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

NCT03367533 | Completed Phase 1 FDA Drug

• 2 other identifiers: 2000021345No NIH funding per PI
• Study Type: interventional
• Target: 13
• Locations: 1 country
• Sites: 1

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.

Conditions

Depressive Disorder, Major; Post Traumatic Stress Disorder; Bipolar Disorder

Keywords

Depression; Ketamine; Magnetic Resonance Imaging

Outcome Measures

Primary Outcomes (2)

• Prefrontal functional connectivity

  This outcome will be assessed via functional magnetic resonance imaging (fMRI).

  During ketamine infusion, approximately 2.5 hours

• Cerebral metabolic rate of oxygen (CMRO2)

  This outcome will be assessed via fMRI.

  During ketamine infusion, approximately 2.5 hours.

Secondary Outcomes (1)

• Clinical improvement.

  24 hours post-infusion

Study Arms (2)

ketamine plus perampanel

EXPERIMENTAL

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; Drug: Perampanel

ketamine plus placebo

PLACEBO COMPARATOR

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: Ketamine; Drug: Placebo

Interventions

Ketamine DRUG

Intravenous ketamine

ketamine plus perampanel; ketamine plus placebo

Perampanel DRUG

Oral perampanel (6 mg)

ketamine plus perampanel

Placebo DRUG

Oral placebo

ketamine plus placebo

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.
• 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. 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.

Sponsors & Collaborators

• Yale University: lead

Study Sites (1)

Yale University

New Haven, Connecticut, 06511, United States

Location

MeSH Terms

Conditions

Depressive Disorder, Major; Stress Disorders, Post-Traumatic; Bipolar Disorder; Depression

Interventions

Ketamine; perampanel

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders; Stress Disorders, Traumatic; Trauma and Stressor Related Disorders; Bipolar and Related Disorders; Behavioral Symptoms; Behavior

Intervention Hierarchy (Ancestors)

Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals

Study Officials

• John Krystal, MD

  Yale University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: The investigators employ a counter-balanced cross-over design in which ketamine plus perampanel is given on one day, and approximately 21 days later ketamine plus placebo is given.

Study Record Dates

• First Submitted: November 14, 2017
• First Posted: December 8, 2017
• Study Start: November 29, 2018
• Primary Completion: July 8, 2022
• Study Completion: July 8, 2022
• Last Updated: February 7, 2025

Record last verified: 2025-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)