Mechanism of Action Underlying Ketamine's Antidepressant Effects: The AMPA Throughput Theory in Patients With Treatment-Resistant Major Depression

  • End date
    Feb 1, 2025
  • participants needed
  • sponsor
    National Institute of Mental Health (NIMH)
Updated on 4 October 2022
blood test
depressive disorder
depressed mood
depressive episode
major depressive disorder
mood disorder
drug evaluation
major depressive disorder, single episode



Most drugs that treat mood disorders take a long time to work. Ketamine works within hours. A dose can last for a week or more. Certain receptors in the brain might help ketamine work. A drug that blocks these receptors might affect how it works.


To see if the antidepressant response of ketamine is linked to AMPA receptors.


Adults ages 18-70 with major depression disorder without psychotic features


Participants will be screened under protocol 01-M-0254. They will have blood tests and a physical exam.

Participants will stay at the NIH Clinical Center for 5 weeks.

Phase 1 lasts 4 weeks. For 2 weeks, participants will taper off their psychiatric medicine. Then they will have the following tests:

  • Blood draws
  • Psychological tests
  • MRI: Participants will lie in a machine that takes pictures of their brain.
  • MEG: Participants will lie down and do tasks. A cone lowered on their head will record brain activity.
  • Optional sleep tests: Electrodes on the scalp and body and belts around the body will monitor participants while they sleep.
  • Optional TMS: Participants will do tasks while a wire coil is held on their scalp. An electrical current will pass through the coil that affects brain activity.

For phase 2, on day 0 participants will take the study drug or a placebo orally. While having a MEG, they will get ketamine infused into a vein in one arm while blood is drawn from a vein in the other arm. On day 1, participants will again take the study drug or a placebo orally. On days 3-7, they will repeat many of the phase 1 tests. Days 8 and 9 are optional and include an open label ketamine treatment and many of the phase 1 tests.



Work by our group and others has demonstrated that a single intravenous dose of the glutamatergic modulator ketamine consistently produces rapid (within two hours), robust, and relatively sustained (approximately one to two weeks) antidepressant effects in patients with treatment-resistant major depressive disorder (MDD) and bipolar depression. Although ketamine is an N-methyl-D-aspartate (NMDA) receptor (NMDAR) antagonist, convergent evidence from behavioral, cellular, and molecular ketamine studies supports the theory that enhanced -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor activity-with a concomitant increase in synaptic plasticity-is critical to its mechanism of antidepressant action and may be the key to developing analogous rapidacting antidepressants. Notably, both animal and human studies indicate that acute, sub-anesthetic ketamine infusion is associated with robust increases in gamma power. Multiple synaptic mechanisms play a role in regulating gamma oscillations, including AMPA receptor (AMPAR)-mediated depolarization and gamma aminobutyric acid (GABA) receptor-mediated inhibition. Ketamine may influence both of these systems, both by silencing GABAergic inhibitory synapses and by increasing glutamate release, thereby activating AMPARs.

This clinical translational mechanistic protocol, in parallel with a preclinical study (Bench-to-Bedside Award, NIH), is designed to begin to disentangle the neurobiological underpinnings of ketamine s mechanism of antidepressant action and to develop a cross-species biomarker of target engagement (i.e., gamma power). The study will test the importance of AMPAR throughput by attempting to block the behavioral (i.e., antidepressant), electrophysiological, and biochemical effects of ketamine with an AMPAR antagonist. We first demonstrated in animal models that administering an AMPAR antagonist (NBQX) could block ketamine s antidepressant-like properties, suggesting that AMPAR neurotransmission was involved in these effects. This finding has now been replicated by multiple labs. In the present study, we propose to evaluate whether pre-treatment with perampanel, an AMPAR antagonist, blocks or reduces the acute antidepressant effects of ketamine in patients with treatment resistant depression (TRD). Further, we will examine whether AMPAR activity is important to the continued antidepressant effects of ketamine by examining whether treatment with perampanel blocks or reduces ketamine s continued antidepressant effects.

