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

Abstract

Introduction. Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) that is used in the management of depression and obsessive compulsive disorders. We report a patient with status epilepticus requiring quadruple anti-convulsant treatment following a fluvoxamine overdose. Case Report. A 25-year-old female presented with drowsiness at 12 hours following deliberate ingestion of 9.6 grams of fluvoxamine. Sixteen hours after ingestion, she developed status epilepticus that required treatment with benzodiazepines (lorazepam and midazolam), 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 with no further episodes of seizures. Discussion. Most patients with fluvoxamine poisoning are either asymptomatic or may develop mild signs of serotonergic toxicity. Although serotonin syndrome and isolated seizures are reported in fluvoxamine poisoning, we report the first patient 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 SSRIs such as fluvoxamine is to inhibit the uptake of serotonin by pre-synaptic receptors, thereby increasing serotonin concentrations within the synapse resulting in increased post-synaptic activity [1]. They have improved safety, both in therapeutic use and in overdose, compared to older conventional anti-depressant drugs such as the tricyclic anti-depressants and the mono-amine oxidase inhibitors (MAOI) [2]. However, there have been case reports of seizures following therapeutic use of fluvoxamine in patients with and without a history of pre-existing seizures [3,4,5]. There have been two previous case reports of repeated multiple self-limiting seizures following overdoses with fluvoxamine, although in both cases there was incomplete toxicological screening undertaken to confirm isolated fluvoxamine ingestion [6,7]. We report here the first case report of survival following status epilepticus induced by isolated fluvoxamine toxicity.

Case report

A 25-year-old woman with known depression, but no other significant past medical history presented 12 hours after ingesting 9.6g of fluvoxamine. The fluvoxamine tablets had been posted from overseas to the patient by members of her family. She was bought in to the Emergency Department (ED) having been found in a collapsed state, but prior to her collapse she had told members of her family that she had ingested fluvoxamine and the amount ingested. Prior to presentation in the ED, there were no witnessed seizures by either family members or the ambulance service. No interventions were performed by the ambulance crew prior to arrival at the ED. On initial review in the ED, her Glasgow Coma Scale (GCS) was 15/15 and she was able to maintain and protect her airway. She was hemodynamically stable with a blood pressure of 128/82 mmHg and a heart rate of 115 beats/minute and her initial ECG showed sinus rhythm with a rate of 145 beats/minute and normal QRS and QTc durations. Over the first 4 hours following her admission, her heart rate ranged between 114 and 136 beats/minute and systolic blood pressure between 110 and 130 mmHg. There was no focal neurological abnormality on examination, reflexes were normal and there was no spontaneous or inducible clonus. Her temperature was 37.5°C. Therefore there were no features suggestive of serotonin toxicity and insufficient evidence to make a diagnosis of Serotonin Syndrome [8]. Initial biochemistry blood test results were sodium 145 mmol/L, potassium 3.9 mmol/L, urea 2.9 mmol/l (8.1 mg/dL), creatinine 75 micromol/L (0.85 mg/dL) and venous blood glucose 13 mmol/L (234 mg/dL). Paracetamol (acetaminophen) and salicylate concentrations were not detected on her admission blood samples. As she appeared clinically well at the time of her presentation, she was transferred to a general medical admitting ward for ongoing observation and psychiatry consultation.

Approximately four hours after presentation to the ED (16 hours post-ingestion), she developed generalised tonic-clonic seizures, which did not respond to intravenous lorazepam (bolus of 7 mg followed by infusion of 2 mg/hr) and midazolam (bolus of 4 mg followed by an infusion of 6 mg/hr). During the prolonged seizure activity, the patient had a pulseless electrical activity (PEA) cardiac arrest, requiring three cycles of cardiopulmonary resuscitation (CPR) before return of spontaneous circulation. There was no other obvious cause of the PEA cardiac arrest, apart from the fluvoxamine ingestion. Following a bolus of 250 mg of thiopentone during intubation and ventilation and loading with 2g of phenytoin over a period of one hour, her spontaneous tonic-clonic seizures had ceased. However, she continued to have seizures induced by minimal stimulation that clinically were classical tonic clonic. She was given phenobarbitone 800 mg over ten minutes and her stimulation-induced seizures ceased completely. Although continuous EEG monitoring could not be undertaken to ensure cessation of her status epilepticus, there was no overt clinical evidence of further seizures. Her renal function and creatinine kinase concentrations remained normal following her prolonged seizures. She remained well, was extubated after she had remained seizure-free for 24 hours and was discharged from hospital after 72 hours, following a psychiatry consultation.

Serum obtained on presentation to the ED was analysed for fluvoxamine and for a general toxicology screen by the Medical Toxicology Laboratory in London. The determination of the fluvoxamine concentration was by high-performance liquid chromatography with ultraviolet detection. Her serum fluvoxamine concentration on presentation to the ED was 1970 μg/L (normal therapeutic range 160–220 μg/L). A toxicological screen for more than 100 compounds was undertaken by gas chromatography with Nitrogen Phosphorus (NPD) and Electron Capture (ECD) detection and failed to identify any other drugs, including all major pro-convulsant drugs.

