole treatment for nocturnal enuresis are only case series with small numbers, but they do suggest that stimulants play a role. Bigger studies suggest a role for stimulants in helping responsiveness to other treatments for bladder disorders. In DUI, there was no evidence that stimulants alone improve symptoms, but there was good response to other bladder treatments for nocturnal enuresis, particularly desmopressin, especially if behaviours were pharmacologically treated with stimulants.
Clonidine and effects on bladder function
Clonidine is an alpha-2 agonist also used routinely to augment the treatment for ADHD as a second-line therapy. While its mechanism of action is unknown, it is thought to aide in improving attention and behaviour via increased sympathetic flow to the prefrontal cortex and possibly by improving the hypothalamus–pituitary axis in conjunction with stress hormones to improve attention and memory . However, there is one study that focussed on the use of clonidine primarily on bladder management, and Ohtomo  found that clonidine was partially or completely effective in 56.1% of 148 children with nocturnal enuresis (both monosymptomatic and non-monosymptomatic) refractory to desmopressin, anticholinergics and alarm therapy. It is unclear if these children had comorbid behavioural disorders. A similar class of alpha agonist known as tizanidine (not used in behavioural management but has been trialled for nocturnal enuresis) found improvement in day- and night-time incontinence frequency as well as urgency symptoms and patient satisfaction .
In summary, there is limited evidence to support the role of alpha agonists in bladder dysfunction management, though the results from two studies appear to suggest a benefit from alpha 2 agonists in refractory nocturnal enuresis and diurnal incontinence.
Serotonin and noradrenergic reuptake inhibitors (SNRIs) and effects on bladder function
Serotonin and/or noradrenaline reuptake inhibitors (SNRIs) such as atomoxetine are used in the treatment of ADHD as well as anxiety/depression and autism, and there have been some anti-enuretic effects noted in studies . In children with nocturnal enuresis and ADHD, the use of atomoxetine in combination with other medications was effective in a 4-child case series . A randomised-control trial of 87 children with nocturnal enuresis and ADHD treated with atomoxetine (mean age 10.2 years) found a significant reduction in wet nights . Atomoxetine was found to be superior to placebo in reducing the number of wet nights per week with 10 of 44 atomoxetine-treated and 17 of 43 placebo-treated children having ADHD. Ohtomo  found that atomoxetine was able to lead to statistically significant reductions in number of wet nights per month in 19 out of 24 children with combined ADHD and nocturnal enuresis who did not respond to alarm, anticholinergics or desmopressin, suggesting that behaviour preferably needs to be treated prior to bladder treatment. Reboxetine has been found to have good effect in combination with desmopressin for treating nocturnal enuresis without the cardiotoxicity of imipramine . In this study, 10 (22.7%) of the test subjects and 17 (39.5%) of the placebo subjects were found to have ADHD . Ghanizadeh  conducted an RCT with 43 children with comorbid ADHD and nocturnal enuresis, and found that treatment with methylphenidate and nortriptyline was superior to methylphenidate and placebo in reducing nocturnal enuresis events, but there was notable relapse of symptoms once treatment was withdrawn. Increased sphincter tone may have led to the reported urinary retention in one case of an 8-year-old child treated with atomoxetine with ADHD . It is thought the mechanism of action of SNRIs is inhibiting reuptake of serotonin and norepinephrine in the presynaptic neuron in Onuf’s nucleus in the sacral spinal cord, which leads to relaxation of the urinary bladder and increased tone in the urethral sphincters .
In summary, the evidence for use of SNRIs in nocturnal enuresis and stress incontinence is strong, with several large RCTS and other small studies supporting its ability to improve symptoms with or without other bladder specific therapy.
Is there evidence that pharmacotherapy to primarily treat behavioural disorders may have negative effects on aspects of bladder dysfunction?