Study Population

70 patients ages 18 to 70 years, with a diagnosis of MDD (without psychotic features) will be recruited for this study.

Study Design

This is a two-phase pathophysiological study that attempts to understand the mechanism of action of ketamine s antidepressant effects. Phase I includes a medication taper, drug-free period, and baseline testing (e.g. clinical rating scales, sEEG, TMS, MEG). In Phase II, participants will receive an open-label ketamine infusion with a randomized, double-blind, add-on intervention (perampanel vs. placebo). Two to three hours prior to receiving ketamine (0.5 mg/kg), subjects will be randomized into one of three arms. Subjects in Arm 1 will receive perampanel (8 mg p.o.), while those randomized to Arm 2 or Arm 3 will receive matching placebo. On Day 1, the second blinded oral medication will be administered after clinical rating scales are obtained. Subjects randomized to Arm 1 and 3 will receive matching placebo, while subjects randomized to Arm 2 will receive perampanel. sEEG, TMS, and MEG will be obtained again on two more occasions during Phase II. Participants who completed Phase II will also be offered one open-label ketamine treatment, during which they will be assessed for mood symptoms and possible side effects.

Outcome Measures

The primary outcome measure is the Montgomery-Asberg Depression Rating Scale (MADRS). Hypothesis 1: By Day 1, patients treated with ketamine who are randomized to pre-treatment with a single oral dose of the AMPAR antagonist perampanel will have significantly more depressive symptoms than those who are randomized to pretreatment with placebo, as measured by the MADRS. Hypothesis 2: By Day 2, patients treated with ketamine who were randomized to perampanel on Day 1 will have significantly more depressive symptoms than those who were randomized to placebo, as measured by the MADRS. To acquire data corroborating that ketamine s antidepressant effects are mediated through AMPARs, surrogate plasticity measures will be obtained using sEEG, TMS, and MEG. In addition, blood samples for biomarkers will also be obtained.

Condition Depression, Major Depressive Disorder, Major Depression
Treatment Ketamine, Placebo, Perampanel, MagPro 100 TMS Therapy System, Arm 1 and 2 Interventions, Arm 1, 2, 3 Interventions, Arm 2 Interventions
Clinical Study IdentifierNCT03973268
SponsorNational Institute of Mental Health (NIMH)
Last Modified on4 October 2022


Yes No Not Sure

Inclusion Criteria

Phases I-II
18 to 70 years of age
Each subject must have a level of understanding sufficient to agree to all required tests and examinations and sign an informed consent document
All subjects must have undergone a screening assessment under protocol 01-M-0254, "The Evaluation of Patients with Mood and Anxiety Disorders and Healthy Volunteers
Subjects must fulfill DSM-IV or -5criteria for Major Depression (Major Depressive Disorder) without psychotic features, based on clinical assessment and informed by a structured diagnostic interview (SCID-P)
Subjects must have an initial score on the MADRS greater than or equal to 22 and a YMRS score of <12 within one week of study entry and upon entry into Phase II
Lack of response to two adequate antidepressant trials, with [at least] one in the current major depressive episode, operationally defined using the Antidepressant Treatment History Form (ATHF); a failed adequate trial of ECT [or TMS] would count as an adequate antidepressant trial
Current major depressive episode lasting at least four weeks
Agree to be hospitalized
Open-Label Ketamine Treatment
Participants must have met all inclusion criteria for and completed Study Phase II as a participant in Group 1 (active crisis)
Individuals who are able to get pregnant must be willing to remain sexually abstinent or use at least one form of effective birth control during participation in Phase III

