| Eligibility |
Inclusion Criteria Substudy #2:
- 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, 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 12th grade education level or equivalent
Exclusion Criteria Substudy #2:
- 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.
- 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
- 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.
- 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. The purpose of including individuals with mild alcohol use
disorder is to extend recruitment to more individuals who can participate safely in
the trial.
- 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. This applies to all subjects, including
those who make criteria for current mild alcohol use disorder.
- 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
- 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
- History of claustrophobia
- Any clinically significant impairment of color vision or visual acuity after
correction available in the scanner
- 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
- Subjects will be advised not to drive or operate heavy machinery for at least 24 hours
after completing the infusion.
- 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.
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