Desmopressin Use in the Treatment of Aripiprazole-Induced Nocturnal Enuresis in a Child Diagnosed with Autistic Disorder

To The Editor:

Aripiprazole is an effective and safe option in the treatment of autistic disorder-induced irritability in children and adolescents (Marcus et al. 2009). Although enuresis was observed as a very rare side effect during the premarketing evaluation of oral aripiprazole, to our knowledge, there is only one diurnal enuresis case in the literature (Bozkurt et al. 2011). Desmopressin is a synthetic replacement for arginine vasopressin (AVP) that binds to V2 receptors at the renal tubule and collecting ducts, and increases water absorption, thus causing denser urine with less volume (Miller et al. 1992). In the case reports of two adults at the beginning of the 1990s, desmopressin use has been found to be safe and effective in the treatment of clozapine-induced enuresis (Bennett et al. 1994; Lurie and Hosmer 1997).

This letter discusses the use of oral desmopressin in the treatment of nocturnal enuresis that developed after aripiprazole use in a child diagnosed as having autistic disorder. Permission was given the patient's family for treatment and for publication.

Case Report

An 8-year-old male patient was admitted to our clinic with complaints of aggression, self-injurious behavior such as biting himself, talking late at night, limited social interaction, and repetitive behavior patterns. As a result of psychiatric and psychometric examinations, he was diagnosed as having autistic disorder and mental retardation. His history revealed that he had also been admitted to other medical centers, and that risperidone had been recommended; however, his family did not continue the treatment because of weight gain and sedation. His anamnesis showed that he been toilet trained at the age of 5 years, and that he had stopped bed-wetting after the age of 6 years. At the end of the first examination, he was started on 2 mg/day of aripiprazole, and a week later, the dose was increased to 4 mg/day. The examination 2 weeks later revealed that there was an obvious recovery in the patient's self-injuring behaviors and aggression; however, he had started to wet his bed at least 5 or 6 nights a week. The family was given behavioral homework and instructions regarding fluid restriction, and the treatment continued. When the patient came for a follow-up visit 2 weeks later, it was found that he was having problems in adapting to his behavioral homework. Therefore, 30 μg/day of desmopressin was added to the treatment, and it was planned to increase the dose to 60 μg/day. At the follow-up visit 3 weeks later, it was found that the patient had stopped bed-wetting. There was no known nocturnal enuresis in the family history. The patient's routine biochemistry and total urine examinations were found to be normal, and the treatment was planned to be continued with 4 mg/day of aripiprazole and 60 μg/day of desmopressin.

Discussion

A great number of cases in the past have reported clozapine-induced (Frankenburg et al. 1996; Praharaj and Arora 2007), risperidone-induced (Hergüner and Mukaddes 2007), and olanzapine-induced (Vernon et al. 2000) nocturnal enuresis. The occurrence mechanism of antipsychotic-induced enuresis has not yet been fully presented (Fuller et al. 1996). Possible mechanisms for antipsychotic-induced enuresis are α-1 adrenergic blockers (Hergüner and Mukaddes 2007), decreased dopaminergic activity in the basal ganglia (Ambrosini 1984), overflow incontinence following urinary retention with antimuscarinic (M4) effect (Barnes et al. 2012), pudendal reflex blockage with 5 HT2 and 5 HT3 antagonism (et al. 2006), activity increase in detrusor muscle with 5 HT4 antagonism (Tonini and Candura 1996), and sedation effect that increases the deepness of sleep (Ambrosini 1984). In addition, nocturnal enuresis induced by diabetes mellitus polyuria caused by long-term antipsychotic use has been presented as another possible mechanism (Ambrosini 1984).

In our case, aripiprazole's 5 HT2A and α-1 receptor antagonism on the detrusor muscle and internal urethral sphincter was the most probable reason for enuresis. In addition, the sedative effect caused by H1 antagonism and the resulting increase in the deepness of sleep could explain why the enuresis was nocturnal. The partial agonistic effect on D2 receptors may also have caused urinary incontinence by decreasing dopaminergic transmission. Another probable effective mechanism is the serotonin uptake blockage that occurs at a medium level. It is known that serotonin indirectly increases cholinergic activity in the detrusor muscle, and may be responsible for enuresis (Tonini et al. 1994).

In cases in which behavioral methods were not sufficient, various agents were used in antipsychotic-induced enuresis treatment. Hergüner et al. used imipramine in risperidone-induced enuresis and were successful (Hergüner et al. 2011). In two case reports of adults, desmopressin use was reported for the treatment of clozapine-induced enuresis (Bennett et al. 1994; Lurie and Hosmer 1997).

Conclusion

In conclusion, we are of the opinion that this case report is important for two reasons. First, it is the first description of aripiprazole-induced nocturnal enuresis in the literature. Second, it is the first publication of desmopressin use in the treatment of atypical antipsychotic-induced nocturnal enuresis in children and adolescents. Future controlled studies will present clinicians with more descriptive methods on rare side effects caused by aripiprazole use, and the solutions for these.