Selective serotonin reuptake inhibitors (SSRIs) and effects on bladder function
Selective serotonin reuptake inhibitors (SSRIs) are predominantly for the management of anxiety/depression and can augment treatments for other behavioural disorders. They are thought to work on the bladder via the 5HT4 receptors which can potentiate the cholinergic receptors on the bladder leading to increased activity of the detrusor muscle [45, 46]. In a large population study of medication use and associated urinary incontinence in 21 735 Norwegian women , a strong association was found for developing incontinence from the use of SSRIs. This was also found in a Dutch study of 13,531 SSRI users demonstrating a risk ratio 1.75 for developing DUI when taking an SSRI . In a case series of 3 children with anxiety and/or depression, sertraline lead to urinary symptoms with the change to fluoxetine resolving the symptoms in one case . This change from sertraline to fluoxetine and resolution of urinary symptoms was also noted in a case reported by Maalouf . Mahdavi-Zafarghandi  found a good response to sertraline in a cohort of 25 adolescents with nocturnal enuresis who failed treatment with desmopressin, with 12 children having full response to sertraline and 6 children having a partial response, though it is unclear if these children had comorbid behavioural disorders.
On the other hand, SSRIs were trialled as a treatment in a cohort of nine children with no significant anti-enuretic effect noted . In a smaller case series of 3 children , SSRIs were found to lead to nocturnal enuresis. Kano  used urinary 17-hydroxycorticosteroids (17-OHCS) and 17-ketosteroid sulfates (17-KS-S) as a stress barometer, and found that it helped to predict which children with nocturnal enuresis would respond to fluvoxamine as a treatment for their nocturnal enuresis as those with higher levels of stress responded more favourably to fluvoxamine.
In summary, SSRIS appear to have negative effect on bladder function and increase the risk of nocturnal enuresis in large population studies, though some small studies have found it may help and changing to other SSRIs can reverse new-onset nocturnal enuresis. Hence, the evidence regarding SSRIs and bladder dysfunction remains unclear.
Antipsychotics and effects on bladder function
Antipsychotics are prescribed in just under a third of patients with autism but may also be prescribed in other disorders such as conduct disorder or ODD to manage aggressive behaviours . There are many case reports and series on the impact of antipsychotics in children and bladder function. It is thought that antipsychotics work through the dopaminergic pathway to control the micturition reflex centrally [50, 51], and also, dopamine can activate alpha-1-adrenergic receptors to increase urethral sphincter tone and improve bladder emptying via these receptors  and 5-HT1A receptors in the bladder . If too much bladder relaxation and increased urethral tone occur, micturition difficulty and even urinary retention may become an issue .
Cop  reported a case of urinary and faecal incontinence in a child with autism taking risperidone even at low doses of 0.25 mg/day with resolution of symptoms when the medication was ceased and no symptoms on olanzapine 5 mg/day. This was thought to be due to the alpha antagonistic effect of risperidone on the urethral and anal sphincters. Herguner  reported two similar cases in autistic children with nocturnal enuresis with symptoms resolving on cessation of risperidone and commencement of olanzapine. Dikshit  reported a case of conduct disorder treated with risperidone where nocturnal enuresis developed, but did not recur with the use of aripiprazole. Kantrowitz  reported three cases of risperidone-induced nocturnal enuresis. However, Bozkurt  noted aripiprazole induced nocturnal enuresis in a 16-year-old male with autism and epilepsy. However, in a 9-year-old boy with intellectual disability and nocturnal enuresis who previously been trialled on multiple antipsychotics, it was noted that starting aripiprazole leads to a cessation of symptoms .
In summary, there are many small case reports and series regarding antipsychotics and new onset of incontinence and nocturnal enuresis. While these are small studies, with reversal of symptoms with cessation of medications and overall poor association in all these studies, the evidence suggests a negative effect of antipsychotics on bladder function.
Is there evidence that pharmacotherapy to primarily treat bladder dysfunction may have a beneficial effect on behavioural disorders?
Tricyclic antidepressants (TCAs) and effects on bladder function
Although tricyclic antidepressants (TCAs) are third-line therapy for nocturnal enuresis, there are reports that there are good behavioural side-effects in children who take imipramine, making them calmer and more focused [33, 54]. Similar effects were noted for those taking reboxetine . It is thought that the bladder effects of TCAs are due to their direct anticholinergic effects on the bladder detrusor . Desipramine has been shown to have some effectivity in both overactive bladder and in ADHD treatment [30, 31]. Imipramine has been used as a third-line therapy for nocturnal enuresis for some time. A study by Gepertz  found 64.6% of children with nocturnal enuresis refractory to other treatments responded well to imipramine and seven children that had concurrent ADHD had a good behavioural response, as well. Imipramine was found to be effective in resolving risperidone-induced nocturnal enuresis in one study .
