Abstract
Introduction
Case History
The patient is an 11-year-old boy who presented to our clinic with a primary diagnosis of obsessive compulsive disorder (OCD), characterized by contamination obsessions, washing compulsions, and ritualistic tracing of other people's steps. The patient also displayed symptoms of social phobia that were moderately impairing. Prior to transfer to our clinic he had been maintained on sertraline 50 mg daily for the previous 2 months and long-acting methylphenidate (MPH) 45 mg daily for the previous month. His treatment at our clinic included group cognitive behavioral therapy (CBT), with exposure and response prevention (ERP), and medication management. To optimize his pharmacological treatment, we increased sertraline to 75 mg daily and continued MPH at 45 mg daily. Three days after the increase, the family reported daily enuresis that occurred during daytime and nightime. Medical work up by the primary care physician was negative. Although the patient did not have any history of urinary problems at an earlier age, parents recalled that he had been having occasional bedwetting incidents (2 times/week) since he was started on sertraline, and these incidents had increased in frequency since sertraline was increased to 75 mg. This had a significant impact on the patient because it worsened his social phobia symptoms, exacerbated his OCD, and made it difficult for him to go to school. Hence, a decision was made to cross taper from sertraline to fluoxetine. As soon as sertraline was discontinued, enuresis completely subsided. The patient was then maintained on fluoxetine 20 mg daily without urinary problems and with significant improvement in his anxiety symptoms.
Discussion
We report a case of nocturnal and diurnal enuresis associated with sertraline in a prepubertal child. Enuresis was dose dependent and resolved on fluoxetine. Here we discuss possible mechanisms that may help explain this association. Serotonin plays a very crucial role in bladder control through central and peripheral mechanisms (Andersson 1999; D'Agostino et al. 2006). Activity in the serotonergic system inhibits the parasympathetic voiding pathway, which facilitates urine storage (Ramage 2006). It is through this mechanism and specifically through their central effect on presynaptic serotonin 1A (5-HT1a) and peripheral 5-HT3 receptors that SSRIs were reported to have antieneuretic effect (Kano and Arisaka 2000). This antienuretic effect has been reported with fluoxetine (Mesaros 1993), sertraline (Sprenger 1997), paroxetine (Murray 1997), and fluvoxamine (Kano and Arisaka 2000).
Although the mechanism of the antieneuretic effect of SSRIs has been elucidated, the mechanism of their eneuretic effect has not been clearly studied. It is well established that acetylcholine, released from cholinergic nerves innervating the detrussor muscle, mediates the main part of voiding contraction, whereas continence is maintained by an α-adrenergically mediated constriction of the bladder sphincter (Andersson 1999). In addition, the modulatory role that serotonin plays on nerve terminals innervating the human bladder muscle involves three different serotonin (5-HT) receptor sites; namely, the 5-HT4, 5-HT7, and 5-HT1A receptors (Tonini et al. 1994; D'Agostino 2006). The first two receptor types are excitatory to acetylcholine release, whereas 5-HT1A is inhibitory. Although inhibitory control prevails at lower intrasynaptic 5-HT concentrations, excitatory effect is prominent at higher 5-HT concentrations; this may explain the clinical finding in this case that urinary incontinence on sertraline was dose dependent.
Interestingly, in the case we report here, enuresis that developed on higher doses of sertraline resolved quickly on fluoxetine. It has been reported that adults on sertraline are at higher risk to develop urinary incontinence compared to those on other SSRIs (Movig et al. 2002), but this is the first such case to be reported in children.
Pharmacologically, sertraline is known to have some α-adrenergic blockade and dopamine reuptake inhibition properties that fluoxetine does not have (Richelson 2003). In addition, fluoxetine has a 5-HT-2C agonist effect that sertraline does not have (Stahl 2000). These properties may explain why enuresis was only observed on sertraline in this case. Indeed, adrenergic blockade, displayed by sertraline but not fluoxetine, can lead to urinary incontinence by decreasing internal bladder sphincter tone (Fuller et al. 1996). In addition, some evidence suggests that activation of dopamine receptors, which can potentially occur with sertraline due to its dopamine reuptake inhibition property, can suppress activity of the urethral sphincter, thus, decreasing the urethral resistance that may cause incontinence symptoms (Ogawa et al. 2006). Finally, some evidence suggests that central 5-HT-2C receptor activation in rats inhibits micturition (Mbaki and Ramage 2008), which if extrapolated to humans may explain an antieneuretic effect of fluoxetine but not of sertraline.
It is also to be noted that children with attention-deficit/hyperactivity disorder (ADHD) are more prone to urinary incontinence than children without ADHD (Chertin et al. 2007), and cases of MPH-associated enuresis have been reported in children with ADHD (Ghanizadeh et al. 2008). It remains unclear whether co-morbid ADHD and co-treatment with MPH may have predisposed our patient to sertraline-induced enuresis, but the fact that it resolved with the switch to fluoxetine makes this unlikely.
In conclusion, while we primarily prescribe SSRIs to enhance serotonin transmission and, as a result, treat depression and anxiety, it is important to be cognizant of potential additional pharmacological properties of this family of medications. Properties, such as enuretic effects, may become clinically significant in individual patients and increased knowledge may help to optimize efficacy and minimize side effects.
Disclosures
Drs. Maalouf and Gilbert have no conflicts of interest or financial ties to disclose.