Efficacy of Fluoxetine Against Seizure-induced Central Apneas

Study Overview
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Brief Summary
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Sudden unexpected death in epilepsy (SUDEP) is a tragic outcome of seizure disorders that primarily affect young adults suffering from refractory epilepsy. In this population, SUDEP incidence is estimated at 0.5%. While the mechanisms of SUDEP are not completely understood, it appears that the majority of such death occurs in the immediate aftermath of a general tonic-clonic seizure. There is currently no validated preventive treatment for SUDEP. Some evidence suggest that modulation of the serotoninergic tone, and more specifically selective serotonin recapture inhibitor (SSRI) such as fluoxetine, might prevent SUDEP. Indeed, fluoxetine prevents seizure-induced lethal central apneas in DBA/2 and DBA/1 mice, one of the few animal models of SUDEP. Furthermore, serotoninergic bulbar nuclei are known to play a major role in the control of breathing, especially during sleep and in response to repeated hypoxia. In patients with epilepsy undergoing in-hospital video-EEG monitoring, about one third of seizures are associated with decrease in SpO2 <90%, an abnormality suspected to represent a risk factor of SUDEP. In a retrospective uncontrolled study, patients treated with SSRIs displayed less frequent ictal/post-ictal hypoxemia than patients not taking SSRIs. The investigators project aimed at testing whether fluoxetine can reduce the risk of ictal/post-ictal hypoxemia by performing a double-blind, randomized, placebo-controlled trial in patients undergoing video-EEG monitoring as part of the pre-surgical evaluation of their focal drug-resistant epilepsy.

Official Title
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Efficacy of Fluoxetine Against Seizure-induced Central Apneas : a Randomized Placebo-controled Double-blind Trial.

Conditions
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Epilepsy, Ictal/Post-ictal Hypoxemia

Intervention / Treatment
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* Drug: fluoxetine 20 mg
* Drug: placebo 20 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient suffering from drug-resistant focal epilepsy Age ≥ 18 years Patient for whom a video-EEG monitoring of their seizures was scheduled as part of a pre-surgical assessment For women of childbearing age, a method of contraception considered effective by the investigator Patient who have given their written informed consent Patient accepting an interview with a psychologist and to be refered to a psychiatrist in the event that mood disorders were detected on mood scores and considered severe by the investigator and / or psychologist, leading to require psychiatric care or immediate antidepressant treatment Patient with a social security number Exclusion Criteria: Age < 18 years Patient under legal protection Pregnant or breastfeeding women Hypersensitivity to fluoxetine or its excipients History of other serious side effects related to an earlier prescription of fluoxetine; Current suicidal ideation or history of suicide attempt Manic episode Disruption of liver enzymes considered material by the investigator using the following criteria: transaminases (ALT and AST)> 2N alkaline phosphatase (ALP)> 2N gamma glutamyl transpeptidase (GGT)> 5N (performed as part of routine monitoring of epileptic patients on antiepileptic treatment. Patients often exhibit changed deemed clinically insignificant due to the enzyme-inducing effect of these drugs) Renal failure with creatinine clearance <30 ml / min Acute heart disease Antidepressant treatment Other prohibited treatment (see detailed list in protocol).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: FLUOXETINE<br>4 weeks of treatment before video-EEG monitoring | Drug: fluoxetine 20 mg<br>* Fluoxetine 20 mg per day during 4 weeks prior to video-EEG, then continued during video-EEG. At the end of video-EEG, and according to patient's decision, treatment was either progressively withdrawn (1 week at 10 mg per day and then 1 week at 5 mg per day), or replaced by fluoxetine 20 mg open-label.<br>|
| Placebo Comparator: PLACEBO<br>1 month of treatment before EEG video. | Drug: placebo 20 mg<br>* Placebo 20 mg per day during 4 weeks prior to video-EEG, then continued during video-EEG. At the end of video-EEG, and according to patient's decision, treatment was either progressively withdrawn (1 week at 10 mg per day and then 1 week at 5 mg per day), or replaced by fluoxetine 20 mg open-label.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ictal/post-ictal hypoxemia | Percentage of patients with at least one seizure associated with ictal/post-ictal SpO2 <90% in the group treated with fluoxetine compared to that receiving placebo. | Duration of video-EEG following 4 weeks of fluoxetine treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in mood score with BDI-II score | Changes in score of BDI-II after four weeks of treatment as compared to baseline in the group treated with fluoxetine compared to that receiving placebo | After four weeks of treatment as compared to baseline | 
| Change in mood score with NDDIE score | Changes in score of NDDIE after four weeks of treatment as compared to baseline in the group treated with fluoxetine compared to that receiving placebo | After four weeks of treatment as compared to baseline | 
| Change in seizure frequency | Changes in seizure frequency after four weeks of treatment as compared to baseline in the group treated with fluoxetine compared to that receiving placebo | After four weeks of treatment as compared to baseline | 
| Change in sleep disorders score with SASDQ score | Changes in score of SASDQ after four weeks of treatment as compared to baseline in the group treated with fluoxetine compared to that receiving placebo | After four weeks of treatment as compared to baseline | 
| Change in sleep disorders score with EPWORTH score | Changes in score of EPWORTH after four weeks of treatment as compared to baseline in the group treated with fluoxetine compared to that receiving placebo | After four weeks of treatment as compared to baseline | 
| Change in score of quality of life | Change in score of QOLIE-89 after four weeks of treatment as compared to baseline in the group treated with fluoxetine compared to that receiving placebo | After four weeks of treatment as compared to baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Epilepsy, SUDEP, fluoxetine, placebo, SpO2