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

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ClinicalTrials.gov Identifier: NCT03973268
Recruitment Status : Recruiting
First Posted : June 4, 2019
Last Update Posted : October 18, 2019
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Mental Health (NIMH) )

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 tests:

Blood draws

Psychological tests

MRI: Participants will like 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 1 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 2, they will get more ketamine. On days 3 7, they will repeat many phase 1 tests.


Condition or disease Intervention/treatment Phase
Depression Major Depressive Disorder Major Depression Drug: Ketamine Drug: Perampanel Other: Placebo Phase 1

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 70 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
Official Title: The Mechanism of Action Underlying Ketamine s Antidepressant Effects: An Investigation of the AMPA Throughput Theory in Patients With Treatment-Resistant Major Depression
Estimated Study Start Date : October 23, 2019
Estimated Primary Completion Date : February 1, 2022
Estimated Study Completion Date : February 1, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Antidepressants
Drug Information available for: Ketamine

Arm Intervention/treatment
Experimental: 1
Individuals in Arm 1 will receive doubleblinded perampanel and open-label ketamine on the firstday, then double-blinded perampanel on the second day.
Drug: Ketamine
Arm 1,2, 3 Interventions

Drug: Perampanel
Arm 1 and 2 Interventions

Experimental: 2
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.
Drug: Ketamine
Arm 1,2, 3 Interventions

Drug: Perampanel
Arm 1 and 2 Interventions

Other: Placebo
Arm 2 and 3 Interventions

Experimental: 3
Individuals in Arm 3 will receive doubleblinded placebo and open-label ketamine on the first day, then double-blinded placebo on the second day.
Drug: Ketamine
Arm 1,2, 3 Interventions

Other: Placebo
Arm 2 and 3 Interventions




Primary Outcome Measures :
  1. Acute Antidepressant Efficacy: Change from baseline Montgomery Asberg Depression Rating Scale (MADRS) score post ketamine infusion [ Time Frame: Baseline, Day 1 ]
    Clinical rating scale of depression

  2. Continued Antidepressant Efficacy: Change from baseline MADRS score post treatment with ketamine with perampanel versus placebo. [ Time Frame: Baseline, Day 1, Day 2 Day 7 ]
    Clinical rating scale of depression


Secondary Outcome Measures :
  1. Acute Antidepressant Efficacy: Change in slow wave activity /slope post ketamine infusion [ Time Frame: Baseline (night), Day 1 (night) ]
    Polysomnography (PSG)/Electroencephalography (EEG) data

  2. Acute Antidepressant Efficacy: Change in synaptic plasticity post ketamine infusion [ Time Frame: Baseline, Day 1 ]
    Transcranial Magnetic Stimulation (TMS) data

  3. Continued Antidepressant Efficacy: Gamma power change from baseline post treatment with ketamine with perampanel versus placebo [ Time Frame: Baseline, Day 1 ]
    Magnetoencephalography (MEG) data

  4. Continued Antidepressant Efficacy: Change in slow wave activity/slope from baseline post treatment with ketamine with perampanel versus placebo [ Time Frame: Baseline (night), Day 1 (night) ]
    PSG/EEG data

  5. Continued Antidepressant Efficacy: Change in synaptic plasticity from baseline post treatment with ketamine with perampanel versus placebo [ Time Frame: Baseline, Day 1 ]
    TMS data

  6. Acute Antidepressant Efficacy: Gamma power change from baseline post ketamine infusion [ Time Frame: Baseline, Day 1 ]
    Magnetoencephalography (MEG) data

  7. Acute Antidepressant Efficacy: Change in peripheral measures associated with the administration of ketamine [ Time Frame: Baseline, Day 1, Day 2, Day 7 ]
    Plasma/serum biomarkers



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

    1. 18 to 70 years of age.
    2. Each subject must have a level of understanding sufficient to agree to all required tests and examinations and sign an informed consent document.
    3. 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 .
    4. 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).
    5. 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.
    6. Lack of response to two adequate antidepressant trials in the current major depressive episode, operationally defined using the Antidepressant Treatment History Form (ATHF); a failed adequate trial of ECT would count as an adequate antidepressant trial.
    7. Current major depressive episode lasting at least four weeks
    8. Agree to be hospitalized

EXCLUSION CRITERIA:

  1. Current psychotic features or a diagnosis of schizophrenia or any other psychotic disorder as defined in the DSM-IV or DSM-5.
  2. 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.
  3. 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.
  4. Pregnant or nursing individuals or those who are physically able to become pregnant. Participants who are physically able to become pregnant 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). These participants must have negative urine pregnancy tests no more than 24 hours prior to receiving the study drugs and undergoing imaging and TMS procedures.
  5. Subjects with one or more seizures without a clear and resolved etiology or current use of medication known to lower seizure threshold.
  6. Presence of any medical illness likely to alter brain morphology and/or physiology (e.g., hypertension, diabetes) even if controlled by medications.
  7. Clinically significant abnormal laboratory tests.
  8. (For imaging procedures) Subjects with hearing loss that has been clinically evaluated and diagnosed and may be worsened through participation in imaging procedures
  9. Positive HIV test
  10. Weight > 119 kg
  11. Treatment with any concomitant psychiatric medication prior to entering Phase II. [Medications must be tapered during Phase I.]
  12. Treatment with any non-psychiatric medication/s.
  13. Any use of opioid medication in the past 3 months
  14. Treatment with a reversible monoamine oxidase inhibitor (MAOI) prior to entering Phase II. [Medications must be tapered during Phase I.]
  15. Treatment with fluoxetine or aripiprazole at the time of screening.
  16. Unwilling to stop undergoing structured, individualized psychotherapy. (Such therapy, including CBT, will not be permitted during Phases I and II of the study.)
  17. Presence of metallic (ferromagnetic) implants (e.g., heart pacemaker, aneurysm clip).
  18. Participants who are uncomfortable in small closed spaces (have claustrophobia).
  19. Are unable to lie comfortably supine for up to 90 minutes and would feel uncomfortable in the MRI and MEG machines.
  20. Subjects who, in the investigator s judgment, pose a current serious suicidal or homicidal risk.
  21. Subjects who have a history of aggressive behavior towards others
  22. A current NIMH employee/staff or their immediate family member

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03973268


Contacts
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Contact: Libby Jolkovsky (877) 646-3644 jolkovsl@mail.nih.gov

Locations
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United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)    800-411-1222 ext TTY8664111010    prpl@cc.nih.gov   
Sponsors and Collaborators
National Institute of Mental Health (NIMH)
Investigators
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Principal Investigator: Carlos A Zarate, M.D. National Institute of Mental Health (NIMH)

Additional Information:
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Responsible Party: National Institute of Mental Health (NIMH)
ClinicalTrials.gov Identifier: NCT03973268     History of Changes
Other Study ID Numbers: 190107
19-M-0107
First Posted: June 4, 2019    Key Record Dates
Last Update Posted: October 18, 2019
Last Verified: May 30, 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute of Mental Health (NIMH) ):
Biomarker
AMPA Antagonist
Magnetoenephalography
Neuropharmacology
Neurobiology
Additional relevant MeSH terms:
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Depression
Depressive Disorder
Depressive Disorder, Major
Behavioral Symptoms
Mood Disorders
Mental Disorders
Ketamine
Antidepressive Agents
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anesthetics, Dissociative
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
Central Nervous System Depressants
Excitatory Amino Acid Antagonists
Excitatory Amino Acid Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Psychotropic Drugs