Actively Recruiting
The Mechanism of Action Underlying Ketamine's Antidepressant Effects: An Investigation of the AMPA Throughput Theory in Patients With Treatment-Resistant Major Depression
Led by National Institute of Mental Health (NIMH) · Updated on 2026-02-24
70
Participants Needed
1
Research Sites
N/A
Total Duration
On this page
AI-Summary
What this Trial Is About
Researchers are investigating the rapid antidepressant effects of ketamine in adults with treatment-resistant major depressive disorder (MDD) without psychotic features. The study aims to understand the role of AMPA receptors in ketamine's action by testing whether blocking these receptors affects ketamine's antidepressant response. This research also explores brain activity patterns and synaptic changes related to ketamine treatment. The study involves two phases over approximately five weeks. In phase one, participants taper off psychiatric medications and undergo various tests including blood draws, psychological assessments, MRI, MEG brain scans, optional sleep monitoring, and optional transcranial magnetic stimulation (TMS). In phase two, participants are randomly assigned to receive either the AMPA receptor blocker perampanel or placebo before an open-label ketamine infusion, followed by repeated assessments similar to phase one. An optional extension includes additional ketamine treatment and testing. Participants will stay at the clinical center for the study duration and complete multiple evaluations including brain imaging, psychological tests, and blood sampling. Researchers will monitor depressive symptoms using the Montgomery-Asberg Depression Rating Scale and study changes in brain activity and synaptic plasticity. The study also tracks safety and side effects throughout treatment and follow-up periods to better understand ketamine's antidepressant mechanism.
CONDITIONS
Brief Title
Mechanism of Action Underlying Ketamine's Antidepressant Effects: The AMPA Throughput Theory in Patients With Treatment-Resistant Major Depression
Who Can Participate
Eligibility Criteria
You may qualify if you...
- 18 to 70 years of age
- Able to understand and agree to all required tests and sign informed consent
- Completed screening under protocol 01-M-0254
- Diagnosed with major depressive disorder without psychotic features per DSM-IV or DSM-5
- Initial Montgomery-Asberg Depression Rating Scale (MADRS) score of 22 or higher and Young Mania Rating Scale (YMRS) score less than 12
- Lack of response to at least two adequate antidepressant trials, including one in current episode
- Current major depressive episode lasting at least four weeks
- Agree to be hospitalized during the study
- For open-label ketamine phase, completion of Phase II and use of effective birth control or sexual abstinence if able to get pregnant
You will not qualify if you...
- Current psychotic features or diagnosis of schizophrenia or other psychotic disorder
- History of substance abuse or dependence within past 3 months, excluding caffeine or nicotine
- Current illicit drug use or positive drug/alcohol screening at study entry
- Serious unstable medical illnesses including liver, kidney, heart, respiratory, endocrine, neurological, immune, or blood diseases
- Pregnant, nursing, or physically able to become pregnant without effective birth control
- History of seizures, epilepsy, stroke, brain surgery, head injury, or structural brain lesion
- Medical conditions likely to affect brain structure or function, such as hypertension or diabetes
- Abnormal laboratory tests deemed clinically significant
- Hearing loss that may worsen with imaging procedures
- Positive HIV test
- Weight over 119 kg
- Use of psychiatric or non-psychiatric medications prior to Phase II (medications must be tapered)
- Use of opioid medication in past 3 months
- Use of reversible MAOIs prior to Phase II
- Use of fluoxetine or aripiprazole at screening
- Unwillingness to stop structured psychotherapy during study phases
- Presence of metallic implants
- Claustrophobia or inability to lie still during MRI/MEG
- Serious suicidal or homicidal risk or history of aggressive behavior
- Employment or immediate family relation to NIMH staff
- For open-label ketamine phase, prior serious adverse reaction to ketamine or positive illicit drug test within 24 hours
- Pregnancy or nursing during open-label ketamine phase
AI-Screening
AI-Powered Screening
Complete this quick 3-step screening to check your eligibility
Your Study Journey
Duration - 2 to 4 weeks
Participants are screened for eligibility to participate in the trial.
Participants undergo screening assessments including clinical rating scales and medical evaluations to confirm eligibility.
Duration - Duration not specified
Participants undergo medication tapering, a drug-free period, and baseline testing including clinical rating scales, sEEG, TMS, and MEG assessments.
Multiple visits for baseline clinical and neurophysiological assessments before treatment.
Duration - 2 days
Participants receive an open-label ketamine infusion combined with randomized, double-blind oral medication (perampanel or placebo) to evaluate ketamine's antidepressant effects.
Visits on Day 1 and Day 2 for ketamine infusion, medication administration, clinical rating scales, and neurophysiological assessments.
Duration - 1 visit
Participants who completed the randomized treatment phase are offered one additional open-label ketamine treatment to assess mood symptoms and side effects.
1 visit (in-person) for open-label ketamine administration and assessments.
Trial Site Locations
Total: 1 location
1
National Institutes of Health Clinical Center
Bethesda, Maryland, United States, 20892
Actively Recruiting
Research Team
Y
Yamila I Carmona
C
Carlos A Zarate, M.D.
How is the study designed?
Study Type
INTERVENTIONAL
Masking
TRIPLE
Allocation
RANDOMIZED
Model
PARALLEL
Primary Purpose
BASIC_SCIENCE
Number of Arms
3
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