Abstract
Fluoxetine is a selective serotonin reuptake inhibitor that is less frequently associated with severe toxicity in acute overdose compared with other psychotropic medications. Although rare, generalized seizure has been reported after isolated fluoxetine overdose. Most cases in the literature have occurred between one- and 16 h following acute ingestion of ≥1000 mg. Here, we present a series of four cases of adolescents who presented to our pediatric emergency department with reported or witnessed seizures after acute fluoxetine overdose between 3/2021 and 1/2022. These cases included intentional ingestions of fluoxetine at doses between 600 and 1200 mg (10–19.5 mg/kg), each of whom had a single, witnessed episode of generalized seizure activity which occurred between three- and nine-hours post-ingestion. All patients had signs of mild serotonin excess and two met conventional criteria for diagnosis of serotonin toxicity. All patients were evaluated by a medical toxicologist and were hospitalized for observation. No patient developed subsequent seizure or further complications related to overdose and no patient received neuroimaging, electroencephalography, or evaluation by a neurologist. Though previously described, seizure is an uncommon and potentially underappreciated complication after fluoxetine overdose and occurred in some of our patients at doses lower than those which have typically been reported in the literature.
1
Introduction
Fluoxetine and its active metabolite, norfluoxetine potently inhibit the serotonin transporter and weakly antagonize the norepinephrine transporter [ , ] with minimal effect on other neurotransmitter systems. Fluoxetine has a favorable toxicity profile in overdoses up to 1500 mg in adults and 3.6 mg/kg in children [ , ]. Nevertheless, several case reports have described serious effects including serotonin toxicity [ ], rhabdomyolysis [ ], cardiac conduction delay, and dysrhythmia [ ]. An underappreciated consequence of fluoxetine overdose is generalized seizure which has been described in animal models [ ] and case reports. Seizures have been reported between one and 16-h after ingestion [ ] of doses ranging from 900 to 3000 mg. It is of note that all but one published case resulted from a dose ≥1000 mg [ , ]. Most of these cases were self-limited and resolved with supportive care alone. Here, we present a series of four cases presenting to our pediatric emergency department with reported or witnessed seizure after intentional fluoxetine overdose. IRB review granted exemption to this retrospective case series.
1.1
Cases
A 14-year-old presented to the emergency department (ED) after ingesting 600 mg (10 mg/kg) of fluoxetine and 25 mg of hydroxyzine. This was corroborated by collateral history from family, pill counts, and review of dispense records. Past medical history (PMH) included anxiety, depression, and bulimia nervosa and prescription medications included fluoxetine, hydroxyzine, and an oral contraceptive. The only symptom at presentation was lightheadedness. Triage vital signs (VS) showed tachycardia (106 bpm), tachypnea (21/min), and normothermia. Examination revealed tongue fasciculation, patellar hyperreflexia, but no ankle myoclonus. Patient was treated with magnesium sulfate for prolonged QTc of 500 ms. Laboratory workup was unremarkable, notably sodium 140 mmol/L, calcium 9.5 mg/dL, glucose 109 mg/dL, acetaminophen, salicylate, and ethanol below the limit of detection. Two hours after arrival, nursing staff witnessed a generalized seizure which resolved after 1 mg of intravenous lorazepam. Patient had no further symptoms, was admitted for observation, medical toxicology was consulted, and patient was medically cleared 22 h after ingestion. A urine immunoassay was positive only for benzodiazepines consistent with administration of lorazepam.
A 13-year-old presented to the ED after intentional overdose of 600–900 mg (9.3–18.6 mg/kg) of fluoxetine. PMH included depression, anxiety, and ADHD with prescriptions for escitalopram, dextroamphetamine, and melatonin. The ingested fluoxetine had been retained by the patient from a previous prescription. Each of the prescriptions were confirmed, to the best of our ability, by pharmacy dispense records, collateral history from family, and pill counts. Triage VS showed tachycardia (111 bpm), and tachypnea (21/min) with normothermia. Examination showed mydriasis, abdominal tenderness, normal patellar reflexes, normal muscle tone, absent ankle myoclonus. Patient received 5 mg oral diazepam per recommendation of the consulting medical toxicologist. Laboratory studies and ECG were unremarkable including sodium 137 mmol/L, calcium 8.8 mg/dL, glucose 104 mg/dL, acetaminophen, ethanol, and salicylate below limit of detection. Urine immunoassay was positive only for amphetamines which was consistent with prescription for dextroamphetamine. Between 8 and 11 h after ingestion, a seizure was observed by the ED nurse who described increased oral secretions requiring suction followed by generalized tonic-clonic activity. Hospital course was characterized by tachycardia and lower extremity hypertonicity, both of which resolved approximately 28 h after ingestion.
