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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 : July 23, 2019
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Mental Health (NIMH) )

Tracking Information
First Submitted Date  ICMJE June 1, 2019
First Posted Date  ICMJE June 4, 2019
Last Update Posted Date July 23, 2019
Estimated Study Start Date  ICMJE July 26, 2019
Estimated Primary Completion Date February 1, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 1, 2019)
  • 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
  • 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
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03973268 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: June 1, 2019)
  • Acute Antidepressant Efficacy: Change in slow wave activity /slope post ketamine infusion [ Time Frame: Baseline (night), Day 1 (night) ]
    Polysomnography (PSG)/Electroencephalography (EEG) data
  • Acute Antidepressant Efficacy: Change in synaptic plasticity post ketamine infusion [ Time Frame: Baseline, Day 1 ]
    Transcranial Magnetic Stimulation (TMS) data
  • Continued Antidepressant Efficacy: Gamma power change from baseline post treatment with ketamine with perampanel versus placebo [ Time Frame: Baseline, Day 1 ]
    Magnetoencephalography (MEG) data
  • 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
  • Continued Antidepressant Efficacy: Change in synaptic plasticity from baseline post treatment with ketamine with perampanel versus placebo [ Time Frame: Baseline, Day 1 ]
    TMS data
  • Acute Antidepressant Efficacy: Gamma power change from baseline post ketamine infusion [ Time Frame: Baseline, Day 1 ]
    Magnetoencephalography (MEG) data
  • 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
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Mechanism of Action Underlying Ketamine s Antidepressant Effects: The AMPA Throughput Theory in Patients With Treatment-Resistant Major Depression
Official Title  ICMJE The Mechanism of Action Underlying Ketamine s Antidepressant Effects: An Investigation of the AMPA Throughput Theory in Patients With Treatment-Resistant Major Depression
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.

Detailed Description

Objective

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.

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
Condition  ICMJE
  • Depression
  • Major Depressive Disorder
  • Major Depression
Intervention  ICMJE
  • Drug: Ketamine
    Arm 1,2, 3 Interventions
  • Drug: Perampanel
    Arm 1 and 2 Interventions
  • Other: Placebo
    Arm 2 and 3 Interventions
Study Arms  ICMJE
  • 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.
    Interventions:
    • Drug: Ketamine
    • Drug: Perampanel
  • 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.
    Interventions:
    • Drug: Ketamine
    • Drug: Perampanel
    • Other: Placebo
  • 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.
    Interventions:
    • Drug: Ketamine
    • Other: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 1, 2019)
70
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE February 1, 2022
Estimated Primary Completion Date February 1, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE
  • 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Libby Jolkovsky (877) 646-3644 jolkovsl@mail.nih.gov
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03973268
Other Study ID Numbers  ICMJE 190107
19-M-0107
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Institutes of Health Clinical Center (CC) ( National Institute of Mental Health (NIMH) )
Study Sponsor  ICMJE National Institute of Mental Health (NIMH)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Carlos A Zarate, M.D. National Institute of Mental Health (NIMH)
PRS Account National Institutes of Health Clinical Center (CC)
Verification Date May 30, 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP