CASE REPORT nsper~done overdose

Overdose of Risperidone

From the Division of Emergency Medicine and Departments of Internal Medicine and Pharmacology, University of New Mexico Medical Center, Albuquerque, New Mexico.

Received for publication December 12, 1991. Revision received August 3i, 1992. Accepted for publication Octobe}" 15, 1992.

Ken Brown, MD Howard Levy, MD Cynthia Brenner, MD

Stephen Leffler, MD Ellen L Hamburg, PharmD

Risperidone is an investigational antipsychotic agent currently being tested in an international mufticenter drug trial. We report the first case of a risperidone overdose in an apparent suicide attempt. This was without serious clinical side effects and mani- fested mainly as ECG abnormalities.

[Brown K, Levy H, Brenner C, Leffler S, Hamburg EL: Overdose of risperidone. Ann Emerg Med December 1993;22:1908-1910.]

INTRODUCTION

Risperidone (R 64,766) is a benzisoxazole derivative that is an investigational antipsychotic agent. It possesses both the traditional dopamine antagonism and the serotonin antagonism. 1,2 The classic antidopamine antipsychotic compounds treat the positive symptoms of schizophrenia (hallucinations, delusions, and thought disorders) effectively but not the negative symptoms (emotional withdrawal, blunted affect, poverty of speech, and avolition). Risperidone, because of the addition of serotonin antagonism, seems to treat the negative symptoms as well as the positive symptoms. 3-r Another advantage of risperid0ne therapy appears to be a distinct diminution of existing extrapyramidal symptoms.3, >r

Risperidone, by review of the literature, in doses less than 25 mg/day, appears to have a safe hematologic and cardiovascular profile. 3-5 There are no previously reported cases of acute overdose. We report a case of an acute ingestion of risperidone in a 29-year-old man in an apparent suicide attempt.

CASE REPORT

A 29-year-old man was brought to the emergency depart- ment by ambulance after stating that he took 120 2-mg risperidone tablets. On examination, the patient was alert and oriented to person, place, and time. The patient admitted to taking the pills in a suicide gesture 45 minutes before arrival. The patient described auditory

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RISPERIDONE OVERDOSE Brown et aI

hallucinations but had no physical complaints. Vital signs were systolic blood pressure, 132 mm Hg/palpation; pulse, 68; temperature, 36.6 C; and respirations, 20. Physical examination was unremarkable.

The patient was placed on a cardiac monitor. Gastric lavage was performed using an Ewald tube and 2 L tap water. Pill fragments were noted in the lavage return. Lavage was followed by 50 mg activated charcoal and 12 oz magnesium citrate. An ECG performed approximately one hour after the alleged ingestion showed a normal sinus rhythm at 96 beats per minute. The QRS axis was +57 degrees. The QRS duration was prolonged at 112 msec, and the QT c was abnormal at 565 msec. Laboratory evalu- ation included electrolytes, hemogram, urinalysis, and a toxicologic screen. Abnormalities included a sodium level of 125 mmol/L and a potassium level of 2.9 mmol/L. These values had been normal one month previously on routine examination. The toxicologic screen, including aspirin and acetaminophen, was negative. The patient was given fiormal saline IV, and a 40-mEq increment of potassium chloride was administered. While in the ED, the patient remained alert and hemodynamically stable.

Because of the cardiac conduction disturbances, the patient was admitted to an ECG-monitored bed. During the next 24 hours, the patient had no arrhythmtas, and the electrolytes returned to normal without further interven- tion. A repeat ECG at 12 hours had reverted to normal. The QRS was 100 msec, and the QT c was 444 msec. After 24 hours, the patient was discharged to the mental health center without any apparent untoward effects, and this was confirmed by follow-up at eight weeks.

