The Impact of AMPA Receptor Blockade on Ketamine's Anti-Suicidal Effects

NCT05786066 | Recruiting Phase 2 FDA Drug

• 1 other identifier: 2000033608
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to test the hypothesis that the anti-depressant and anti-suicidal effects of the N-methyl-D-aspartate receptor (NMDAR) antagonist Ketamine is critically dependent on stimulation of Alpha-Amino-3-Hydroxy-5-Methyl-4-Isoxazole Propionic Acid receptors (AMPAR).

Conditions

Depressive Disorder; Major Depressive Disorder; Bipolar Disorder; Post Traumatic Stress Disorder; Suicidal Ideation

Keywords

Ketamine; Suicide

Outcome Measures

Primary Outcomes (2)

• Change in suicidal ideations in response to Ketamine

  Change in suicidal ideation will be assessed 24 hours post-Ketamine infusion using a Scale for Suicidal Ideation, composed of the first five items of the Beck Suicide Inventory + the Hamilton Depression Rating Scale (HAMD-7) suicidality item. The first five items of the Beck Suicide Inventory are rated on a scale of 0-2, and the suicidality item on the HAMD-7 is rated from 0-4. Scores are totaled and will be analyzed as the dependent variable in a mixed-effects model with drug condition (placebo/perampanel) and time (baseline, 24-hour follow up) as within-subject factors.

  Baseline and 24 hours post infusion

• Change in antidepressant response to Ketamine

  Changes in depressive symptoms will be assessed 24 hours post-Ketamine infusion using the full Hamilton Depression Rating Scale (HAMD-7), a 7-item survey to assess depression. Scores range from 0-26 with scores indicating full remission (0-3) and partial/non-response (4-26). Scores are totaled and will be analyzed as the dependent variable in a mixed-effects model with drug condition (placebo/perampanel) and time (baseline, 24-hour follow up) as within-subject factors.

  Baseline and 24 hours post infusion

Study Arms (2)

Perampanel + Ketamine

EXPERIMENTAL

Participants will receive oral perampanel or placebo, in counterbalanced order, 2.5 hours before a standard, subanesthetic Ketamine infusion (0.5 mg/kg over 40 minutes). Ketamine infusions will be at least three weeks apart. Participants will refrain from caffeine and over-the-counter medication seven days before the infusion day.

Drug: Perampanel 6 MG; Drug: Ketamine

Placebo + Ketamine

PLACEBO COMPARATOR

Participants will receive oral perampanel or placebo, in counterbalanced order, 2.5 hours before a standard, subanesthetic Ketamine infusion (0.5 mg/kg over 40 minutes). Ketamine infusions will be at least three weeks apart. Participants will refrain from caffeine and over-the-counter medication seven days before the infusion day.

Drug: Ketamine; Drug: Placebo

Interventions

Perampanel 6 MG DRUG

Perampanel will be administered 2.5 hours before Ketamine infusion

Perampanel + Ketamine

Ketamine DRUG

Ketamine infusion (0.5 mg/kg infusion over 40 minutes) will be administered 2.5 hours post perampanel or placebo administration.

Perampanel + Ketamine; Placebo + Ketamine

Placebo DRUG

Placebo will be administered 2.5 hours before Ketamine infusion

Placebo + Ketamine

Eligibility Criteria

• Age: 21 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Current depression as indicated by a score greater than 17 on the full Hamilton Depression Rating Scale (HDRS-17) AND current major depressive episode as determined by structured clinical interview (SCID-5)
• Current suicidal ideation as indicated by a score ≥ 2 on the HDRS-17 Item #3 ("wishes to be dead (or any thoughts of possible death to self)")
• Anti-depressant resistant depressive symptoms, defined by a history of failure of one or more adequate anti-depressant trials
• 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 mental health treatment outside of the research protocol. Those who are not receiving treatment with a mental health provider at the time of the phone screen may be referred for treatment and will have their admission to the protocol deferred until they are receiving treatment with a mental health provider for at least 4 weeks, at which time they may re-apply for admission to the protocol.
• Individuals who are receiving pharmacotherapy for depression must have been receiving the current medication and dose for 4 weeks before randomization. Those who are not stable on their current medication and dose for 4 weeks at the time of the phone screen may have their admission to the protocol deferred until they are stable on their current psychopharmacotherapy. In addition, all individuals admitted to the protocol 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. Those who are not stable on their current regime of psychotherapy for 4 weeks at the time of the phone screen may have their admission to the protocol deferred until they are stable on their current regime of psychotherapy.
• Willing to refrain from caffeine, drug, and alcohol use for one week prior to each Ketamine infusion
• 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 \[43\] in the "intent" or "intent with plan" categories within the last 3 months or judged by Dr. Krystal or Dr. Driesen to be at serious risk for suicide.
• Psychiatric hospitalization in the past two months
• Suicide attempt in the past two months
• Neurological disorder excluding migraine headaches or mild head injury. 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
• Previous trial of Ketamine without therapeutic benefit
• 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. Individuals experiencing psychosis during the current depressive episode will be excluded.

Sponsors & Collaborators

• Yale University: lead
• National Center for PTSD: collaborator
• VA Connecticut Healthcare System: collaborator
• American Foundation for Suicide Prevention: collaborator

Study Sites (1)

VA Connecticut Healthcare System

West Haven, Connecticut, 06516, United States

RECRUITING

MeSH Terms

Conditions

Depressive Disorder; Depressive Disorder, Major; Bipolar Disorder; Stress Disorders, Post-Traumatic; Suicidal Ideation; Suicide

Interventions

perampanel; Ketamine

Condition Hierarchy (Ancestors)

Mood Disorders; Mental Disorders; Bipolar and Related Disorders; Stress Disorders, Traumatic; Trauma and Stressor Related Disorders; Self-Injurious Behavior; Behavioral Symptoms; Behavior

Intervention Hierarchy (Ancestors)

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

Study Officials

• Naomi Driesen, PhD

  Yale University / VACHS West Haven

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Naomi Driesen, PhD

CONTACT

203-508-7765; naomi.driesen@yale.edu

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This study will include Veterans and non-Veterans. Both Veterans and non-Veterans will be included because of the large sample size of individuals currently in a major depressive episode and experiencing suicidal ideation required. Subjects with treatment-resistant depression currently in a major depressive episode and experiencing at least passive suicidal ideation. The investigators are studying this symptom complex in individuals with Major Depressive Disorder (MDD), Bipolar Disorder, and Posttraumatic Stress Disorder (PTSD). These three groups have high rates of suicide and are sensitive to Ketamine's antidepressant effects. The investigators will utilize a within-subject double-blinded, cross-over design with a counter-balanced, randomized order.

Study Record Dates

• First Submitted: March 14, 2023
• First Posted: March 27, 2023
• Study Start: April 3, 2023
• Primary Completion (Estimated): March 1, 2033
• Study Completion (Estimated): March 1, 2033
• Last Updated: May 6, 2026

Record last verified: 2026-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)