Nasal and Gingival Bleeding During Aripiprazole but not Haloperidol Treatment

To The Editor:

Aripiprazole is a partial agonist at dopamine D2 and serotonin 5-HT1A receptors, and is an antagonist at serotonin 5-HT2A receptors. Several studies have reported that it was effective for treatment in children and adolescents with irritability associated with autistic spectrum disorder, and that it was safe and well tolerated (Marcus et al. 2011). Fatigue, increased appetite, headache, sedation, and somnolence were among the most reported adverse effects of aripiprazole (Owen et al. 2009).

In this report, we will describe a pediatric patient who developed nasal and gingival bleeding during aripiprazole treatment.

Case Report

A 12-year-old boy with diagnoses of autism spectrum disorder and moderate intellectual disability was referred to our outpatient clinic with complaints of self-injurious behaviors, aggression, and irritability. According to his medical history, he had coagulation disorder (factor VII deficiency) and was receiving daily factor VII replacement treatment. Aripiprazole 2.5 mg/day was prescribed for his self-injurious and disruptive behaviors, and the dose was increased to 5 mg/day 5 days later. During their second visit to our clinic 3 weeks later, his mother reported that on the 2nd day of aripiprazole treatment he had experienced nasal and gingival bleeding. His bleeding occurred every day, and its frequency and severity increased when the dose of aripiprazole was increased to 5 mg/day. They were referred to the hematology clinic 10 days after beginning the aripiprazole treatment because of the patient's nasal and gingival bleeding. This condition was considered by his physician to be a possible adverse effect of aripiprazole, and the medication was discontinued. After the cessation of aripiprazole, bleeding did not reoccur. However, because of the severity of the patient's behaviors, the patient and his mother were referred to our clinic. We decided to initiate haloperidol, and titrated the dose up to 1.5 mg/day. He had no bleeding during this treatment and tolerated the medication well.

We presented a case who experienced nasal and gingival bleeding during aripiprazole treatment but did not during haloperidol treatment. To our knowledge, there is no report in the literature of bleeding associated with aripiprazole. The chronological relationship between the time of aripiprazole administration and the development of bleeding and the fact that there was no occurrence after aripiprazole discontinuation suggest aripiprazole to be the probable causative agent.

Discussion

Bleeding is a rarely reported side effect of antipsychotics, including risperidone. The bleeding side effect of risperidone was suggested to be associated with 5-HT2A receptor antagonism (Coskun and Mukaddes 2008). The 5-HT2A receptor has a role on mediating platelet aggregation and vasoconstriction in human coronary arteries (Przyklenk et al. 2010). Antagonism of the 5-HT2A receptor was suggested to cause bleeding by increasing blood flow in microcirculation, reducing the platelet aggregation, and inhibiting the release of vasoconstrictors from platelets (Coskun and Mukaddes 2008). Therefore, in this reported case, we may speculate that aripiprazole's 5-HT2A antagonism might have possibly caused bleeding by its antithrombotic effect on microcirculation. However, this potential explanation may not describe the entire mechanism of this adverse reaction.

Another issue that needs to be discussed is development of bleeding during aripiprazole treatment but not during haloperidol treatment. Aripiprazole has a higher 5-HT2A antagonism than haloperidol (Amato 2015). Haloperidol's low affinity to 5-HT2A receptors might be the reason for nonoccurrence of bleeding.

Although bleeding is a rare side effect, clinicians should be aware that aripiprazole may cause bleeding, especially in susceptible patients with coagulation disorders.