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

Inclusion Criteria:

• Current depression as indicated by a score greater than 17 on the full HamiltonDepression Rating Scale (HDRS-17) AND current major depressive episode as determinedby 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 ofone or more adequate anti-depressant trials

• Participants will meet DSM-5 Criteria for MDD, PTSD or Bipolar Disorder asdetermined by the SCID-5

• All participants given Ketamine must be engaged in mental health treatment outsideof the research protocol. Those who are not receiving treatment with a mental healthprovider at the time of the phone screen may be referred for treatment and will havetheir admission to the protocol deferred until they are receiving treatment with amental health provider for at least 4 weeks, at which time they may re-apply foradmission to the protocol.

• Individuals who are receiving pharmacotherapy for depression must have beenreceiving the current medication and dose for 4 weeks before randomization. Thosewho are not stable on their current medication and dose for 4 weeks at the time ofthe phone screen may have their admission to the protocol deferred until they arestable on their current psychopharmacotherapy. In addition, all individuals admittedto the protocol should have a plan to continue the current regime of pharmacotherapyfor the duration of the trial.

• Individuals who are receiving psychotherapy must have been in treatment for fourweeks and should have a plan to continue the current regime of psychotherapy for theduration of the trial. Those who are not stable on their current regime ofpsychotherapy for 4 weeks at the time of the phone screen may have their admissionto the protocol deferred until they are stable on their current regime ofpsychotherapy.

• Willing to refrain from caffeine, drug, and alcohol use for one week prior to eachKetamine infusion

• Females will be included if they are not pregnant or breastfeeding and agree toutilize a medically accepted birth control method (to include oral, injectable, orimplant birth control, condom, diaphragm with spermicide, intrauterine device, tuballigation, abstinence, or partner with vasectomy). Women who are surgically sterileor post-menopausal with cessation of menses for at least one year are not requiredto use birth control. If a woman should become pregnant during the study, she willbe excluded from the trial.

• Females will receive Ketamine during the follicular phase, i.e., in the first weekafter the start of the menstrual period, if at all possible. If a prospectiveparticipant typically has significant menstrual cramps during this entire follicularphase, she will be studied during another part of her cycle. She will be studiedduring 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:

• 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 orDr. 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 thanmild 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, difficultyconcentrating or visual disturbances lasting more than one week after injury.

• Concussive symptoms as defined above in the first week after injury causingmore than one day impairment in typical duties.

• Four or more concussive events of less severity than the above will also begrounds for exclusion. These events would include post-trauma symptoms such asthe individual being dazed, seeing stars, unconscious for less than one halfhour, 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 ofrandomization

• 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 twoweeks of randomization

• Psychosis other than psychotic experiences congruent with depressed mood during aperiod of depression. Individuals experiencing psychosis during the currentdepressive 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 ofextenuating circumstances. For example, an individual whose violent behavior wasalways coupled with substance abuse and had obtained stable sobriety with no violentincidents or an individual who had received successful pharmacotherapy for impulsecontrol difficulties may be included.

• Individual meets criteria for a diagnosis of substance or alcohol use disorderwithin the three months prior to screening date. Individuals who meet criteria formild alcohol use disorder within three months prior to screening date may beincluded in the study at investigator discretion. The diagnosis of mild alcohol usedisorder shall be per DSM-5 and involve 2-3 symptoms. The PI's discretion will bebased on the symptoms that are reported and the judged consistency and accuracy ofthe subjects' self-report.

• A positive on screening urine drug test or, at the study physicians' discretion, onany drug screens given before the infusion visits.

• A positive screening alcohol breathalyzer or alcohol saliva test or, at the studyphysicians' discretion, on any alcohol breathalyzer or alcohol saliva test givenbefore the infusion visits.

• A 12-lead ECG at screening has clinically significant abnormalities as determined bythe physician reading the ECG.

• Abnormality on clinical chemistry or hematology examination at the pre-study medicalscreening. Subjects with laboratory parameters outside the reference range for thisage group will only be included if the study physician considers that such findingswill not introduce additional risk factors.

• History of positive HIV or Hepatitis B

• Has received either prescribed or over-the-counter (OTC) centrally active medicineor herbal supplements within the week prior to the Ketamine infusion visit. Subjectswho have taken OTC medication or herbal supplements may still be entered into thestudy, if, in the opinions of the Principal/Co-Investigator, the medication receivedwill 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 ratelower than 45/min or higher than 100/min, unless cleared by study physician. If asubject meets these blood pressure entrance criteria, but is being treated for highblood pressure, the study team will check with the subject's primary care physicianor treatment provider to confirm that the subject is stable and normotensive ontheir current treatment plan.

• History of general intellectual disability

• Donation of blood in excess of 500 mL within 56 days prior to dosing or similar lossof blood due to other causes.

• Potential participants may be eliminated at the discretion of Dr. Krystal, Dr.Driesen, or the study physician.