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

NCT03973268 | Recruiting Phase 1 FDA Device

• 2 other identifiers: 19010719-M-0107
• Study Type: interventional
• Target: 70
• Locations: 1 country
• Sites: 1

Brief Summary

Background: 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. Objective: To see if the antidepressant response of ketamine is linked to AMPA receptors. Eligibility: Adults ages 18-70 with major depression disorder without psychotic features Design: 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.

Conditions

Major Depressive Disorder; Major Depression; Depression

Keywords

Biomarker; AMPA Antagonist; Magnetoencephalography; Neuropharmacology; Neurobiology

Outcome Measures

Primary Outcomes (2)

• Acute Antidepressant Efficacy: Change from baseline Montgomery Asberg Depression Rating Scale (MADRS) score post ketamine infusion

  Clinical rating scale of depression

  Baseline, Day 1

• Continued Antidepressant Efficacy: Change from baseline MADRS score post treatment with ketamine with perampanel versus placebo.

  Clinical rating scale of depression

  Baseline, Day 1, Day 2 Day 7

Secondary Outcomes (7)

• Acute Antidepressant Efficacy: Change in slow wave activity/slope post ketamine infusion

  Baseline (night), Day 1 (night)

• Acute Antidepressant Efficacy: Change in synaptic plasticity post ketamine infusion

  Baseline, Day 1

• Continued Antidepressant Efficacy: Gamma power change from baseline post treatment with ketamine with perampanel versus placebo

  Baseline, Day 1

• Continued Antidepressant Efficacy: Change in slow wave activity/slope from baseline post treatment with ketamine with perampanel versus placebo

  Baseline (night), Day 1 (night)

• Continued Antidepressant Efficacy: Change in synaptic plasticity from baseline post treatment with ketamine with perampanel versus placebo

  Baseline, Day 1

Study Arms (3)

1

EXPERIMENTAL

Individuals in Arm 1 will receive double-blinded perampanel and open-label ketamine on the first day, then double-blinded perampanel on the second day.

Device: Arm 1, 2, 3 device interventions; Drug: Arm 1, 2, 3 drug Interventions; Drug: Arm 1 and 2 Interventions

2

EXPERIMENTAL

Individuals in Arm 2 will receive double-blinded placebo and open-label ketamine on the first day, then double-blinded perampanel on the second day.

Device: Arm 1, 2, 3 device interventions; Other: Arm 2 Interventions; Drug: Arm 1, 2, 3 drug Interventions; Drug: Arm 1 and 2 Interventions

3

EXPERIMENTAL

Individuals in Arm 3 will receive double-blinded placebo and open-label ketamine on the first day, then double-blinded placebo on the second day.

Device: Arm 1, 2, 3 device interventions; Drug: Arm 1 and 2 Interventions

Interventions

Arm 1, 2, 3 drug Interventions DRUG

Ketamine

1; 2

Arm 1 and 2 Interventions DRUG

Perampanel

1; 2; 3

Arm 1, 2, 3 device interventions DEVICE

MagPro 100 TMS Therapy System

1; 2; 3

Arm 2 Interventions OTHER

Placebo

2

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Phases I-II
• 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
• 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.

You may not qualify if:

• 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. \[Medications must be tapered during Phase I.\]

Sponsors & Collaborators

• National Institute of Mental Health (NIMH): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

RECRUITING

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Depression; Depressive Disorder, Major

Condition Hierarchy (Ancestors)

Behavioral Symptoms; Behavior; Depressive Disorder; Mood Disorders; Mental Disorders

Study Officials

• Carlos A Zarate, M.D.

  National Institute of Mental Health (NIMH)

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Yamila I Carmona

CONTACT

(301) 256-8971; yamila.carmona@nih.gov

Carlos A Zarate, M.D.

CONTACT

(301) 326-5836; zaratec@mail.nih.gov

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 1, 2019
• First Posted: June 4, 2019
• Study Start: January 21, 2020
• Primary Completion (Estimated): February 1, 2027
• Study Completion (Estimated): February 1, 2027
• Last Updated: February 24, 2026

Record last verified: 2025-12-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: SAP
• Time Frame: Starting within 1 year of completion of the study.
• Access Criteria: The Branch Chief will review requests and access will need to be approved by the NIMH/DIRP SD and OCD NIMH and the NIH IIRB.

Locations

US (1)