Alpha-Amino-3-Hydroxy-5-Methyl-4- Isoxazole Propionic Acid Receptor Components of the Anti-Depressant Ketamine Response
- Conditions
- Depressive Disorder, MajorPost Traumatic Stress Disorder
- Interventions
- Registration Number
- NCT05915013
- Lead Sponsor
- Yale University
- 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.
- 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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 50
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- CROSSOVER
- Arm && Interventions
Group Intervention Description ketamine plus perampanel Ketamine A screening session is conducted to ensure that the subject can safely receive perampanel and ketamine (physical exam, blood and urine analyses, electrocardiogram, drug and alcohol testing). The participant will then receive 6 milligrams (mg) oral perampanel and intravenous ketamine. Participants will then undergo a 2-hour magnetic resonance imagining (MRI) scan. The following day, participants will return for an additional scan and symptom assessment. ketamine plus placebo Placebo A screening session is conducted to ensure that the subject can safely receive perampanel and ketamine (physical exam, blood and urine analyses, electrocardiogram, drug and alcohol testing). The participant will then receive an oral placebo (in lieu of 6 mg oral perampanel) and intravenous ketamine. Participants will then undergo a 2-hour MRI scan. The following day, participants will return for an additional scan and symptom assessment. ketamine plus perampanel Perampanel A screening session is conducted to ensure that the subject can safely receive perampanel and ketamine (physical exam, blood and urine analyses, electrocardiogram, drug and alcohol testing). The participant will then receive 6 milligrams (mg) oral perampanel and intravenous ketamine. Participants will then undergo a 2-hour magnetic resonance imagining (MRI) scan. The following day, participants will return for an additional scan and symptom assessment. ketamine plus placebo Ketamine A screening session is conducted to ensure that the subject can safely receive perampanel and ketamine (physical exam, blood and urine analyses, electrocardiogram, drug and alcohol testing). The participant will then receive an oral placebo (in lieu of 6 mg oral perampanel) and intravenous ketamine. Participants will then undergo a 2-hour MRI scan. The following day, participants will return for an additional scan and symptom assessment.
- Primary Outcome Measures
Name Time Method Prefrontal functional connectivity During ketamine infusion, approximately 2.5 hours This outcome will be assessed via functional magnetic resonance imaging (fMRI).
Cerebral metabolic rate of oxygen (CMRO2) During ketamine infusion, approximately 2.5 hours. This outcome will be assessed via fMRI.
- Secondary Outcome Measures
Name Time Method Clinical improvement. 24 hours post-infusion This outcome will be assessed by the Hamilton Depression Inventory, a clinician-rated instrument.
Trial Locations
- Locations (1)
Yale University
🇺🇸New Haven, Connecticut, United States