Clinical Toxicology (2007) 45, 791–793 Copyright © Informa Healthcare USA, Inc.ISSN: 1556-3650 print / 1556-9519 onlineDOI: 10.1080/15563650701664574

LCLTCASE REPORT

Status epilepticus following intentional overdose of fluvoxamine: A case report with serum fluvoxamine concentration

Status epilepticus following fluvoxamine overdoseDAVID M. WOOD1, YADHUNANTHANAN RAJALINGAM2, SHAUN L. GREENE3, PHILLIP E. MORGAN1, DAVID GERRIE1, ALISON L. JONES3, and PAUL I. DARGAN1

1Guy’s and St. Thomas’ Poisons Unit, Guy’s and St Thomas’ NHS Foundation Trust, London, United Kingdom2Intensive Care Medicine, Royal Free Hospital, London, United Kingdom3University of Newcastle, Callaghan Drive, Newcastle, NSW, Australia

Introduction. Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) that is used in the management of depression and obsessivecompulsive disorders. We report a patient with status epilepticus requiring quadruple anti-convulsant treatment following a fluvoxamineoverdose. Case Report. A 25-year-old female presented with drowsiness at 12 hours following deliberate ingestion of 9.6 grams offluvoxamine. Sixteen hours after ingestion, she developed status epilepticus that required treatment with benzodiazepines (lorazepam andmidazolam), thiopentone, phenytoin and phenobarbitone. Her serum fluvoxamine concentration on presentation was 1970 μg/L(therapeutic 160–220 μg/L) and routine toxicological screening was negative for other drugs. She was discharged home after 72 hours withno further episodes of seizures. Discussion. Most patients with fluvoxamine poisoning are either asymptomatic or may develop mildsigns of serotonergic toxicity. Although serotonin syndrome and isolated seizures are reported in fluvoxamine poisoning, we report the firstpatient with confirmed isolated fluvoxamine toxicity who developed status epilepticus.

Keywords Poisoning; Fluvoxamine; Status epilepticus; Seizure; Selective serotonin re-uptake inhibitor (SSRI); Kinetics.

Introduction

Fluvoxamine is a selective serotonin re-uptake inhibitor(SSRI) that is used in the treatment of depression and obsessive-compulsive disorder. The pharmacological action of SSRIssuch as fluvoxamine is to inhibit the uptake of serotonin bypre-synaptic receptors, thereby increasing serotonin concen-trations within the synapse resulting in increased post-synapticactivity [1]. They have improved safety, both in therapeuticuse and in overdose, compared to older conventional anti-depressant drugs such as the tricyclic anti-depressants and themono-amine oxidase inhibitors (MAOI) [2]. However, therehave been case reports of seizures following therapeutic useof fluvoxamine in patients with and without a history of pre-

existing seizures [3,4,5]. There have been two previous casereports of repeated multiple self-limiting seizures followingoverdoses with fluvoxamine, although in both cases therewas incomplete toxicological screening undertaken to con-firm isolated fluvoxamine ingestion [6,7]. We report here thefirst case report of survival following status epilepticusinduced by isolated fluvoxamine toxicity.

Case report

A 25-year-old woman with known depression, but no othersignificant past medical history presented 12 hours afteringesting 9.6g of fluvoxamine. The fluvoxamine tablets hadbeen posted from overseas to the patient by members of herfamily. She was bought in to the Emergency Department(ED) having been found in a collapsed state, but prior to hercollapse she had told members of her family that she hadingested fluvoxamine and the amount ingested. Prior topresentation in the ED, there were no witnessed seizures byeither family members or the ambulance service. No inter-ventions were performed by the ambulance crew prior toarrival at the ED. On initial review in the ED, her GlasgowComa Scale (GCS) was 15/15 and she was able to maintainand protect her airway. She was hemodynamically stablewith a blood pressure of 128/82 mmHg and a heart rate of

Received 24 July 2006; accepted 16 November 2006.DW, SG, PD and AJ provided toxicology advice on the manage-

ment of the patient, YR was the physician in charge of the patientsimmediate medical care, PM and DG undertook the toxicologicalscreening and the measurement of fluvoxamine concentration, DWand PD drafted the first draft of this manuscript and all authorscontributed to the final draft of the manuscript.