A 16-year-old presented to the ED after intentional ingestion of 1000 mg fluoxetine (19.5 mg/kg) and three glasses of wine. Past medical history included major depressive disorder and prescription medications included fluoxetine, trazodone, and an oral contraceptive pill. There was no history of chronic alcohol use. Presenting symptoms were dizziness, nausea, vomiting, fingertip paresthesia, and intermittent leg tremor. Vital signs showed tachycardia (124 bpm), elevated blood pressure (141/97), and tachypnea (20/min). Examination showed akathisia, mydriasis, and patellar hyperreflexia without ankle myoclonus or hypertonicity. Laboratory studies were notable for sodium 138 mmol/L, calcium 9.3 mg/dL, glucose 101 mg/dL, acetaminophen, ethanol, and salicylate below the limit of detection. ECG showed QTc 480 ms, and urine immunoassay for drugs of abuse was negative. Four hours after ingestion, patient had a generalized tonic-clonic seizure witnessed by ED nurse which was treated with 2 mg intravenous lorazepam. Serial examinations revealed hypertonicity of the lower extremities with inducible clonus which resolved over the course of 72 h. Serial ECGs were performed with no change in QTc. Patient was medically cleared and ultimately discharged after evaluation by psychiatry.
A 16-year-old presented to the ED after parents witnessed a seizure and activated EMS who described a post-ictal period. Patient reported taking 600 mg of prescribed fluoxetine (12.5 mg/kg) five hours prior to presentation. Triage VS showed tachycardia (118 bpm) but were otherwise unremarkable. Examination revealed horizontal nystagmus, hypertonicity in upper and lower extremities, and absence of ankle myoclonus or patellar hyperreflexia. Laboratory investigations showed mild leukocytosis (11.1× 10 9 /L), but were otherwise unremarkable including serum sodium 140 mmol/L, calcium 9.1 mg/dL, glucose 122 mg/dL, qualitative serum pregnancy negative, and acetaminophen, ethanol, and salicylate below limit of detection. ECG showed QTc 474 ms, and urine immunoassay for drugs of abuse was negative. Serial examination noted mydriasis and lower extremity hyperreflexia, both of which resolved within 38 h without further treatment. Outpatient primary care notes do not make mention of further seizure nor neurologic sequelae.
2
Discussion
We report four cases of intentional fluoxetine overdose complicated by seizure in adolescents. Dose ranged from 600 mg to 1200 mg (10 mg/kg to 19.5 mg/kg) though two patients ingested only 600 mg. We observed time from ingestion to seizure consistent with previous reports (3 to 8.5 h). History and review of dispense records were used to quantify dose and rule out co-ingestion. All patients had signs of serotonin excess and met Sternbach criteria for serotonin toxicity [ ] while patients in cases 1 and 3 satisfied Hunter and Radomski criteria [ , ]. No patient had signs of severe serotonin toxicity. Three patients developed QTc prolongation (Bazett calculation) but none had a recorded dysrhythmia on telemetry. Three patients were treated with benzodiazepines, and none had recurrent seizure. Medical toxicology was consulted in all cases, however neurology was not consulted in any case and no patient underwent intracranial imaging or electroencephalography. Outpatient follow up documentation is incompletely available but no patient was referred to neurology and no patient had a return ED visit, to the best of our knowledge. It is noteworthy that one patient in our series had reported ingestion of only 600 mg which is less than the dose implicated in most reported cases.
Seizures in the setting of fluoxetine toxicity are described infrequently and are without clearly defined pathophysiology. There are data to suggest that CYP2DC and 2C9 genotypes alter serum concentrations of fluoxetine and norfluoxetine at therapeutic dosing. This may also contribute to variable severity of toxicity despite lower dose [ , ]. Additional data regarding pharmacogenetics and serum levels of fluoxetine and norfluoxetine in overdose would be of interest, though are unfortunately unavailable in these cases. Additionally, inhibition of neuronal TREK-1 potassium channels by fluoxetine and norfluoxetine might play a role in this phenomenon [ ]. This channel is related to regulation of neuronal excitability, resistance to epilepsy, and protection from excitotoxicity. Knockout mice with a disrupted Trek1 gene were shown to have increased sensitivity to both ischemia and epilepsy [ ]. Therefore, we postulate that inhibition in the setting of toxicity might lead to neuroexcitation and possibly seizure.
There are notable limitations within our report. While we assume an accurate description of events, seizures are difficult to diagnose by semiology alone. Laboratory studies sufficiently ruled out electrolyte and metabolic derangements as a cause, though no patient had neuroimaging nor electroencephalography. It would be impossible to exclude a first presentation of a primary seizure disorder or a seizure mimic (e.g., PNEA) though this would be unusual given the demonstrated risk of secondary seizure related to fluoxetine overdose.
The most notable limitation is the lack of measured concentrations of fluoxetine and norfluoxetine and the absence confirmatory expanded urine assay. While each patient had documentation suggesting ingested dose and denial of co-ingested xenobiotics, historical data is limited in its reliability and we have no way of excluding concomitant ingestion or confirming lack of access to other xenobiotics, particularly those which may have epileptogenic potential or lower the seizure threshold. In each case, collateral history from family members, pill counts, and review of pharmacy dispense records were utilized to attempt to quantify dose and rule out co-ingestion.
Despite its limitations, this series adds to the repository of literature describing the infrequently, but potentially significant correlation between fluoxetine overdose and generalized seizure. Additional data is necessary to stratify risk after acute fluoxetine overdose, particularly in adolescent patients [ ].
Funding source
No funding was secured for this study.
CRediT authorship contribution statement
Matthew K. Kolbeck: Writing – review & editing, Writing – original draft, Investigation, Conceptualization. Rachel F. Schult: Investigation, Conceptualization, Writing – review & editing. Nicholas Nacca: Writing – review & editing, Investigation, Conceptualization.
Declaration of Competing Interest
The authors have no conflicts of interest to disclose.
References
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