Neuropharmacologic Imaging and Biomarker Assessments of Response to Acute and Repeated-Dosed Ketamine Infusions in Major Depressive Disorder
Phase I randomized, double-blind crossover study (n=150) of IV ketamine (0.5 mg/kg; crossover with saline placebo) in patients with MDD and healthy volunteers; includes a metabolites substudy (single 0.5 mg/kg IV infusion) and a Phase III randomised repeated-dose comparison (0.5 vs 0.1 mg/kg twice weekly).
This multi-phase NIH study evaluates the neuropharmacodynamics and biomarkers of acute and repeated IV ketamine in patients with major depressive disorder and healthy volunteers using fMRI, MEG, EEG, TMS-EP and sleep EEG.
Phase II is a double-blind crossover with four weekly infusions (two ketamine 0.5 mg/kg and two saline placebo) paired with neuroimaging; Phase III randomises relapsing MDD patients to repeated ketamine (0.5 mg/kg or 0.1 mg/kg) twice weekly for 4 weeks.
Primary outcomes include pharmacodynamic fMRI and MEG responses; secondary outcomes include MADRS change at 24 hours, biomarker and metabolite analyses (including CSF in the metabolites substudy), and safety/tolerability.
Study Protocol
Preparation
sessions
Locations
National Institutes of Health Clinical Center — Bethesda, Maryland, United States
Dosing
4 sessions
Integration
sessions
Study Arms & Interventions
Metabolites Substudy
experimental
Open-label single IV ketamine infusion in healthy volunteers with optional CSF sampling.
Interventions
Ketamine0.5 mg/kg
via IV• single dose• 1 doses total
Single 0.5 mg/kg IV infusion; some participants may undergo CSF collection.
Phase I
experimental
Screening, medication taper and baseline assessments with TMS device positioning.
Interventions
Compound
via Other• single dose
Cobot TS MV robotic arm for TMS (device for coil positioning).
Phase II — Ketamine
experimental
Double-blind single-dose ketamine arm (crossover with placebo) with fMRI/EEG or MEG.
Interventions
Ketamine0.5 mg/kg
via IV• weekly• 4 doses total
Crossover: subjects receive 2 ketamine and 2 placebo infusions across 4 weekly sessions.
Compound
via Other• weekly• 4 doses total
Cobot TS MV robotic arm for TMS (concurrent device use during assessments).
Phase II — Placebo
inactive
Double-blind single-dose saline placebo comparator with fMRI/EEG or MEG.
Interventions
Placebo
via IV• weekly• 4 doses total
Saline placebo infusions (crossover).
Compound
via Other• weekly• 4 doses total
Cobot TS MV robotic arm for TMS.
Phase III
active comparator
Randomised repeated-dose comparison of ketamine 0.5 mg/kg vs 0.1 mg/kg, twice weekly for 4 weeks.
Interventions
Ketamine0.5 mg/kg
via IV• twice weekly• 8 doses total
Active dose arm (0.5 mg/kg).
Ketamine0.1 mg/kg
via IV• twice weekly• 8 doses total
Lower-dose comparator (0.1 mg/kg).
Compound
via Other• twice weekly• 8 doses total
NeurOptics PLR-30000 pupillometer for assessments.
Phase IV Follow-up
waitlist
Follow-up evaluations for responders; no investigational intervention.
Participants
Ages
18 – 65
Sexes
Male & Female
BMI
-
Psychosis History
-
Inclusion Criteria
INCLUSION CRITERIA:
Inclusion Criteria: All Subjects (Main Study)
1. 18 to 65 years of age.
2. Each subject must have a level of understanding sufficient to agree to all required tests and examinations and sign an informed consent document.
3. All subjects must have undergone a screening assessment under either protocol 01-M-0254, "The Evaluation of Patients with Mood and Anxiety Disorders and Healthy Volunteers" or protocol 17-M-0181 ("Recruitment and Characterization of Research Volunteers for NIMH Intramural Studies").
4. Agree to be hospitalized
Additional Inclusion Criteria: Patients with MDD (Main Study)
1. At the initial study enrollment, subjects must have fulfilled DSM-IV or DSM-5 criteria for Major Depression, single episode or recurrent. Subjects must be experiencing a current major depressive episode of at least 2 weeks duration.
2. At the initial screening and beginning of Phases II and III, subjects must have a baseline score on the MADRS >= 20 and YMRS of < 12.
3. Current or past history of lack of response to one adequate antidepressant trial, operationally defined using the Antidepressant Treatment History Form (ATHF); a failed adequate trial of ECT would count as an adequate antidepressant trial.
2. Each subject must have a level of understanding sufficient to agree to all required tests and examinations and sign an informed consent document.