Address correspondence to Dr. David M. Wood, Locum Consult-ant Physician and Clinical Toxicologist, Guy’s and St. ThomasPoisons Unit, Avonley Road, London SE14 5ER, United Kingdom.E-mail: David.Wood@gstt.nhs.uk

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115 beats/minute and her initial ECG showed sinus rhythmwith a rate of 145 beats/minute and normal QRS and QTcdurations. Over the first 4 hours following her admission, herheart rate ranged between 114 and 136 beats/minute and sys-tolic blood pressure between 110 and 130 mmHg. There wasno focal neurological abnormality on examination, reflexeswere normal and there was no spontaneous or inducible clo-nus. Her temperature was 37.5°C. Therefore there were nofeatures suggestive of serotonin toxicity and insufficient evi-dence to make a diagnosis of Serotonin Syndrome [8]. Initialbiochemistry blood test results were sodium 145 mmol/L,potassium 3.9 mmol/L, urea 2.9 mmol/l (8.1 mg/dL), creati-nine 75 micromol/L (0.85 mg/dL) and venous blood glucose13 mmol/L (234 mg/dL). Paracetamol (acetaminophen) andsalicylate concentrations were not detected on her admissionblood samples. As she appeared clinically well at the time ofher presentation, she was transferred to a general medicaladmitting ward for ongoing observation and psychiatryconsultation.

Approximately four hours after presentation to the ED (16hours post-ingestion), she developed generalised tonic-clonicseizures, which did not respond to intravenous lorazepam(bolus of 7 mg followed by infusion of 2 mg/hr) and mida-zolam (bolus of 4 mg followed by an infusion of 6 mg/hr).During the prolonged seizure activity, the patient had a pulse-less electrical activity (PEA) cardiac arrest, requiring threecycles of cardiopulmonary resuscitation (CPR) before returnof spontaneous circulation. There was no other obvious causeof the PEA cardiac arrest, apart from the fluvoxamine inges-tion. Following a bolus of 250 mg of thiopentone duringintubation and ventilation and loading with 2g of phenytoinover a period of one hour, her spontaneous tonic-clonicseizures had ceased. However, she continued to have seizuresinduced by minimal stimulation that clinically were classicaltonic clonic. She was given phenobarbitone 800 mg over tenminutes and her stimulation-induced seizures ceased com-pletely. Although continuous EEG monitoring could not beundertaken to ensure cessation of her status epilepticus, therewas no overt clinical evidence of further seizures. Her renalfunction and creatinine kinase concentrations remained nor-mal following her prolonged seizures. She remained well,was extubated after she had remained seizure-free for 24hours and was discharged from hospital after 72 hours,following a psychiatry consultation.

Serum obtained on presentation to the ED was analysed forfluvoxamine and for a general toxicology screen by the Med-ical Toxicology Laboratory in London. The determination ofthe fluvoxamine concentration was by high-performance liq-uid chromatography with ultraviolet detection. Her serumfluvoxamine concentration on presentation to the ED was1970 μg/L (normal therapeutic range 160–220 μg/L). A toxi-cological screen for more than 100 compounds was under-taken by gas chromatography with Nitrogen Phosphorus(NPD) and Electron Capture (ECD) detection and failed toidentify any other drugs, including all major pro-convulsantdrugs.

Discussion

Fluvoxamine is a selective serotonin re-uptake inhibitor(SSRI) and its principal action, similar to that of other SSRIs,is to prevent the re-uptake of serotonin by the pre-synapticneurones, thereby leading to an increased concentration ofserotonin within the synaptic cleft [1]. It has been shown tohave little or no activity on the re-uptake of other neurotrans-mitters, as seen with non-specific uptake inhibitors such asthe tricyclic antidepressants [9]. The onset of action withtherapeutic use of SSRIs is usually over a period of weeks,which may reflect dynamic changes in the pre- and post-synapticserotonin receptors in response to the increased concentra-tions of serotonin within the synaptic cleft [10]. Fluvoxamineis currently licensed for the management of both depressionand obsessive-compulsive disorders, and is used in adults to amaximum of 300 mg/day given in divided doses [11].

