Abnormal Ventilatory Response to Carbon Dioxide: a Potential Biomarker for Seizure Induced Respiratory Depression & Modification by SSRI
Condition: Epilepsy; SUDEP
MeSH terms: Respiratory Insufficiency; Seizures
Study type: Interventional
Phase: Phase 2

Summary: 
      Sudden unexpected death in epilepsy patients (SUDEP) is devastating outcome for some patients
      with epilepsy. It ranks second only to stroke among neurological diseases in years of
      potential life lost. Patho-mechanisms of SUDEP remain not well understood, however peri-ictal
      respiratory dysfunction likely plays an important role in many cases.

      Literature supports a critical role for the serotonergic system in central control of
      ventilation. Serotonin neurons in the raphe nuclei of the brainstem sense rising carbon
      dioxide and low pH, thereby stimulating breathing and arousal. These responses may serve as
      mechanisms that protect against asphyxia, particularly during sleep or the post-ictal state.
      In mouse models of seizure-induced sudden death, pre-treatment with selective serotonin
      reuptake inhibitor (SSRI) agents prevents death following seizures. Hence, the investigators
      hypothesize that a subset of drug resistant epilepsy patients who have impaired central
      chemo-responsiveness have a greater degree of peri-ictal respiratory depression, therefore a
      higher risk of SUDEP. The investigators further hypothesize that fluoxetine will improve
      central chemo-responsiveness and therefore will reduce peri-ictal respiratory depression.
    

Detailed description: 
      Sudden unexpected death in epilepsy (SUDEP) refers to the sudden, unexpected, nontraumatic,
      non-drowning, witnessed or unwitnessed death of an individual with epilepsy. Postmortem
      examination in such cases fails to reveal an obvious medical or toxicologic cause for the
      death, and patients who die from SUDEP are typically healthy apart from their epilepsy. The
      incidence of SUDEP in epilepsy patients is estimated to be 0.1 in 1000 patient years, and
      this rate increases to >9.3 per 1000 for those with durg resistant epilepsy (DRE) who are
      candidates for epilepsy surgery. Although thought to be rare, SUDEP is estimated to be
      responsible for 17% of all deaths in patients with epilepsy, and approximately 50% of all
      deaths in patients with DRE. It is second only to stroke among neurological diseases in YPLL
      because many who die of SUDEP are relatively young and therefore it is a major public health
      concern. While there are some acknowledged risk factors for SUDEP, the actual cause, or
      causes, of SUDEP is not known. Seizure induced respiratory depression is likely to be a major
      contributor in SUDEP in many cases.

      Preliminary results from the ventilatory response to CO2 or hypercapnic ventilatory response
      (HCVR) study of patient with epilepsy in epilepsy monitoring unit (EMU) suggests prolonged
      period of CO2 elevation after seizures correlating with low HCVR. These findings suggest a
      defect in CO2 responsiveness in this high-risk population that may predispose to SUDEP.
      Serotonin nerve cells in the brain stem are responsible for detecting increases in CO2, and
      in response stimulating breathing and arousal from sleep. Fluoxetine is a selective serotonin
      reuptake inhibitor (SSRI) drug that increases availability of serotonin in the brain. As
      such, it may serve to stimulate breathing after seizures in patients with epilepsy who
      exhibit low CO2 sensitivity at baseline and this may alter SUDEP risk.

      This study consists of a double blind randomized controlled clinical trial with a 6-week
      titration of an intervention. It is designed to evaluate primarily feasibility of a larger
      clinical trial testing efficacy of fluoxetine in modifying HCVR in patients with epilepsy
      while also collecting important secondary and exploratory outcomes that would be valuable for
      designing future larger studies.

      We will evaluate challenges in screening, enrollment, randomization, and completion of
      study-related procedures by quantifying the numbers of subjects eligible for screening, the
      number of subjects enrolled in the study per month, the proportion of patients successfully
      completing the study, and the specific challenges at each step. We will also assess
      challenges in setting up and performing outpatient HCVR testing.
    

Intervention name(s): Fluoxetine; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Standard 6 weeks titration, starting 10 mg per day.; Standard 6 weeks titration.
Other intervention name(s): Prozac
Intervention MeSH terms: Fluoxetine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Prevention
Keywords: Fluoxetine