In summary, there is large-volume good-quality evidence, including a Cochrane review [Caldwell 2016] for the use of TCA in managing nocturnal enuresis, and it is already a recommended third-line treatment. Our review suggests that there may be beneficial effects on behavioural disorders, as well.
Is there evidence that pharmacotherapy to primarily treat bladder dysfunction may have a negative effect on behavioural disorders?
Desmopressin and anticholinergics
Desmopressin was found to aggravate ADHD symptoms with aggression noted to be a side-effect in 4% of 399 children in a Swedish trial . This has been noted in other studies  and anticholinergics can also evoke hyperactivity and attention problems.
Is there evidence that pre-treatment of behavioural disorders gives better results for bladder dysfunction treatment and what other factors impact effectiveness of non-pharmacological or first-line nocturnal enuresis treatment strategies in children concomitant behaviour and bladder issues?
Importance of pre-treating behaviour before bladder treatment and consideration of multimodal therapy
In a review of treatments for day-time and night-time wetting, von Gontard  suggests that behaviours need to be treated prior to instituting bladder treatments due to needing cooperation and compliance as well as the improved attention, focus and awareness on the treatment and its outcomes. In a conference abstract, Giuseppe  demonstrated a response to urotherapy in 6 children with autism; however, it is not specified if pharmacologically treated or what the response was. Hence, there are sparsity of data regarding the efficacy of urotherapy in this group and treatment response in general. An additional question is whether PMFT and timed voiding with watch to improve efficacy of urotherapy as demonstrated in other groups [58, 59], but further bladder behavioural treatments may not work in children with behavioural disorder given previous treatment response to bladder behavioural treatments such as alarm therapy . A study by Eliezer et al.  suggested that urotherapy in a treated cohort of children with behavioural disorders, and improvement would be most noted in the children with day-time incontinence and bladder–bowel dysfunction particularly.
In many cases, simply treating ADHD with medications such as stimulants may resolve nocturnal enuresis . In a study of 75 children with ADHD and incontinence (60 were on medication), all children had DUI, 87% had nocturnal enuresis and 88% had frequency . Treatment was successful in 83.9% with a mixture of behavioural, anticholinergics and biofeedback. However, behavioural treatment alone was only effective (partial or complete resolution) in 11 of 56 (19.6%) of children who completed the study. The treatment success rate of monotherapy in nocturnal enuresis in this cohort is lower (23–60%) with a higher relapse rate than in children without behavioural or psychological disorders [64,65,66,67,68].
Chertin  performed a randomised-control trial with 54 children comparing imipramine to oxybutynin combined with desmopressin for treatment of nocturnal enuresis. In both groups, 23 of 27 children were on methylphenidate. They started all children on urotherapy and used adherence to this as an inclusion criteria for the study. While they stated that the response to this behavioural program was insignificant, the exact results were not reported. The study found that the combination treatment had a significant reduction in dysfunction voiding symptoms scoring and incidence of nocturnal enuresis which was superior to imipramine alone. Gor  performed a retrospective review of the efficacy of desmopressin and or anticholinergic in treating nocturnal enuresis in ADHD or Autism and found that they were as effective these children with behavioural disorders as in those without behavioural disorder.