Similar to other SSRIs, fluvoxamine is thought to be arelatively safe drug with minimal unwanted effects in thera-peutic dosages. The most commonly reported adverse eventsin therapeutic use are nausea and vomiting, similar to that ofother SSRIs [3]. Post-marketing surveillance undertaken bythe manufacturers following use in over 28 million patients,found only 6,658 (0.02%) reported adverse reactions ofwhich the majority were minor in nature and were of similarfrequencies to the other SSRIs [12]. One of the main con-cerns with anti-depressant use, including SSRIs, is theincreased risk of seizures in patients with a previous historyof seizures. Additionally there have been case reports ofseizures occurring in patients without a previous history ofseizures following therapeutic use of fluvoxamine [4,5].However there has been no data to support the hypothesis ofa significant increased risk of seizures with therapeutic dosesof fluvoxamine [3,13]. Following its initial registration andlicensing in the UK, of a total of 961 adverse events reportedto the UK committee on safety of Medicines (CSM), nowpart of the Medicines and Healthcare products RegulatoryAuthority (MHRA), over a 56 month period, only 13 (1.4%)of these related to seizures following therapeutic use offluvoxamine [3]. Additionally in a clinical trial of therapeuticfluvoxamine use in 35 patients with known epilepsy over aminimum of 4 weeks of fluvoxamine treatment, there was noreported increase in the frequency of epileptic seizures whencompared to the frequency prior to initiation of fluvoxaminetreatment [13].

The effects of fluvoxamine in overdose have been reportedin a large series of 299 patients in France [14]. Two hundredtwenty-one cases were reported to the Paris Poison Centre(PCC) and 78 cases to the International Drug Safety Depart-ment (IDSD) of the French manufacturer. Toxicological anal-yses to confirm fluvoxamine ingestion were only undertakenin 53 (17.7%) patients. Symptoms following ingestion of<1000mg of fluvoxamine were usually mild and includednausea, vomiting, drowsiness and anticholinergic effects suchas dry mouth and tachycardia. Data from the PCC showedthat seizures were reported in only 5 (1.7%) cases and there

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Status epilepticus following fluvoxamine overdose 793

we no cases of seizures reported to the IDSD. Additionallyseizures were only seen in those patients who had reportedingestion of >1500mg of fluvoxamine. However it is possiblethat many of the patients who developed seizures followingfluvoxamine overdose had co-ingested other drugs, such astricyclic antidepressants, barbiturates, phenothiazines, benzo-diazepines and alcohol, which could have precipitated theseizures.

The have been only two reports of recurrent seizures inpatients with fluvoxamine toxicity [6,7]. Following reportedingestion of 6g of fluvoxamine, a patient had initial self-limiting generalised seizures, which recurred and weretreated with IV diazepam (2.5mg) and paralysis and mechan-ical ventilation [7]. There was no toxicological analysis per-formed to confirm fluvoxamine ingestion and to excludeingestion of other drugs that could cause recurrent seizures.Following a reported ingestion of 10 g of fluvoxamine, a 40year old male had recurrent self-limiting generalised seizuresover the initial 24 hours following ingestion that were treatedwith intravenous lorazepam and phenytoin [6]. Toxicologicalscreening confirmed fluvoxamine ingestion and was negativefor drugs of abuse and tricyclic antidepressants. This case hasbeen reported in abstract only so there is limited informationon the drug treatments given and it is unclear whether inges-tion of other pro-convulsant drugs had been excluded withthorough toxicological screening. In our reported case wehave excluded tricyclic antidepressants and other pro-convulsantdrugs on toxicological screening, and demonstrated statusepilepticus following isolated fluvoxamine ingestion.

Conclusion

We have described a case of a status epilepticus and subse-quent PEA cardiac arrest following severe poisoning withfluvoxamine. The patient responded to quadruple anti-convulsant therapy and subsequently made an uneventful

recovery and was discharged home within 72 hours.Extended serum toxicological screening detected only flu-voxamine and there was no other medical cause identified forher status epilepticus or PEA cardiac arrest.

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