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

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. 2. Perampanel pre-treatment reduces ketamine-induced increases in prefrontal CMRO2 and functional connectivity observed at 24 hours. 3. Perampanel pre-treatment reduces the positive effect of ketamine on clinical improvement as measured by the Hamilton Depression Inventory (1) at 24 hours. Exploratory: Changes in prefrontal functional connectivity and CMRO2 during ketamine infusion and 48 hours post-infusion are correlated with clinical improvement as measured by the Hamilton Depression Inventory. 

Inclusion Criteria:

• Participants between the ages of 21-65
• 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 a positive response but were not rated clinically will be treated as ketamine naïve.  Individuals who were rated clinically, must have a 50% or larger improvement over baseline.
• 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.
• 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 12^th grade education level or equivalent

Exclusion Criteria:

• 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 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 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 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
• History of claustrophobia
• 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