Angioedema – an unusual serious side effect of risperidone injection

To the Editor:

Risperidone is an antipsychotic drug which is predominantly used in the treatment of schizophrenia and schizoaffective disorder. Risperidone has several side effects. The most common side effects are non-serious including drowsiness, increased appetite, fatigue, insomnia, agitation and anxiety.¹ Another important side effect of risperidone is angioedema which rarely occurs. In the previous publications, it was stated that angioedema developed only in three cases.² In these cases, angioedema was observed after oral administration of risperidone.² We present a case who developed angioedema after parenteral risperidone administration.

A 55-year-old woman was admitted to our department with the complaint of periorbital oedema, swelling over the face, dyspnoea and dysphagia. A year ago she was diagnosed with paranoid schizophrenia and was given venlefaxin HCL 75 mg/day, biperidene HCL 1 mg/day and risperidone 1 mg/day. After a month, she discontinued her medications. A month later, she developed agitation and her hallucinative symptoms. She was taken to a hospital by her family. As the patient refused oral medication, risperidone 25 mg was administered via intramuscular injection. After three days, she developed periorbital oedema and swelling over the face, and had life-threatening difficulty in breathing and swallowing. Her history revealed no allergic reaction, food allergies or asthma. The physical examination showed no remarkable findings other than periorbital and perioral oedema. The biochemical and haematological screening test (haemogram, renal function tests, liver function tests, electrolytes, ELISA, thyroid function tests and ANA) results were within the normal range. No drugs other than risperidone were administered during that time period. We also observed that Naranjo scale value was 7. This score probably indicated the adverse drug reaction. Risperidone body fluid concentrations were not measured. Placebo and re-challenge with risperidone were not done. We thought that angioedema was probably caused by risperidone intramuscular injection. Therefore, risperidone was stopped and haloperidol was started. At the same time, feniramin maleat 45.5 mg and methylprednisolone 40 mg were administered via intravenous injection. Dyspnoea and swallowing problem were immediately resolved. Periorbital and perioral oedema disappeared in two weeks.

To date, only three cases have been reported in the literature that developed periorbital oedema due to oral risperidone administration. In 1995, Cooney et al. reported the first case of angioedema associated with risperidone. The case was a 30-year-old female who developed angioedema in the second week of the treatment with 6 mg of oral risperidone administration. After the dose of risperidone was decreased to 3 mg/day, her symptoms completely resolved. However, when the dose of oral risperidone was again increased to 6 mg/day, angioedema recurred in 3 days.³ The second case was a 15-year-old boy diagnosed with schizophrenia. He was started on treatment with oral risperidone 1 mg/day and clonazepam 0.5 mg/day. Then, the dose of risperidone was increased to 2 mg/day and that of clonazepam was stopped, and within a week of increasing risperidone, he developed angioedema.² The third case who was a 63-year-old female was reported by Kores Plesnicar et al. They stated that the patient developed angioedema on three occasions when exposed to oral risperidone and that the angioedema subsided each time with the discontinuation of risperidone.⁴

The previous publications demonstrated that in the first case, only periorbital oedema was associated with intramuscular risperidone. She developed periorbital oedema about two weeks after the intramuscular risperidone injection (37.5 mg). However, angioedema has not been reported on parenteral risperidone application.⁵ The mechanism of angioedema has not been clearly defined. C1 esterase deficiency and decreasing complement levels are blamed for angioedema.^2–3 The underlying mechanism of the angioedema can be a non-allergic drug reaction caused by delayed (type 4) hypersensitivity. It is commonly seen 48–72 h after the first administration of the medication. The route of administration and dose of risperidone can be important factors in developing angioedema. The previous studies reported that angioedema developed after intramuscular and oral applications of risperidone. In all the previous cases, angioedema was reported to develop when the dose of risperidone was increased. As for our case, the patient did not develop angioedema after an oral administration of risperidone, but severe angioedema developed after a high dose of intramuscular risperidone administration. Therefore, high-dose administrations of risperidone seem to be the most important factor in the present case.

In conclusion, angioedema is an extremely rare but serious side effect. The patients who need high doses of risperidone and intramuscular risperidone should be carefully monitored in terms of the risk of angioedema. Patients who are to be administered high doses of intramuscular risperidone should be warned about periorbital oedema, swelling over the face, dyspnoea and dysphagia, which could be seen in the first 48–72 h after treatment.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.