Alpha-Amino-3-Hydroxy-5-Methyl-4- Isoxazole Propionic Acid Receptor Components of the Anti-Depressant Ketamine Response
Condition: Depressive Disorder, Major; Bipolar Disorder; Post Traumatic Stress Disorder
MeSH terms: Depressive Disorder; Stress Disorders, Traumatic; Bipolar Disorder; Stress Disorders, Post-Traumatic; Depressive Disorder, Major
Study type: Interventional
Phase: Phase 1

Summary: 
      The proposed study will assess the combined effect of perampanel and ketamine on the
      anti-depressant response in individuals with treatment resistant depression. The purpose of
      this study is to test the hypothesis that stimulation of Alpha-Amino-3-Hydroxy-5-Methyl-4-
      Isoxazole Propionic Acid receptors (AMPAR) is critical to the anti-depressant response of
      ketamine.
    

Detailed description: 
      The proposed study is the first in humans to assess the necessity of
      Alpha-Amino-3-Hydroxy-5-Methyl-4- Isoxazole Propionic Acid receptors (AMPAR) stimulation for
      the emergence of the anti-depressant effects of ketamine. Despite the overall safety and
      efficacy of ketamine, concerns remain. For example, ketamine is a drug with abuse liability.
      Similarly, it produces transient cognitive and perceptual changes that are distressing for
      some patients. Therefore, it is critical to determine which aspects of ketamine's effects on
      neural systems. To do this, we employ perampanel, an FDA-approved drug that blocks calcium
      and non-calcium dependent AMPARs. We employ a counter-balanced cross-over design in which
      ketamine plus perampanel is given on one day, and approximately 21 days later ketamine plus
      placebo is given. The effects of these drug combinations are assessed via fMRI studies of
      neural functional connectivity and oxidative metabolism as well as interview and self-report
      measures on the infusion day and 24 hours later. If perampanel blocks the capacity of
      ketamine to ameliorate the clinical and neural signatures of major depression, it would
      suggest that AMPAR stimulation is critical for the anti- depressant effects of ketamine in
      humans. This would support the further exploration of drugs that selectively enhance the
      stimulation of AMPARs without blocking N-methyl-D-aspartate receptors (NMDARs), such as
      AMPAkines and metabotropic glutamate receptor 2 (mGluR2) antagonists as anti-depressants.

      Specific hypotheses include:

      The purpose of this study is to test the hypothesis that stimulation of
      Alpha-Amino-3-Hydroxy-5-Methyl-4- Isoxazole Propionic Acid receptors (AMPAR) is critical to
      the anti-depressant response of ketamine.

      Specifically, we will test the following hypotheses:

        1. Perampanel pre-treatment reduces ketamine-related increases in prefrontal functional
           connectivity and CMRO2 during ketamine infusion in individuals with treatment-resistant
           depression.

        2. Perampanel pre-treatment reduces ketamine-induced increases in prefrontal CMRO2 and
           functional connectivity observed at 24 hours in individuals with treatment resistant
           depression.

        3. Perampanel pre-treatment reduces the positive effect of ketamine on clinical improvement
           as measured by the Hamilton Depression Inventory (1) at 24 hours in individuals with
           treatment resistant depression.

      Exploratory: Changes in prefrontal functional connectivity and CMRO2 during ketamine infusion
      and 24 hours post-infusion are correlated with clinical improvement as measured by the
      Hamilton Depression Inventory in individuals with treatment resistant depression.

      As this study is the first, to the investigator's knowledge, to involve using ketamine and
      perampanel in human subjects, the investigators have included a small out-of-scanner study to
      test the safety of the ketamine/perampanel combination on 3 healthy subjects. This
      registration focuses on the main study that will follow the safety evaluation and evaluate
      the effect of perampanel and ketamine on individuals with treatment resistant depression.
    

Intervention name(s): Ketamine; Perampanel; Placebo
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Intravenous ketamine; Oral perampanel (6 mg); Oral placebo
Intervention MeSH terms: Ketamine
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: The investigators employ a counter-balanced cross-over design in which ketamine plus perampanel is given on one day, and approximately 21 days later ketamine plus placebo is given.
Masking: Double (Participant, Investigator)
Primary purpose: Basic Science