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

 Phases I-II

 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, 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.

 7. Current major depressive episode lasting at least four weeks

 8. Agree to be hospitalized

 Open-Label Ketamine Treatment

 1. Participants must have met all inclusion criteria for and completed Study Phase II as
 a participant in Group 1 (active crisis)

 2. 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

 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 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.

 5. 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.

 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

 Open-Label Ketamine Treatment

 1. Intolerable or serious adverse reaction to ketamine during Phase II

 2. Participants with a positive urine for an illicit substance no more than 24 hours
 prior to ketamine treatment.

 3. Pregnant or nursing individuals or those who plan to become pregnant.