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

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ClinicalTrials.gov Identifier: NCT03367533
Recruitment Status : Not yet recruiting
First Posted : December 8, 2017
Last Update Posted : September 12, 2018
Sponsor:
Information provided by (Responsible Party):
Yale University

Brief Summary:
The proposed study will assess the combined effect of perampanel and ketamine on the anti-depressant response in individuals with treatment resistant depression. The purpose of this study is to test the hypothesis that stimulation of Alpha-Amino-3-Hydroxy-5-Methyl-4- Isoxazole Propionic Acid receptors (AMPAR) is critical to the anti-depressant response of ketamine.

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

Detailed Description:

The proposed study is the first in humans to assess the necessity of Alpha-Amino-3-Hydroxy-5-Methyl-4- Isoxazole Propionic Acid receptors (AMPAR) stimulation for the emergence of the anti-depressant effects of ketamine. Despite the overall safety and efficacy of ketamine, concerns remain. For example, ketamine is a drug with abuse liability. Similarly, it produces transient cognitive and perceptual changes that are distressing for some patients. Therefore, it is critical to determine which aspects of ketamine's effects on neural systems. To do this, we employ perampanel, an FDA-approved drug that blocks calcium and non-calcium dependent AMPARs. We employ a counter-balanced cross-over design in which ketamine plus perampanel is given on one day, and approximately 14 days later ketamine plus placebo is given. The effects of these drug combinations are assessed via fMRI studies of neural functional connectivity and oxidative metabolism as well as interview and self-report measures on the infusion day and 24 hours later. If perampanel blocks the capacity of ketamine to ameliorate the clinical and neural signatures of major depression, it would suggest that AMPAR stimulation is critical for the anti- depressant effects of ketamine in humans. This would support the further exploration of drugs that selectively enhance the stimulation of AMPARs without blocking N-methyl-D-aspartate receptors (NMDARs), such as AMPAkines and metabotropic glutamate receptor 2 (mGluR2) antagonists as anti-depressants.

Specific hypotheses include:

The purpose of this study is to test the hypothesis that stimulation of Alpha-Amino-3-Hydroxy-5-Methyl-4- Isoxazole Propionic Acid receptors (AMPAR) is critical to the anti-depressant response of ketamine.

Specifically, we will test the following hypotheses:

  1. Perampanel pre-treatment reduces ketamine-related increases in prefrontal functional connectivity and CMRO2 during ketamine infusion in individuals with treatment-resistant depression.
  2. Perampanel pre-treatment reduces ketamine-induced increases in prefrontal CMRO2 and functional connectivity observed at 24 hours in individuals with treatment resistant depression.
  3. Perampanel pre-treatment reduces the positive effect of ketamine on clinical improvement as measured by the Hamilton Depression Inventory (1) at 24 hours in individuals with treatment resistant depression.

Exploratory: Changes in prefrontal functional connectivity and CMRO2 during ketamine infusion and 24 hours post-infusion are correlated with clinical improvement as measured by the Hamilton Depression Inventory in individuals with treatment resistant depression.

As this study is the first, to the investigator's knowledge, to involve using ketamine and perampanel in human subjects, the investigators have included a small out-of-scanner study to test the safety of the ketamine/perampanel combination on 3 healthy subjects. This registration focuses on the main study that will follow the safety evaluation and evaluate the effect of perampanel and ketamine on individuals with treatment resistant depression.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: The investigators employ a counter-balanced cross-over design in which ketamine plus perampanel is given on one day, and approximately 14 days later ketamine plus placebo is given.
Masking: Double (Participant, Investigator)
Primary Purpose: Basic Science
Official Title: Alpha-Amino-3-Hydroxy-5-Methyl-4- Isoxazole Propionic Acid Receptor Components of the Anti-Depressant Ketamine Response
Estimated Study Start Date : January 2019
Estimated Primary Completion Date : December 2032
Estimated Study Completion Date : December 2032

