Clinical TrialTreatment-Resistant Depression (TRD)KetamineKetaminePlaceboCompleted

Alpha-Amino-3-Hydroxy-5-Methyl-4-Isoxazole Propionic Acid Receptor Components of the Anti-Depressant Ketamine Response

Counter-balanced crossover study (n=13) testing whether perampanel (6 mg oral) pre-treatment blocks IV ketamine antidepressant effects in treatment-resistant depression; outcomes include fMRI connectivity, CMRO2 and clinical scales at 24 hours.

Target Enrollment
13 participants
Study Type
Phase I interventional
Design
Randomized, double Blind

Detailed Description

Randomized, double-blind, counter-balanced crossover in individuals with treatment-resistant depression comparing ketamine with perampanel pre-treatment versus ketamine with placebo; primary outcomes are changes in prefrontal functional connectivity and CMRO2 during infusion and at 24 hours.

The study includes a small safety substudy in three healthy subjects; clinical response is assessed with the Hamilton Depression Rating Scale and imaging measures to test whether AMPAR stimulation is necessary for ketamine’s antidepressant effects.

Study Protocol

Preparation

sessions

Dosing

2 sessions
120 min each

Integration

sessions

Study Arms & Interventions

ketamine + perampanel

experimental

Counter-balanced crossover: oral perampanel 6 mg pre-treatment + IV ketamine; MRI during infusion and follow-up scan next day.

Interventions

  • Ketamine
    via IV• single dose

    Intravenous ketamine (dose per protocol) administered after oral pre-treatment

  • Compound6 mg
    via Oral• single dose

    Perampanel 6 mg oral pre-treatment

ketamine + placebo

inactive

Counter-balanced crossover: oral placebo pre-treatment + IV ketamine; MRI during infusion and follow-up scan next day.

Interventions

  • Ketamine
    via IV• single dose

    Intravenous ketamine (dose per protocol)

  • Placebo
    via Oral• single dose

    Oral placebo replacing perampanel

Participants

Ages
18 – 65
Sexes
Male & Female

Inclusion Criteria

  • Inclusion Criteria Substudy #2:
  • Participants between the ages of 18-65
  • Right-handed as determined by the Edinburgh Handedness Inventory
  • Current depression as indicated by a score greater than 17 on the full Hamilton Depression Rating Scale
  • Anti-depressant resistant depressive symptoms, defined by a history of failure of one or more adequate anti-depressant trials
  • Individuals who have previously received ketamine must have had a positive response. Individuals who report reduced depressive symptoms will be treated as ketamine responders and entered directly into the closed label trial.
  • Participants will meet DSM-5 Criteria for MDD, Bipolar or PTSD as determined by the SCID-5
  • All participants given ketamine must be engaged in treatment outside of the research protocol. Those who are not currently in treatment may be referred for treatment.
  • Individuals who are receiving pharmacotherapy for depression must have been receiving the current medication and dose for 4 weeks before randomization. In addition, they should have a plan to continue the current regime of pharmacotherapy for the duration of the trial.
  • Individuals who are receiving psychotherapy must have been in treatment for four weeks and should have a plan to continue the current regime of psychotherapy for the duration of the trial.
  • Willing to refrain from caffeine, drug and alcohol use for one week prior to each MRI session
  • Females will be included if they are not pregnant or breastfeeding and agree to utilize a medically accepted birth control method (to include oral, injectable, or implant birth control, condom, diaphragm with spermicide, intrauterine device, tubal ligation, abstinence, or partner with vasectomy). Women who are surgically sterile or post-menopausal with cessation of menses for at least one year are not required to use birth control. If a woman should become pregnant during the study, she will be excluded from the trial.
  • Females will receive ketamine during the follicular phase, i.e., in the first week after the start of the menstrual period, if at all possible. If a prospective participant typically has significant menstrual cramps during this entire follicular phase, she will be studied during another part of her cycle. She will be studied during the same part of her cycle for each scan, if possible.
  • Able to read and write English
  • Have at least a 12th grade education level or equivalent

Exclusion Criteria

  • Exclusion Criteria Substudy #2:
  • A score on the Columbia Suicide Severity Rating Scale in the "intent" or "intent with plan" categories or judged by Dr. Krystal or Dr. Driesen to be at serious risk for suicide.
  • Neurological disorder excluding migraine headaches or more than mild head injury. Individuals with migraines will not complete any ketamine infusion visits within 24 hours of a migraine. More than mild head injury is indicated by the presence of any of the following:
  • * More than half hour unconsciousness after trauma
  • * More than one hour post-traumatic amnesia
  • * Concussive symptoms such as headache, memory problems, nausea/vomiting, irritability, ringing in the ears, dizziness, balance problems, difficulty concentrating or visual disturbances lasting more than one week after injury.
  • * Concussive symptoms as defined above in the first week after injury causing more than one day impairment in typical duties.
  • * Four or more concussive events of less severity than the above will also be grounds for exclusion. These events would include post-trauma symptoms such as the individual being dazed, seeing stars, unconscious for less than one half hour, or post-traumatic amnesia of less than an hour.
  • Current therapeutic treatment with ketamine
  • Current treatment with topiramate, memantine, or barbiturates within two weeks of randomization
  • Daytime use of benzodiazepines
  • Current treatment with monoamine oxidase inhibitors within 4 weeks of randomization
  • Treatment with a vagal nerve stimulator, ECT or deep brain stimulation within two weeks of randomization
  • Psychosis other than psychotic experiences congruent with depressed mood during a period of depression
  • Insulin-dependent diabetes or non-insulin dependent diabetes that is poorly controlled
  • Other major medical disorder unless cleared by a study physician
  • History of violence unless cleared by Dr. Driesen or Dr. Krystal because of extenuating circumstances.
  • Individual meets criteria for a diagnosis of substance or alcohol use disorder within the three months prior to screening date. Individuals who meet criteria for mild alcohol use disorder within three months prior to screening date may be included in the study at investigator discretion.
  • A positive on screening urine drug test or, at the study physicians' discretion, on any drug screens given before the scans.
  • A positive screening breathalyzer test or, at the study physicians' discretion, on any breathalyzer test given before the scans.
  • A 12-lead ECG at screening has clinically significant abnormalities as determined by the physician reading the ECG.
  • Abnormality on clinical chemistry or hematology examination at the pre-study medical screening.
  • History of positive HIV or Hepatitis B
  • Has received either prescribed or over-the-counter (OTC) centrally active medicine or herbal supplements within the week prior to the MRI scan.
  • Known sensitivity to ketamine or heparin
  • Resting blood pressure lower than 85/55 or higher than 140/90, or resting heart rate lower than 45/min or higher than 100/min, unless cleared by study physician.
  • History of general intellectual disability
  • History of claustrophobia
  • Any clinically significant impairment of color vision or visual acuity after correction available in the scanner
  • Presence of cardiac pacemaker or other electronic device or ferromagnetic metal foreign bodies in vulnerable positions as assessed by a Yale Magnetic Resonance Research Center standard pre-MRI screening questionnaire
  • Subjects will be advised not to drive or operate heavy machinery for at least 24 hours after completing the infusion.
  • Donation of blood in excess of 500 mL within 56 days prior to dosing or similar loss of blood due to other causes.
  • Potential participants may be eliminated at the discretion of Dr. Krystal, Dr. Driesen, or the study physician.

Study Details

Locations

Yale University — New Haven, Connecticut, United States

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