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-synaptic neurones, thereby leading to an increased concentration of serotonin within the synaptic cleft [1]. It has been shown to have little or no activity on the re-uptake of other neurotransmitters, as seen with non-specific uptake inhibitors such as the tricyclic antidepressants [9]. The onset of action with therapeutic use of SSRIs is usually over a period of weeks, which may reflect dynamic changes in the pre- and post-synaptic serotonin receptors in response to the increased concentrations of serotonin within the synaptic cleft [10]. Fluvoxamine is currently licensed for the management of both depression and obsessive-compulsive disorders, and is used in adults to a maximum of 300 mg/day given in divided doses [11].

Similar to other SSRIs, fluvoxamine is thought to be a relatively safe drug with minimal unwanted effects in therapeutic dosages. The most commonly reported adverse events in therapeutic use are nausea and vomiting, similar to that of other SSRIs [3]. Post-marketing surveillance undertaken by the manufacturers following use in over 28 million patients, found only 6,658 (0.02%) reported adverse reactions of which the majority were minor in nature and were of similar frequencies to the other SSRIs [12]. One of the main concerns with anti-depressant use, including SSRIs, is the increased risk of seizures in patients with a previous history of seizures. Additionally there have been case reports of seizures occurring in patients without a previous history of seizures following therapeutic use of fluvoxamine [4,5]. However there has been no data to support the hypothesis of a significant increased risk of seizures with therapeutic doses of fluvoxamine [3,13]. Following its initial registration and licensing in the UK, of a total of 961 adverse events reported to the UK committee on safety of Medicines (CSM), now part of the Medicines and Healthcare products Regulatory Authority (MHRA), over a 56 month period, only 13 (1.4%) of these related to seizures following therapeutic use of fluvoxamine [3]. Additionally in a clinical trial of therapeutic fluvoxamine use in 35 patients with known epilepsy over a minimum of 4 weeks of fluvoxamine treatment, there was no reported increase in the frequency of epileptic seizures when compared to the frequency prior to initiation of fluvoxamine treatment [13].

The effects of fluvoxamine in overdose have been reported in a large series of 299 patients in France [14]. Two hundred twenty-one cases were reported to the Paris Poison Centre (PCC) and 78 cases to the International Drug Safety Department (IDSD) of the French manufacturer. Toxicological analyses to confirm fluvoxamine ingestion were only undertaken in 53 (17.7%) patients. Symptoms following ingestion of <1000mg of fluvoxamine were usually mild and included nausea, vomiting, drowsiness and anticholinergic effects such as dry mouth and tachycardia. Data from the PCC showed that seizures were reported in only 5 (1.7%) cases and there we no cases of seizures reported to the IDSD. Additionally seizures were only seen in those patients who had reported ingestion of >1500mg of fluvoxamine. However it is possible that many of the patients who developed seizures following fluvoxamine overdose had co-ingested other drugs, such as tricyclic antidepressants, barbiturates, phenothiazines, benzodiazepines and alcohol, which could have precipitated the seizures.

The have been only two reports of recurrent seizures in patients with fluvoxamine toxicity [6,7]. Following reported ingestion of 6g of fluvoxamine, a patient had initial self-limiting generalised seizures, which recurred and were treated with IV diazepam (2.5mg) and paralysis and mechanical ventilation [7]. There was no toxicological analysis performed to confirm fluvoxamine ingestion and to exclude ingestion of other drugs that could cause recurrent seizures. Following a reported ingestion of 10 g of fluvoxamine, a 40 year old male had recurrent self-limiting generalised seizures over the initial 24 hours following ingestion that were treated with intravenous lorazepam and phenytoin [6]. Toxicological screening confirmed fluvoxamine ingestion and was negative for drugs of abuse and tricyclic antidepressants. This case has been reported in abstract only so there is limited information on the drug treatments given and it is unclear whether ingestion of other pro-convulsant drugs had been excluded with thorough toxicological screening. In our reported case we have excluded tricyclic antidepressants and other pro-convulsant drugs on toxicological screening, and demonstrated status epilepticus following isolated fluvoxamine ingestion.

Conclusion

We have described a case of a status epilepticus and subsequent PEA cardiac arrest following severe poisoning with fluvoxamine. 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 fluvoxamine and there was no other medical cause identified for her status epilepticus or PEA cardiac arrest.

Notes

* DW, SG, PD and AJ provided toxicology advice on the management of the patient, YR was the physician in charge of the patients immediate medical care, PM and DG undertook the toxicological screening and the measurement of fluvoxamine concentration, DW and PD drafted the first draft of this manuscript and all authors contributed to the final draft of the manuscript.

11. Faverin Tablets 50 or 100 mg. Summary of product characteristics, UK. Solvay Healthcare Limited, June 2006.