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Antidepressants

Arm Intervention/treatment
Experimental: ketamine plus perampanel
A screening session is conducted to ensure that the subject can safely receive perampanel and ketamine (physical exam, blood and urine analyses, electrocardiogram, drug and alcohol testing). The participant will then receive 6 milligrams (mg) oral perampanel and intravenous ketamine. Participants will then undergo a 2-hour magnetic resonance imagining (MRI) scan. The following day, participants will return for an additional scan and symptom assessment.
Drug: Ketamine
Intravenous ketamine

Drug: Perampanel
Oral perampanel (6 mg)

Placebo Comparator: ketamine plus placebo
A screening session is conducted to ensure that the subject can safely receive perampanel and ketamine (physical exam, blood and urine analyses, electrocardiogram, drug and alcohol testing). The participant will then receive an oral placebo (in lieu of 6 mg oral perampanel) and intravenous ketamine. Participants will then undergo a 2-hour MRI scan. The following day, participants will return for an additional scan and symptom assessment.
Drug: Perampanel
Oral perampanel (6 mg)

Drug: Placebo
Oral placebo




Primary Outcome Measures :
  1. Prefrontal functional connectivity [ Time Frame: During ketamine infusion, approximately 2.5 hours ]
    This outcome will be assessed via functional magnetic resonance imaging (fMRI).

  2. Cerebral metabolic rate of oxygen (CMRO2) [ Time Frame: During ketamine infusion, approximately 2.5 hours. ]
    This outcome will be assessed via fMRI.


Secondary Outcome Measures :
  1. Clinical improvement. [ Time Frame: 24 hours post-infusion ]
    This outcome will be assessed by the Hamilton Depression Inventory, a clinician-rated instrument.



Information from the National Library of Medicine

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Ages Eligible for Study:   21 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria :

  • Right-handed as determined by the Edinburgh Handedness Inventory (30)
  • Current depression as indicated by a score greater than 14 on the HAM-D
  • Anti-depressant resistant depressive symptoms, defined by a history of failure of two or more adequate anti-depressant trials
  • Reduction of depressive symptoms on previous ketamine trial
  • Participants will meet DSM-5 Criteria for MDD, PTSD or Bipolar Disorder 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.
  • Able to read and write English
  • Have at least a 12th grade education level or equivalent

Exclusion Criteria:

  • A score on the Columbia Suicide Severity Rating Scale (28) 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 more than mild head injury as 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 treatment with lithium or other anti-psychotic medication
  • 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. For example, an individual whose violent behavior was always coupled with substance abuse and had obtained stable sobriety with no violent incidents or an individual who had received successful pharmacotherapy for impulse control difficulties may be included.
  • Individual meets criteria for a diagnosis of substance or alcohol use disorder within the three months prior to screening date.
  • 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. Subjects with laboratory parameters outside the reference range for this age group will only be included if the study physician considers that such findings will not introduce additional risk factors.
  • 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. Subjects who have taken OTC medication or herbal supplements may still be entered into the study, if, in the opinion of the Principal/Co-Investigator, the medication received will not interfere with the study procedures or compromise safety.
  • Is currently medicated with lithium or anticonvulsants

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): NCT03367533


Contacts
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Contact: Naomi Driesen, Ph.D. (203) 932-5711 ext 3329 naomi.driesen@yale.edu
Contact: Margaret Rowland margaret.rowland@yale.edu

Sponsors and Collaborators
Yale University
Investigators
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Principal Investigator: John Krystal, MD Yale University

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Responsible Party: Yale University
ClinicalTrials.gov Identifier: NCT03367533     History of Changes
Other Study ID Numbers: 2000021345
First Posted: December 8, 2017    Key Record Dates
Last Update Posted: September 12, 2018
Last Verified: September 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

Additional relevant MeSH terms:
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Depressive Disorder
Depression
Depressive Disorder, Major
Mood Disorders
Mental Disorders
Behavioral Symptoms
Ketamine
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
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
Excitatory Amino Acid Agonists