Effectiveness of urotherapy
Urotherapy has good effect in day-time incontinence and moderate effect in nocturnal enuresis [62,63,64,65,66,67,68,69,70]. For over 50% of children with bladder bowel dysfunction, symptoms will settle with urotherapy which includes adequate fluid intake and constipation management. However, biofeedback or pharmacological agents may be required such as anticholinergics or alpha blockers . In children with behavioural disorders, the ongoing use of antipsychotics in those with bladder bowel dysfunction and autism makes treatment difficult . Additionally, it is unclear what the response to urotherapy would be without treating behaviour first, though a study by von Gontard [von Gontard 2019]  suggests that this would be difficult. A recent prospective study (DABBED) by several of this review’s authors  found urotherapy to be an effective treatment for children with medically treated behavioural disorders particularly day-time or bladder bowel dysfunction. However, response to urotherapy was poor in those with nocturnal enuresis, particularly non-monosymptomatic nocturnal enuresis, even after adjunctive therapies were added. In children with bladder disorders, bladder capacity and minimal voids/day predict good response to urotherapy. These results are not specific or have subgroup analysis data available for children with behavioural disorders and so generalisability is poor.
Effectiveness of bladder treatment adjuncts in behavioural disorders
Kovacevic  found that pharmacological intervention for nocturnal enuresis with desmopressin and/or anticholinergics was much more effective than bladder behavioural treatment alone in children with ADHD (p = 0.012). In addition, whether or not the child was on stimulant medications for ADHD did not affect the good response to pharmacological treatment for nocturnal enuresis. This suggests that early pharmacological treatment for nocturnal enuresis is more effective than behavioural modification in children with ADHD. A similar finding was reported by Yang  with the use of desmopressin in ADHD and non-ADHD children with nocturnal enuresis.
Compliance and adherence to treatment
Treatment of bladder dysfunction is more difficult in children with ADHD. In one study of 113 children with ADHD and nocturnal enuresis, ADHD children treated with alarms were only dry in 19% at 12 months compared to 66% of controls , and there was no difference if they were treated with medication (Desmopressin). However, non-compliance was noted in 38% of children with ADHD compared to 22% of controls . Similarly day-time wetting resolved in 68% of children with ADHD compared to 91% of controls . Once again, non-compliance was a major factor in timed voiding as a treatment with 48% of children with ADHD not adhering to treatment compared to 14% of those without ADHD. Adherence is a significant issue with adherence to urotherapy and medications found to be 70% for nocturnal enuresis in the general population  with the previously mentioned increased non-adherence rates in ADHD . In paediatrics, adherence is complicated by the need for parental/guardian supervision and support .
We are able to list the beneficial effects and the possible clinical situations where different classes of medications may produce a positive impact on the bladder dysfunction (Table 2). The overall quality of the evidence is low, and hence, strong recommendations are not yet possible.
From review of the evidence, our primary recommendation is that treatment of behavioural disorder prior to assessing and treating the bladder dysfunction is preferable. Evidence suggests that aspects such as poor attention and focus due to the behavioural disorder may be contributing to bladder dysfunction. In addition, some of the central mechanisms between behaviour and bladder may be shared such as brainstem inhibition in ADHD leading to inability to detect bladder signals or decreased arousal to a full bladder or reduced central adrenergic stimulation [77, 78]. Hence, the untreated behavioural disorder will likely negatively impact on adherence and compliance with treatment of bladder dysfunction and thus should be addressed in the first instance.
A number of findings from this review summarised in Table 2 may help with treatment decisions for children with comorbid behavioural disorders and bladder dysfunction. An understanding of the effects of the behavioural medications on bladder functioning is important to help predict treatments response and potential bladder effects. For example, autistic children started on risperidone who subsequently develop urinary incontinence may do better when switched to olanzapine to manage both behavioural and bladder symptoms. Children with ADHD and nocturnal enuresis may benefit from combination methylphenidate and atomoxetine treatment; though one should treat the behaviour disorder first, as incontinence drops to similar rates as the general population, and nocturnal enuresis may self-resolve.
In children with behavioural disorders, particularly ADHD, alarm training for nocturnal enuresis may be difficult despite adequate treatment of behaviour disorder. In children with anxiety, psychotherapy for management of both behaviour and bladder appears to be highly effective, though medications may be needed for refractory bladder symptoms. Methylphenidate can resolve nocturnal enuresis in children with ADHD when the ADHD is well controlled. Clonidine may be effective in nocturnal enuresis refractory to alarms, desmopressin and anticholinergics in the paediatric population. SSRIs do not appear to help with urinary symptoms unless they are stress-induced such as in children with anxiety. In this group, fluoxetine appears to be the safest of all the options and resolves unintended bladder symptoms caused by other SSRIs. SNRIs such as atomoxetine are very useful for both behavioural disorder and bladder dysfunction treatment, and may be an important therapy for combined symptoms, particularly ADHD and nocturnal enuresis. TCAs are useful in nocturnal enuresis as third-line treatment but also may have positive effects on children with behavioural symptoms. They also can counteract bladder symptoms that are induced by antipsychotics.
