Clinical TrialTreatment-Resistant Depression (TRD)KetaminePlaceboKetaminePlaceboPlaceboKetaminePlaceboRecruiting

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

Randomised, triple-blind, placebo-controlled add-on study (n=70) testing whether oral perampanel (8 mg) blocks the antidepressant effects of intravenous ketamine (0.5 mg/kg) in adults with treatment-resistant major depressive disorder.

Target Enrollment
70 participants
Study Type
Phase I interventional
Design
Randomized, triple Blind

Detailed Description

Ketamine produces rapid antidepressant effects; this study tests whether AMPA receptor throughput is necessary for those effects by pre-treating patients with the AMPAR antagonist perampanel versus placebo and measuring clinical and electrophysiological outcomes.

Phase I entails medication taper and baseline imaging/physiology; Phase II randomises participants to blinded perampanel or placebo with an open-label ketamine infusion (0.5 mg/kg IV) and repeated sEEG, TMS and MEG and clinical ratings (MADRS) to assess antidepressant response and neurophysiological biomarkers.

Study Protocol

Preparation

sessions

Dosing

1 sessions

Integration

sessions

Study Arms & Interventions

Perampanel + ketamine

experimental

Double-blinded perampanel given pre-ketamine (Day 0) with open-label ketamine infusion on Day 0; blinded perampanel on Day 1.

Interventions

  • Ketamine0.5 mg/kg
    via IV• single dose• 1 doses total

    Open-label ketamine infusion on Day 0

  • Placebo8 mg
    via Oral• single dose

    Perampanel 8 mg orally (blinded, given 2–3 hours pre-ketamine)

  • Compound
    via Other

    MagPro 100 TMS Therapy System (device interventions)

Placebo→Perampanel

experimental

Blinded oral placebo pre-ketamine (Day 0) with open-label ketamine on Day 0; blinded perampanel on Day 1.

Interventions

  • Ketamine0.5 mg/kg
    via IV• single dose• 1 doses total

    Open-label ketamine infusion on Day 0

  • Placebo
    via Oral• single dose

    Oral placebo (blinded) given pre-ketamine on Day 0

  • Placebo8 mg
    via Oral• single dose

    Perampanel 8 mg orally on Day 1 (blinded)

  • Compound
    via Other

    MagPro 100 TMS Therapy System (device interventions)

Placebo + ketamine

experimental

Blinded oral placebo pre-ketamine (Day 0) with open-label ketamine on Day 0; blinded placebo on Day 1.

Interventions

  • Ketamine0.5 mg/kg
    via IV• single dose• 1 doses total

    Open-label ketamine infusion on Day 0

  • Placebo
    via Oral• single dose

    Oral placebo (blinded) given pre-ketamine on Day 0 and Day 1

  • Compound
    via Other

    MagPro 100 TMS Therapy System (device interventions)

Participants

Ages
18 – 70
Sexes
Male & Female

Inclusion Criteria

  • INCLUSION CRITERIA:
  • Phases I-II
  • 1. 18 to 70 years of age.
  • 2. Each subject must have understanding sufficient to agree to all required tests and sign informed consent.
  • 3. Subjects must have undergone screening under protocol 01-M-0254 ("The Evaluation of Patients with Mood and Anxiety Disorders and Healthy Volunteers").
  • 4. DSM-IV or DSM-5 diagnosis of Major Depressive Disorder without psychotic features (confirmed by clinical assessment and structured interview, e.g., SCID-P).
  • 5. Initial MADRS ≥ 22 and YMRS < 12 within one week of study entry and upon entry into Phase II.
  • 6. Lack of response to two adequate antidepressant trials (operationalised using ATHF); failed adequate trial of ECT or TMS counts as adequate.
  • 7. Current major depressive episode lasting at least four weeks.
  • 8. Agree to be hospitalised for study participation.

Exclusion Criteria

  • EXCLUSION CRITERIA (Phases I-II):
  • 1. Current psychotic features or diagnosis of schizophrenia or other psychotic disorder.
  • 2. History of substance abuse/dependence or substance use disorder within preceding 3 months (except caffeine or nicotine); illicit drug use in 2 weeks prior to screening; positive alcohol/drug urine test at screening.
  • 3. Serious unstable medical illnesses (hepatic, renal, gastroenterologic, respiratory, cardiovascular, endocrinologic, neurologic, immunologic, hematologic).
  • 4. Pregnant or nursing individuals or those able to become pregnant without effective birth control; negative urine pregnancy test prior to drug/imaging.
  • 5. History of seizure (unless clearly resolved) or current use of medications that lower seizure threshold; epilepsy in self or first-degree relatives; stroke, brain surgery, head injury, or known structural brain lesion (excludes TMS procedures).
  • 6. Medical illness likely to alter brain morphology/physiology (e.g., uncontrolled hypertension, diabetes).
  • 7. Clinically significant abnormal laboratory tests.
  • 8. For imaging: evaluated hearing loss that may be worsened by 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) that would preclude participation.
  • 13. Any use of opioid medication in the past 3 months.
  • 14. Treatment with a reversible MAOI prior to Phase II (must be tapered in Phase I).
  • 15. Treatment with fluoxetine or aripiprazole at time of screening.
  • 16. Unwilling to stop structured, individualised psychotherapy during Phases I and II (e.g., CBT not permitted).
  • 17. Presence of metallic (ferromagnetic) implants (e.g., pacemaker, aneurysm clip).
  • 18. Claustrophobia or inability to lie supine for up to 90 minutes for MRI/MEG.
  • 19. Subjects judged by investigator to pose current serious suicidal or homicidal risk.
  • 20. History of aggressive behaviour towards others.
  • 21. Current NIMH employee/staff or immediate family member.
  • Open-Label Ketamine Treatment exclusions include intolerable/serious adverse reaction to ketamine during Phase II; positive urine for illicit substance within 24 hours prior to ketamine; pregnancy or nursing.

Study Details

Locations

National Institutes of Health Clinical Center — Bethesda, Maryland, United States

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