Alpha-Amino-3-Hydroxy-5-Methyl-4- Isoxazole Propionic Acid Receptor Components of the Anti-Depressant Ketamine Response

Brief 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.

Intervention / Treatment

  • Drug: Ketamine
  • Drug: Perampanel
  • Drug: Placebo

Condition or Disease

  • Depressive Disorder, Major
  • Bipolar Disorder
  • Post Traumatic Stress Disorder

Phase

Study Design

Study type: Interventional
Status: Recruiting
Study results: No Results Available
Age: 21 Years to 65 Years   (Adult, Older Adult)
Enrollment: 50 ()
Funded by: Other

Masking

Clinical Trial Dates

Start date: Nov 29, 2018
Primary Completion: Dec 31, 2020
Completion Date: Dec 31, 2020
Study First Posted: Dec 08, 2017
Results First Posted: Aug 31, 2020
Last Updated: Jul 14, 2020

Sponsors / Collaborators

Lead Sponsor: N/A
Responsible Party: N/A

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.

Eligibility Criteria

Sex: All
Minimum Age: 21
Maximum Age: 65

This clinical trial is recruiting

Are you interested in participating in this trial or others? We'd love to help.

More Details

NCT Number: NCT03367533
Other IDs: 2000021345
Study URL: https://ClinicalTrials.gov/show/NCT03367533
Last updated: Jun 17, 2022