From this review, we propose a simple decision-making algorithm to optimise the treatment of children with behaviour and bladder dysfunction (Fig. 1). Children with well-treated behavioural disorders, response to bladder interventions may be similar to the general population, but developmental delay should be expected, particularly in children with ASD.
Areas for further research
This review has elicited several areas where further research is required. In terms of pharmacological effects, the studies looking at the effect of antipsychotics are very small and larger cohort studies are required to verify this evidence; perhaps best achieved by systematic review through synthesis of available evidence. Alpha agonists have only been studied for their bladder effects, not in children with comorbid behavioural disorder and this effect in children with behavioural disorders requires further assessment.
In terms of treatment of comorbid problems, the evidence is very limited and studies looking at specific behavioural conditions and comorbid bladder dysfunction and the specific bladder treatments are required across all behaviours and treatments. An important consideration for developmental paediatricians would be if bladder dysfunction should be a criteria for pharmacotherapy in children with mild ADHD who would normally not require medication, and similarly with children with anxiety and concurrent bladder dysfunction, two domains where randomised controlled trials may be designed and implemented.
This review demonstrates an important link between behavioural pharmacological agents and bladder function, especially in children with behavioural disorders. Overall, the evidence suggests that behavioural treatments such as stimulants, alpha 2 agonists and SNRIs have positive effects on the bladder. Certain SSRIs in specific instances can ameliorate bladder symptoms, but in other instances can worsen them. Antipsychotics have overwhelmingly negative effects on the bladder, though some are worse than others. Additionally, certain treatments specific to bladder may or may not work effectively in children with behavioural disorders; behavioural treatments such as alarm training working poorly in these children and medications such as anticholinergics potentially worsening behaviour. These demonstrated effects on bladder function can help clinicians choose or help refrain from groups of medications, depending on the nature and severity of underlying bladder dysfunction in a given child with behavioural disorder(s).
Lawrence D et al (2016) Key findings from the second Australian child and adolescent survey of mental health and wellbeing. Aust N Z J Psychiatry 50(9):876–886
Sawyer MG, Reece CE, Sawyer ACP, Johnson SE, Lawrence D (2018) Has the prevalence of child and adolescent mental disorders in Australia changed between 1998 and 2013 to 2014? J Am Acad Child Adolesc Psychiatry 57(5):343-350.e5
Harpin VA (2005) The effect of ADHD on the life of an individual, their family, and community from preschool to adult life. Arch Dis Child 90(suppl 1):i2–i7
Matson JL et al (2010) Developmental milestones in toddlers with autistic disorder, pervasive developmental disorder–not otherwise specified and atypical development. Dev Neurorehabil 13(4):239–247
Von Gontard A et al (2015) Incontinence and parent-reported oppositional defiant disorder symptoms in young children—a population-based study. Pediatr Nephrol 30(7):1147–1155
von Gontard A et al (2015) Incontinence in children with autism spectrum disorder. J Pediatr Urol 11(5):264.e1–7
Sayal K et al (2018) ADHD in children and young people: prevalence, care pathways, and service provision. Lancet Psychiatry 5(2):175–186
