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Zonisamide Toxicity in a Patient with an Intentional Overdose

TO THE EDITOR: Zonisamide is an antiepileptic agent approved for use in managing partial seizures. Its foremost mechanism of action is believed to involve blockade of axonal sodium and calcium channels. It has a biphasic effect on dopamine function.1 We report the case of a patient who stated that she ingested only zonisamide in a suicide attempt. Case Report. A 20-year-old female with a history of bipolar disease, epilepsy, and 3 previous suicide attempts ingested up to 8.7 g of zonisamide, based on capsule count. The ingestion occurred at approximately 0900 hours. One episode of emesis occurred at 1200 hours and the patient saw “many” capsules in the vomitus. There was a second episode of emesis, but no capsules were seen. In the emergency department 5 hours after ingestion, the patient’s vital signs were temperature 36.7 ̊C, blood pressure 130/80 mm Hg, heart rate 75 beats per minute, respiratory rate 20 breaths per minute, and pulse oximetry 100% on room air. Results of an electrocardiogram were within normal limits. She complained of nausea, diffuse chest pain, blurred vision, dizziness, and mild headache. Results of basic metabolic panel, complete blood cell count, and arterial blood gas values were noncontributory, other than mild leukocytosis. Activated charcoal was recommended if feasible and there was no undue risk of aspiration. The patient had a 5-minute episode of seizure-like activity consisting of tremors and altered mental status responsive solely to sternal rub. She recovered spontaneously with no obvious postictal state. An electroencephalogram showed no epileptiform discharges. Plasma zonisamide concentrations measured 5.5 and 48 hours postingestion were 110 mg/L and 38 mg/L, respectively (therapeutic concentration 10-30). The calculated half-life was 30 hours. The patient became asymptomatic and was transferred to the inpatient psychiatric ward on hospital day 2. Discussion. To our knowledge, this is the first reported case of a zonisamide overdose as a single agent in which 2 plasma concentrations were obtained. Zonisamide is completely absorbed from the gastrointestinal tract and peak plasma concentrations are reached in 2-6 hours.1 This patient’s plasma concentrations likely represented a postabsorption phase based on the stated time of ingestion. Zonisamide’s calculated half-life of 30 hours in this patient deviates from the published half-life of 63 hours in the nonoverdose setting.1 Explanations for the shortened half-life in this patient include (1) time of ingestion by history was incorrect (a higher peak concentration would have resulted in a longer half-life), (2) the drug’s halflife varies widely among patients,1 and (3) enzyme-inducing agents would have shortened the half-life. Zonisamide undergoes hepatic metabolism via CYP3A4, CYP2C19, and CYP3A5 enzymes and is renally excreted. This patient’s constellation of symptoms is distinctly different from previous reported cases of zonisamide poisoning. Naito et al. reported on a 26-year-old female who exhibited hypotension, respiratory depression, and coma after ingesting zonisamide, clonazepam, and carbamazepine.2 Her zonisamide plasma concentration 31 hours after ingestion was 100.1 mg/L; the half-life was 56.5 hours. In another case, an 18-year-old female died of sustained cardiopulmonary arrest and anoxic brain injury after ingesting zonisamide.3 A perimortem blood concentration was 44 mg/L and the comprehensive drug screen indicated the presence of caffeine, diphenhydramine metabolites, and mirtazapine. The patient reported here, despite having toxic plasma zonisamide concentrations, did not exhibit the range or severity of symptoms associated with zonisamide poisoning. Clinicians should be aware that zonisimide’s half-life might be altered in the overdose patient.