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
Intervention: Fluoxetine; Placebo
Intervention description: Standard 6 weeks titration, starting 10 mg per day.; Standard 6 weeks titration.
Intervention MeSH terms: Fluoxetine
Phase: Phase 2
Study type: Interventional
Primary purpose: Prevention
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 30.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: Fluoxetine

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.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Adult patients aged 18 or older

          2. Patients with epilepsy

          3. Native English speaker or adequate fluency in English to provide informed consent.

          4. Female patients of child-bearing potential must be using an acceptable method of
             contraception, and willing to refrain from sexual intercourse during the study.

        Exclusion Criteria:

          1. Progressive neurological disease.

          2. Clinical diagnosis of bipolar disease, panic disorder, psychosis or severe depression,
             or PHQ-9 score > 20

          3. Patients with prior hospitalization related to depression or Electroconvulsive
             therapy.

          4. History of suicidal ideation or intent in past or present

          5. Clinical history or laboratory evidence of hepatic or renal insufficiency.

          6. Pregnant or lactating women.

          7. Current heavy alcohol use (>14 drinks per week for men or >7 drinks per week for
             women) or) known medical disorder related to alcohol use or current illicit drug use,
             other than marijuana and its derivatives.

          8. Patients with recent use (<1 month) or already taking fluoxetine or other selective
             serotonin reuptake inhibitors (SSRIs).

          9. Concurrent use of monoamine oxidase inhibitors, antipsychotic agents, antidepressant
             agents other than SSRIs or frequent use of triptan agents (>2/week).

         10. History of a previous allergic reaction or adverse effects with fluoxetine,
             hypersensitive reaction-anaphylaxis; laryngeal edema; hives

         11. History of serotonin syndrome.

         12. History of uncontrolled pulmonary or cardiac illness.

         13. Patients with hypercapnic ventilatory response (HCVR) slope of > 2.0

         14. Patients with known prolong QT interval

         15. Patients with family history of prolong QT interval

         16. Patients with family history of sudden cardiac death under the age of 40 in a first
             degree relative.