Exclusion Criteria

Phases I-II
Current psychotic features or a diagnosis of schizophrenia or any other psychotic disorder as defined in the DSM-IV or DSM-5
Subjects with a history of substance abuse or dependence diagnosis (DSM-IV) or substance use disorder (DSM-5 equivalent) (except for caffeine or nicotine dependence) within the preceding 3 months. In addition, subjects who currently are using drugs (except for caffeine or nicotine) must not have used illicit substances or known drugs of abuse in the 2 weeks prior to screening and must have a negative alcohol and drug urine test (except for prescribed benzodiazepines or stimulants) at screening
Serious, unstable illnesses including hepatic, renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease, coronary artery disease, atherosclerotic ischemic stroke, and atrial fibrillation), endocrinologic, neurologic, immunologic, or hematologic disease
Pregnant or nursing individuals or those who are physically able to become pregnant. Participants who are physically able to become pregnant or cause a pregnancy must use at least one form of effective birth control or remain completely abstinent from sexual intercourse during the entire period of study participation (or until the last clinical labs and ratings). Participants able to become pregnant must have negative urine pregnancy tests no more than 24 hours prior to receiving the study drugs and undergoing imaging procedures
Subjects with one or more seizures without a clear and resolved etiology or current use of medication known to lower seizure threshold. History of seizure (regardless of age or etiology), history of epilepsy in self or first-degree relatives, stroke, brain surgery, head injury, or known structural brain lesion will be excluded from the TMS procedures
Presence of any medical illness likely to alter brain morphology and/or physiology (e.g., hypertension, diabetes) even if controlled by medications
Clinically significant abnormal laboratory tests
(For imaging procedures) Subjects with hearing loss that has been clinically evaluated and diagnosed and may be worsened through participation in imaging procedures
Positive HIV test
Weight > 119 kg
Treatment with any concomitant psychiatric medication prior to entering Phase II. [Medications must be tapered during Phase I.]
Treatment with any non-psychiatric medication/s
Any use of opioid medication in the past 3 months
Treatment with a reversible monoamine oxidase inhibitor (MAOI) prior to entering Phase II. [Medications must be tapered during Phase I.]
Treatment with fluoxetine or aripiprazole at the time of screening
Unwilling to stop undergoing structured, individualized psychotherapy. (Such therapy, including CBT, will not be permitted during Phases I and II of the study.)
Presence of metallic (ferromagnetic) implants (e.g., heart pacemaker, aneurysm clip)
Participants who are uncomfortable in small closed spaces (have claustrophobia)
Are unable to lie comfortably supine for up to 90 minutes and would feel uncomfortable in the MRI and MEG machines
Subjects who, in the investigator s judgment, pose a current serious suicidal or homicidal risk
Subjects who have a history of aggressive behavior towards others
A current NIMH employee/staff or their immediate family member
Open-Label Ketamine Treatment
Intolerable or serious adverse reaction to ketamine during Phase II
Participants with a positive urine for an illicit substance no more than 24 hours prior to ketamine treatment
Pregnant or nursing individuals or those who plan to become pregnant
Clear my responses

How to participate?

Step 1 Connect with a study center
What happens next?
  • You can expect the study team to contact you via email or phone in the next few days.
  • Sign up as volunteer  to help accelerate the development of new treatments and to get notified about similar trials.

You are contacting

Investigator Avatar

Primary Contact


Additional screening procedures may be conducted by the study team before you can be confirmed eligible to participate.

Learn more

If you are confirmed eligible after full screening, you will be required to understand and sign the informed consent if you decide to enroll in the study. Once enrolled you may be asked to make scheduled visits over a period of time.

Learn more

Complete your scheduled study participation activities and then you are done. You may receive summary of study results if provided by the sponsor.

Learn more

Similar trials to consider


Browse trials for

Not finding what you're looking for?

Every year hundreds of thousands of volunteers step forward to participate in research. Sign up as a volunteer and receive email notifications when clinical trials are posted in the medical category of interest to you.

Sign up as volunteer

user name

Added by • 



Reply by • Private

Lorem ipsum dolor sit amet consectetur, adipisicing elit. Ipsa vel nobis alias. Quae eveniet velit voluptate quo doloribus maxime et dicta in sequi, corporis quod. Ea, dolor eius? Dolore, vel!

  The passcode will expire in None.

No annotations made yet

Add a private note
  • abc Select a piece of text from the left.
  • Add notes visible only to you.
  • Send it to people through a passcode protected link.
Add a private note