Diphenhydramine Use in the Treatment of Risperidone-Induced Sialorrhea

To the Editor:

T he management of behavioral problems in mental retardation is typically multidisciplinary and may involve a number of different psychosocial interventions and pharmacotherapies. Antipsychotics are widely used for controlling disruptive behaviors in mental retardation. Risperidone is an atypical agent widely used for treating such patients in clinical practice.

Sialorrhea reduces the quality of life of the patients receiving antipsychotics and may result in social stigmatization that is difficult to cope with; both for the family and the patient. This may impair compliance with treatment. The patient, K.A., was a 14-year-old male suffering from cerebral palsy and moderate mental retardation. The main complaints of family were self-destructive behaviors, tantrums, hyperactivity, and sleep problems, lasting for 1 year. After the first medical evaluation of these complaints, he was started on 1 mg/day risperidone treatment and scheduled for weekly follow-up. Although in the first weeks of the treatment significant improvement was observed, hypersalivation throughout the day leading to dribbling down from lips and wetting the pillow in the mornings were reported. Esophageal dysfunction, which may be associated with extrapyramidal symptoms (EPS) of antipsychotic agents may lead to hypersalivation, however physical and neurological examinations revealed no additional EPS or signs/symptoms of esophageal dysfunction; therefore the risperidone dose was reduced to 0.5 mg/day.

Although hypersalivation significantly reduced with dose titration, the complaints re-emerged after the second week. Along with behavioral recommendations (chewing gum, etc.), 25 mg/day diphenhydramine was started and titrated to 50 mg/day in a week. Risperidone dosage was also titrated to 1 mg/day and clinical improvement was observed. Two weeks later, the hypersalivation was markedly decreased along with other complaints.

In a patient such as ours with underlying neurological problems, the etiology of sialorrhea should be clearly differentiated. It may be caused by the underlying esophageal dysfunction due to neurological disease, or the result of antipsychotic-receptor interaction, or both. Because of a lack of history of esophageal dysfunction and physical/neurological examinations which were in normal limits; sialorrhea in our case was thought to be caused by risperidone.

Hypersalivation is possibly due to the antimuscarinic or alpha-2 adrenergic receptor activating properties of several antipsychotics. Sialorrhea in the pediatric population using risperidone is not common and reported to be 3% in those with bipolar disorder and 9% with autism. It may also be dose related (Highlights of Prescribing Information). Also, reported cases tend to be with higher doses of risperidone than used in our patient and in those using combination therapies (especially with lithium) (Gajwani et al. 2001).

The most likely mechanism seems to be through alpha-adrenergic antagonism of risperidone particularly via alpha-2 receptors, since risperidone has no clinically significant effect on the muscarinic receptors (Lavalaye et al. 2001). Diphenhydramine is a powerful anti-muscarinic drug and the reduction of hypersalivation may be due to M3 receptor blockade alone or a combination of the effects of risperidone on alpha-2 and diphenydramine on M3 receptors. These may decrease secretion and thicken the saliva (Liu and Farley 2005).

To our knowledge this is the first case report of a risperidone-induced sialorrhea in lower doses responding to diphenhydramine. The data about the efficacy of diphenhydramine in the treatment of risperidone-induced hypersalivation is limited and further studies may be needed.