Robson WL et al (1997) Enuresis in children with attention-deficit hyperactivity disorder. South Med J 90(5):503–505
Joinson C, Heron J, von Gontard A (2006) Psychological problems in children with daytime wetting. Pediatrics 118(5):1985–1993
Joinson C et al (2007) Psychological problems in children with bedwetting and combined (day and night) wetting: a UK population-based study. J Pediatr Psychol 32(5):605–616
Yousefichaijan P et al (2016) Attention-deficit/hyperactivity disorder in children with overactive bladder; a case-control study. J Renal Inj Prev 5(4):193–199
Niemczyk J et al (2015) Incontinence in children with treated attention-deficit/hyperactivity disorder. J Pediatr Urol 11(3):141.e1-141.e6
Tsakiris P, Oelke M, Michel MC (2008) Drug-induced urinary incontinence. Drugs Aging 25(7):541–549
Hong M et al (2017) Prescription trends of psychotropics in children and adolescents with autism based on nationwide health insurance data. J Korean Med Sci 32(10):1687–1693
von Gontard A et al (2019) Are psychological comorbidities important in the aetiology of lower urinary tract dysfunction-ICI-RS 2018? Neurourol Urodyn 38(Suppl 5):S8–S17
Olcucu MT et al (2020) Effects of methylphenidate on the lower urinary tract in patients with attention deficit hyperactivity disorder and without voiding dysfunction. J Pediatr Urol 16(3):351.e1-351.e6
Bozkurt H, Abali O (2011) Aripiprazole-induced enuresis in a child with autistic disorder. Arch Neuropsychiatry 48:164–166
Williamson LB, Gower M, Ulzen T (2011) Enuresis and ADHD in older children and an adolescent treated with stimulant medication: a case series. J Can Acad Child Adolesc Psychiatry 20(1):53–55
Bahali K, Ipek H, Uneri OS (2013) Methylphenidate and atomoxetine for treatment of nocturnal enuresis in a child with attention-deficit hyperactivity disorder. Eur Child Adolesc Psychiatry 22(10):649–650
Ferrara P et al (2017) ADHD and enuresis: a study about effectiveness of treatment with methylphenidate or desmopressin in a pediatric population. Minerva Pediatr 03:03
Ohtomo Y (2017) Clonidine may have a beneficial effect on refractory nocturnal enuresis. Pediatr Int 59(6):711–713
Mauseth SA et al (2018) Medication use and association with urinary incontinence in women: data from the Norwegian prescription database and the HUNT study. Neurourol Urodyn 37(4):1448–1457
Movig KL et al (2002) Selective serotonin reuptake inhibitor-induced urinary incontinence. Pharmacoepidemiol Drug Saf 11(4):271–279
Chaudhry S, Alex N (2019) Case series suggesting an association between Sertraline and urinary side effects in a Sheffield Child and Adolescent Mental Health Services (CAMHS) population. British Journal of Medical Practitioners 12(3):a017
Maalouf FT, Gilbert AR (2010) Sertraline-induced enuresis in a prepubertal child resolves after switching to fluoxetine. J Child Adolesc Psychopharmacol 20(2):161–162
Mahdavi-Zafarghandi R, Seyedi A (2014) Treatment of monosymptomatic nocturnal enuresis: sertraline for non-responders to desmopressin. Iran J Med Sci 39(2):136–139
Sumner CR et al (2006) Placebo-controlled study of the effects of atomoxetine on bladder control in children with nocturnal enuresis. J Child Adolesc Psychopharmacol 16(6):699–711
Shatkin JP (2004) Atomoxetine for the treatment of pediatric nocturnal enuresis. J Child Adolesc Psychopharmacol 14(3):443–447
Lundmark E et al (2016) Reboxetine in therapy-resistant enuresis: a randomized placebo-controlled study. J Pediatr Urol 12(6):397.e1-397.e5
Maan JS, Rosani A, Saadabadi A (2020) Desipramine. In: StatPearls [Internet]. Treasure Island (FL).