3. All subjects must have undergone a screening assessment under either protocol 01-M-0254 "The Evaluation of Patients with Mood and Anxiety Disorders and Healthy Volunteers") or 17-M-0181 ("Recruitment and Characterization of Research Volunteers for NIMH Intramural Studies").
4. Agree to be hospitalized.
Exclusion Criteria
EXCLUSION CRITERIA:
Additional Exclusion Criteria: Patients with MDD (Main Study)
1. Current diagnosis of Bipolar Disorder including Bipolar I, Bipolar II, or Bipolar NOS diagnoses.
2. Current psychotic features or a diagnosis of Schizophrenia or any other psychotic disorder as defined in the DSM-IV or DSM-5.
3. Subjects with a history of DSM-IV or DSM-5 drug or alcohol dependency or abuse (except for caffeine or nicotine dependence) within the preceding 3 months. In addition, subjects who currently are using drugs (except for caffeine or nicotine) must not have used illicit substances or known drugs of abuse in the 2 weeks prior to screen and must have a negative alcohol and drug urine test (except for prescribed benzodiazepines or stimulants) urine test at screening.
4. Treatment with a reversible MAOI within two weeks prior to Phase II.
5. Subjects who, in the investigator s judgment, pose a current serious suicidal or homicidal risk.
Exclusion Criteria: All Subjects (Main Study)
1. Pregnant or nursing women or women who plan to become pregnant. Women who are able to get pregnant must be willing to use at least one form of effective birth control during the entire period of study participation (or until last clinical labs and rating) and have a negative pregnancy test that was obtained no more than 24 hours prior to MRI and infusion of ketamine.
2. Serious, unstable illnesses including hepatic, renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease, coronary artery disease, atherosclerotic ischemic stroke, and atrial fibrillation), endocrinologic, neurologic, immunologic, or hematologic disease.
4. Subjects with one or more seizures without a clear and resolved etiology or current use of medication known to lower seizure threshold. History of seizure (regardless of age or etiology), history of epilepsy in self or first-degree relatives, stroke, brain surgery, head injury, or known structural brain lesion will be excluded from the TMS procedures.
5. Treatment with any other concomitant medication 14 days prior to Phase II. An exception of this would be necessary for those who are taking Fluoxetine or Aripiprazole. Prior to Phase II, treatment with Fluoxetine must be discontinued for at least 5 weeks and treatment with Aripiprazole must be discontinued for at least 3 weeks.
6. Any use of opioid medication in the past 3 months
7. Presence of metallic (ferromagnetic) implants (e.g, heart pacemaker, aneurysm clip) (for subjects doing imaging component of the study only).
8. Presence of any medical illness likely to alter brain morphology and/or physiology (e.g., hypertension, diabetes) even if controlled by medications.
9. Subjects who have hearing loss that has been clinically evaluated and diagnosed
10. Participants who are uncomfortable in small closed spaces (have claustrophobia), unable to lie comfortably supine for up to 90 minutes, and would feel uncomfortable in the MRI machine (for subjects doing imaging component of the study only).
11. Positive HIV test
12. Weight > 119 kg
13. [for participants undergoing NPU Threat Test with Auditory Startle] Known history of hearing loss
1. Current or past history of any DSM-IV or DSM-5 Axis I disorder based on clinical assessment and confirmed by a structured diagnostic interview (SCID).
1. Current or past history of any DSM-IV or DSM-5 Axis I disorder based on clinical assessment and confirmed by a structured diagnostic interview (SCID).
2. Current (within the past 3 months) or past alcohol or substance abuse or dependence diagnosis (except for nicotine or caffeine)
3. Pregnant or nursing women or women who plan to become pregnant. Women who are able to get pregnant must be willing to use at least one form of effective birth control during the 4-days of the study participation (or until last clinical labs and rating) and have a negative pregnancy test that was obtained no more than 24 hours prior to infusion of ketamine.
4. Serious, unstable illnesses including hepatic, renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease, coronary artery disease, atherosclerotic ischemic stroke, and atrial fibrillation), endocrinologic, neurologic, immunologic, or hematologic disease.
6. Subjects with one or more seizures without a clear and resolved etiology or current use of medication known to lower seizure threshold.
7. Treatment with any other concomitant medication.
8. Any use of opioid medication in the past 3 months
9. Positive HIV test
10. Weight > 119 kg
11. Presence of metallic (ferromagnetic) implants (e.g, heart pacemaker, aneurysm clip) (for subjects doing neuroimaging component of the study only).
12. Participants who are uncomfortable in small closed spaces (have claustrophobia), unable to lie comfortably supine for up to 90 minutes, and would feel uncomfortable in the MRI machine (for subjects requiring clinical MRI scans for safety and/or structural MRI scans for MEG coregistration).