DISCUSSION

Resperidone is an investigational agent used in the treat- ment of diverse psychotic behaviors with potent serotonin (S 2) and dopamine (D2) receptor-blocking activities. Previous human clinical trials have been performed, and currently, there is a multicenter, international clinical trial under way. In previous animal studies, the LDso for oral administration has been established for rats, mice, and dogs, and ranges from 18.3 mg/kg to i 13 mg/kg.1 No acute overdose in human subjects has been documented previously. In human trials, oral dosing has ranged from 2 mg/day to 25 rag/day. 3-6 Blood chemistry and hema- tologic monitoring have shown no significant abnormality, and no clinically significant ECG changes were seen in patients taking up to 25 mg of risperidone a day. >5

This report describes an acute ingestion of the investi- gational antipsychotic drug risperidone by a 29-year-old man in an apparent suicide attempt. This patient had been on 12 mg/day for seven months before this ingestion. Evaluation of this patient's last medication refill and dosing Schedule revealed that acute ingestion was at the very least 100 mg (four times the previous maximum daily dosing regimen), and may have been as much as 240 mg. Drug levels of risperidone were not obtained.

Mild electrolyte abnormalities including hyponatremia and hypokalemia developed presumably secondary to this ingestion. As stated previously, normal chemistries were obtained one month before this ingestion. It seems unlikely that an ingestion of risperidone would cause these specific electrolyte abnormalities acutely. Nevertheless, the history was not suggestive of excessive fluid intake or fluid losses; the patient stated he was eating well, and he denied other drug ingestion such as diuretics. Also, thyroid-stimulating hormone and cortisol levels were found to be normal.

Cardiac conduction abnormalities reminiscent of tricyclic agents occurred; QT c and QRS interval prolonga- tion was documented on ECG. The patient had no history of cardiac conduction disturbances and denied any ingestion of other medications such as cyclic anti- depressant agents or quinidine. The above abnormalities resolved over a 12-hour period without serious sequelae.

In this specific case, the clinical course was benign. However, the exact amount of ingestion is unknown, and there were significant ECG and electrolyte changes. Therefore, it seems prudent to approach risperidone ingestion with caution until further information is avail- able regarding the safety of this drug.

The management of this acute ingestion consisted of close monitoring Of blood electrolytes with appropriate treatment and cardiac monitoring in the ICU. Th e manage- ment was similar to that recommended for tricyclic antidepressant agents.

SUMMARY

We describe the case of an alleged overdose of the investi- gational antipsychotic agent risperidone. The patient's clinical course was benign although significant ECG and electrolyte abnormalities were seen. All patients with a suspected risperidone ingestion should have electrolyte and ECG monitoring. If significant abnormalities are pre- sent, appropriate treatment of the electrolyte abnormality and cardiac monitoring should be instituted.

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RISPERIDONE OVERDOSE Brown et aI

R E F E R E N C E S

1. Janssen PAJ, Niemegeers CJE, Aweuters F, et ah Pharmacology of risperidone (R 64 766), a new entipsychotic with serotonin-S2 and dopamioe-B2 antagonistic properties. J Pharmacol Exp Ther 1 £88;244:685-693,

2. Leysen JE, Gommeren W, Eens A, et ah Biochemical profile of risperidene, a new antipsychotic. J Pharmacol Exp Ther 1988;247:661-670.

3. Castelao JF, Ferreira L, Gelders YG, et al: ]'he efficacy of the D2 and 5-HT2 antagonist risperidone (R 64 766) in the treatment of chronic psychosis. Schizophr Res 1989;2:411-415.

4. Mace G, Badioi L, Bonifati V, et el: Risperidone in the treatment of chronic schizophrenia with tardive dyskinesia. Curr Ther Res 1989;46:876-883.

5. Mesotteo F, Suy E, Pietquin M, et ah Therapeutic effect and safety of increasing doses of risperidone (R 64766)in psychotic patients. Psychopharmacalegy1989;99:445-449.

6. Roose K, Gelders Y, Heylen S: Risperidone (R 64 766) in psychotic patients. A first clinical therapeutic exploration. Acta Psychiatr Belg 1988;88:233-241.

7. Meert TF, Awouters F: Serotonin 5-HT2 antagonists: A preciinical evaluation of possible therapeutic effects, in Idzikowski C, Oowen-Wrightson P (eds): Serotonin: Sleep and Mental Disorders. Petersfield, Hampshire, Wrightson Biomedical Publishing, 1991.

The authors thank Dr M Reed for aiding in the literature review, Dr C Yee of Jenssen Research Laboratories for supplying drug information, and M Allen, RN, for supplying clinical data and reference materials.

Address for reprints:

Ken Brown, MD

1011 Princeton NE

Albuquerque, NM 87106

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