The Impact of AMPA Receptor Blockade on Ketamine's Anti-Suicidal Effects
This crossover intervention trial (n=30) conducted by Yale University investigates whether pre-treatment with perampanel attenuates ketamine's anti-suicidal and antidepressant effects (ketamine 0.5 mg/kg IV).
This within-subject, double-blind, randomized crossover trial (n=30) tests whether AMPA receptor blockade with perampanel reduces ketamine's anti-suicidal and antidepressant effects in participants with MDD, bipolar disorder, or PTSD and current suicidal ideation.
Participants receive oral perampanel 6 mg or placebo 2.5 hours before a standard subanesthetic ketamine infusion (0.5 mg/kg over 40 minutes); infusions are separated by at least three weeks with follow-up assessments through interview and electronic diary.
Study Protocol
Preparation
sessions
Dosing
2 sessions
40 min each
Locations
VA Connecticut Healthcare System — West Haven, Connecticut, United States
Integration
sessions
Study Arms & Interventions
Perampanel + Ketamine
experimental
Oral perampanel 6 mg or placebo given 2.5 h before a subanesthetic ketamine infusion (0.5 mg/kg over 40 minutes); within-subject crossover, counterbalanced.
Interventions
Compound6 mg
via Oral• single dose
Perampanel 6 mg oral administered 2.5 h before ketamine.
Ketamine0.5 mg/kg
via IV• single infusion
Infusion over 40 minutes (0.5 mg/kg).
Placebo + Ketamine
inactive
Oral placebo given 2.5 h before a standard ketamine infusion (0.5 mg/kg over 40 minutes) in counterbalanced crossover.
Interventions
Placebo
via Oral• single dose
Oral placebo administered 2.5 h before ketamine.
Ketamine0.5 mg/kg
via IV• single infusion
Infusion over 40 minutes (0.5 mg/kg).
Participants
Ages
21 – 65
Sexes
Male & Female
BMI
-
Psychosis History
-
Inclusion Criteria
Inclusion Criteria:
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
Exclusion Criteria
Exclusion Criteria:
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.
* 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
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.
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. 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. The diagnosis of mild alcohol use disorder shall be per DSM-5 and involve 2-3 symptoms. The PI's discretion will be based on the symptoms that are reported and the judged consistency and accuracy of the subjects' self-report.
A positive on screening urine drug test or, at the study physicians' discretion, on any drug screens given before the infusion visits.
A positive screening alcohol breathalyzer or alcohol saliva test or, at the study physicians' discretion, on any alcohol breathalyzer or alcohol saliva test given before the infusion visits.
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 Ketamine infusion visit. Subjects who have taken OTC medication or herbal supplements may still be entered into the study, if, in the opinions of the Principal/Co-Investigator, the medication received will not interfere with the study procedures or compromise safety.
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. If a subject meets these blood pressure entrance criteria, but is being treated for high blood pressure, the study team will check with the subject's primary care physician or treatment provider to confirm that the subject is stable and normotensive on their current treatment plan.
History of general intellectual disability
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.