Hillelsohn JH et al (2014) Use of desipramine for the treatment of overactive bladder refractory to antimuscarinic therapy. Urol J 10(4):1114–1118
Cosso SE (2002) Enuresis. South Med J 95(2):183–187
Gepertz S, Neveus T (2014) Imipramine for therapy resistant enuresis: a retrospective evaluation. J Urol 171(6 Pt 2):2607–2610
Herguner S, Herguner A, Kucukapan HU (2011) Imipramine for enuresis associated with risperidone. J Clin Psychopharmacol 31(6):782–783
Herguner S, Mukaddes NM (2007) Risperidone-induced enuresis in two children with autistic disorder. J Child Adolesc Psychopharmacol 17(4):527–530
Cop E, Oner P, Oner O (2011) Risperidone and double incontinence in a child with autism. J Child Adolesc Psychopharmacol 21(6):647–648
Dikshit R, Karia S, De Sousa A (2017) Risperidone-induced Enuresis in a 12-year-old Child. J Neurosci Rural Pract 8(1):122–123
Kantrowitz JT, Srihari VH, Tek C (2006) Three cases of risperidone-induced enuresis. Schizophr Res 84(1):174–175
Ming S et al (2011) Safety and efficacy of clonidine and clonidine extended-release in the treatment of children and adolescents with attention deficit and hyperactivity disorders. Adolesc Health Med Ther 2:105
El-Hefnawy AS et al (2012) Doxazosin versus tizanidine for treatment of dysfunctional voiding in children: a prospective randomized open-labeled trial. Urology 79(2):428–433
Ohtomo Y (2017) Atomoxetine ameliorates nocturnal enuresis with subclinical attention-deficit/hyperactivity disorder. Pediatr Int 59(2):181–184
Ghanizadeh A, Haghighat R (2012) Nortriptyline for treating enuresis in ADHD–a randomized double-blind controlled clinical trial. Pediatr Nephrol 27(11):2091–2097
Mutlu C et al (2015) Acute urinary retention associated with increased dose of atomoxetine in a child: a case report. Klin Psikofarmakol Bulteni 25(3):299–301
Jost W, Marsalek P (2004) Duloxetine: mechanism of action at the lower urinary tract and Onuf’s nucleus. Clin Auton Res 14(4):220–227
Tonini M, Candura SM (1996) 5-HT4 receptor agonists and bladder disorders. Trends Pharmacol Sci 17(9):314–316
Votolato NA, Stern S, Caputo RM (2000) Serotonergic antidepressants and urinary incontinence. Int Urogynecol J Pelvic Floor Dysfunct 11(6):386–388
Toren P et al (2001) Fluvoxamine is ineffective in the treatment of enuresis in children and adolescents: an open-label pilot study. Hum Psychopharmacol 16(4):327–332
Herguner S et al (2007) Serotonin-selective reuptake inhibitor-induced enuresis in three pediatric cases. J Child Adolesc Psychopharmacol 17(3):367–369
Kano K, Arisaka O (2003) Relationship between fluvoxamine and stress barometer for nocturnal enuresis. Pediatr Int 45(6):688–691
Ambrosini PJ (1984) A pharmacological paradigm for urinary incontinence and enuresis. J Clin Psychopharmacol 4(5):247–253
Kilinc S, Herguner A, Herguner S (2017) Cessation of nocturnal enuresis with aripiprazole. J Child Adolesc Psychopharmacol 27(2):213–214
Lei S (2014) Cross interaction of dopaminergic and adrenergic systems in neural modulation. Int J Physiol Pathophysiol Pharmacol 6(3):137–142
Yalcin O (2014) Micturition difficulty and urinary retention associated with aripiprazole and citalopram treatment in a male adolescent with Asperger syndrome. J Child Adolesc Psychopharmacol 24(10):598–599
Caldwell PH, Sureshkumar P, Wong WC (2016) Tricyclic and related drugs for nocturnal enuresis in children. Cochrane Database Syst Rev 1:274
Tullus K et al (1999) Efficacy and safety during long-term treatment of primary monosymptomatic nocturnal enuresis with desmopressin. Swedish enuresis trial group. Acta Paediatr 88(11):1274–1278
von Gontard A, Lehmkuhl G (1996) Drug therapy of enuresis. Z Kinder Jugendpsychiatr Psychother 24(1):18–33
Giuseppe DR, F, Pierpaolo P, Giuseppe M, Marianna S, Alessandra L, Maria CA (2010) The efficacy of a behavioral urotherapy in ASDS children with LUTS. In: Neurourology and Urodynamics. Conference: 34th Annual Congress of the Italian-Urodynamic-Society/8th SIUD. 29
Hagstroem S et al (2008) Treatment outcome of day-time urinary incontinence in children. Scand J Urol Nephrol 42(6):528–533
