Aripiprazole-Induced Sialorrhea Responsive to Diphenhydramine Treatment

To The Editor:

Several studies have shown that aripiprazole was associated with improvement in irritability, aggression, self-injurious behaviors, and hyperactivity in children and adolescents with intellectual disability and autistic spectrum disorder (Deb et al. 2014). The most reported adverse effects include fatigue, headache, sedation, and nausea (Marcus et al. 2009; Owen et al. 2009).

Sialorrhea is an uncomfortable adverse effect of antipsychotics that may be particularly troubling for patients, resulting in treatment nonadherence or discontinuation (Praharaj et al. 2006). With excess of saliva, pooling occurs in the oral cavity, causing drooling. Sialorrhea and drooling in the pediatric population using aripiprazole are not uncommon. It was reported that ∼9% of children and adolescents with autism spectrum disorder developed drooling during aripiprazole treatment (Marcus et al. 2009; Owen et al. 2009).

In this report, we describe a pediatric patient who developed sialorrhea during aripiprazole treatment and responded well to the administration of diphenhydramine.

Case Report

A 14-year-old boy with diagnoses of moderate intellectual disability and cerebral palsy was admitted to the child and adolescent psychiatry outpatient clinic by his parents with complaints of self-injurious behaviors, irritability, aggression, and hyperactivity. For his disruptive behaviors, he was started on risperidone 0.25 mg twice daily. He developed severe sedation after the initiation of first dose and his mother ceased the medication within the first week. Then we decided to put the patient on aripiprazole 2.5 mg/day, and increased the dose to 5 mg/day in the 2nd week. At his next visit to the clinic 4 weeks later, his mother reported significant improvement in his disruptive behaviors. The only side effect was sialorrhea, which was leading to drooling most of the day. His clothing was becoming soaked with saliva during the daytime and his pillow during the sleep. According to his mother's report, his sialorrhea began when the dose of aripiprazole was increased up to 5 mg/day. At his physical examination, he had a normal gait, had no muscular rigidity, and had no symptoms of esophageal dysfunction. Because of the significant improvement in his disruptive behaviors, we decided to add diphenhydramine 12.5 mg twice daily to the treatment, and his sialorrhea resolved significantly within 1 week.

We presented a patient who experienced sialorrhea during aripiprazole treatment and remitted after diphenhydramine treatment. Based on the temporal relationship between administration of aripiprazole and the onset of sialorrhea, it is possible that the sialorrhea was associated with aripiprazole. In the literature, there is only one reported case, 27-year-old male, with aripiprazole-induced sialorrhea responsive to trihexyphenidyl (Praharaj et al. 2009). To our knowledge, this is the first report of a pediatric patient with aripiprazole-induced sialorrhea that remitted with diphenhydramine administration.

Discussion

All antipsychotics have the potential to induce drooling, as they can cause a decrease in swallowing caused by throat muscle rigidity, which is the result of pseudoparkinsonian bradykinesia. The reported patient had no extrapyramidal symptoms or signs of esophageal dysfunction; therefore drooling seems to have been the result of sialorrhea induced by aripiprazole.

Although the exact pathophysiology of antipsychotic-induced sialorrhea is unknown, proposed mechanisms include sympathetic α-adrenergic receptor antagonism and parasympathetic cholinergic (muscarinic) receptor agonism (Praharaj et al. 2006). Aripiprazole is a partial agonist at D2, D3, and 5HT1A receptors, and an antagonist at 5HT2A, H1, and adrenergic receptors, but has no clinically significant effect on the muscarinic receptors (Deb et al. 2014). Therefore, in this case, the most likely mechanism of aripiprazole-induced sialorrhea seems to have been through its central adrenergic antagonism.

Antipsychotic-related sialorrhea may be dose related. The reported patient did not develop sialorrhea during treatment with aripiprazole 2.5 mg/day, but did during treatment with aripiprazole 5 mg/day. We might have reduced the dose of aripiprazole to stop sialorrhea; however as the patient's disruptive behaviors had improved significantly, we did not choose this option.

Treatment of antipsychotic-induced sialorrhea include anticholinergic drugs and α2-adrenergic receptor agonists. Diphenhydramine is a centrally acting H1 histamine receptor antagonist, and is reported as a treatment alternative for antipsychotic-induced sialorrhea (Praharaj et al. 2006). Usta et al. (2012) reported a pediatric case of risperidone-induced sialorrhea responding to diphenhydramine. The reduction of sialorrhea by diphenhydramine is suggested to be the result of its muscarinic (M3) receptor blockade (Liu and Farley 2005).

Clinicians should be aware that aripiprazole may induce sialorrhea, and should monitor their patients for this potentially troublesome adverse effect. Diphenhydramine may be a therapeutic option for patients having sialorrhea when treated with aripiprazole.