Campos RM et al (2013) Comparative, prospective, and randomized study between urotherapy and the pharmacological treatment of children with urinary incontinence. Einstein (São Paulo) 11(2):203–208
Crimmins CR, Rathbun SR, Husmann DA (2003) Management of urinary incontinence and nocturnal enuresis in attention-deficit hyperactivity disorder. J Urol 170(4 Pt 1):1347–1350
Eliezer DD et al (2021) Effectiveness of standard urotherapy (basic bladder advice) and combination therapies in managing bladder dysfunction in children with treated behavioral disorders: results of a prospective cohort (DABBED) study. Low Urin Tract Symptoms. 13(4):490–497
Williamson LB, Gower M, Ulzen T (2011) Clinical case rounds in child and adolescent psychiatry: enuresis and ADHD in older children and an adolescent treated with stimulant medication: a case series. J Can Acad Child Adolesc Psychiatry 20(1):53–55
Kaye JD, P.L. (2010) Characterization and management of voiding dysfunction in children with attention deficit hyperactivity disorder. Urology 76(1):220–224
Deshpande AV et al (2012) Management of daytime urinary incontinence and lower urinary tract symptoms in children. J Paediatr Child Health 48(2):E44–E52
Glazener CM, Evans JH (2002) Desmopressin for nocturnal enuresis in children. Cochrane Database of Syst Rev. https://doi.org/10.1002/14651858.CD002112
Glazener CM, Evans JH, Peto RE (2005) Alarm interventions for nocturnal enuresis in children. Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.CD002911
Lottmann H et al (2009) Long-term desmopressin response in primary nocturnal enuresis: open-label, multinational study. Int J Clin Pract 63(1):35–45
von Gontard A et al (2011) Psychological and psychiatric issues in urinary and fecal incontinence. J Urol 185(4):1432–1436
Chertin B et al (2007) Treatment of nocturnal enuresis in children with attention deficit hyperactivity disorder. J Urol 178(4 Pt 2):1744–1747
Gor RA, Fuhrer J, Schober JM (2012) A retrospective observational study of enuresis, daytime voiding symptoms, and response to medical therapy in children with attention deficit hyperactivity disorder and autism spectrum disorder. J Pediatr Urol 8(3):314–317
Dos Santos J, Lopes RI, Koyle MA (2017) Bladder and bowel dysfunction in children: an update on the diagnosis and treatment of a common, but underdiagnosed pediatric problem. Can Urol Assoc J 11:S64–S72
Gubbiotti M et al (2019) Urinary and bowel disfunction in autism spectrum disorder: a prospective, observational study. Psychiatr Danub 31(Suppl 3):475–478
Kovacevic L et al (2018) Children with nocturnal enuresis and attention deficit hyperactivity disorder: a separate entity? J Pediatr Urol 14(1):47.e1-47.e6
Yang TK et al (2015) Attention deficit-hyperactivity disorder symptoms and daytime voiding symptoms in children with primary enuresis: an observational study to evaluate the effectiveness of desmopressin treatment. TheScientificWorldJOURNAL 2015:356121
Baeyens D et al (2009) Adherence in children with nocturnal enuresis. J Pediatr Urol 5(2):105–109
Nock MK, Ferriter C (2005) Parent management of attendance and adherence in child and adolescent therapy: a conceptual and empirical review. Clin Child Fam Psychol Rev 8(2):149–166
Duel BP et al (2003) A survey of voiding dysfunction in children with attention deficit-hyperactivity disorder. J Urol 170(4 Pt 2):1521–1523
Ornitz EM et al (1999) Prepulse inhibition of startle and the neurobiology of primary nocturnal enuresis. Biol Psychiatry 45(11):1455–1466
Open Access funding enabled and organized by CAUL and its Member Institutions.
Conflict of interest
Below is the link to the electronic supplementary material.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Eliezer, D.D., Lam, C., Smith, A. et al. Optimising the management of children with concomitant bladder dysfunction and behavioural disorders. Eur Child Adolesc Psychiatry (2022). https://doi.org/10.1007/s00787-022-02016-4
- Bladder dysfunction
- Behavioural disorder