Background:
Most medications that treat depression take weeks or months to work. Researchers want to develop fast-acting treatments. One dose of ketamine has a rapid antidepressant effect. For most people, this lasts a week or less. Repeated doses of ketamine may help maintain this effect.
Objective:
Main Study: To study the effects of ketamine in treating depression.
Ketamine Metabolites Substudy: To study how ketamine effects brain chemistry.
To study how ketamine effects the brain. This is done by looking at metabolites, which are created when a drug is broken down.
Eligibility:
Main Study: People ages 18-65 with major depressive disorder and healthy volunteers
Ketamine Metabolites Substudy: Healthy volunteers ages 18-65
Design:
Main Study:
Participants will be screened in another study, with:
* Medical and psychiatric history * Psychiatric and physical exam * Blood, urine, and heart tests
Participants will be inpatients at NIH for 4 phases totaling 14-20 weeks.
Phase I (2-7 weeks):
* Gradually stop current medications * MRI: Participants lie and perform tasks in a machine that takes pictures of the body. * Mood and thinking tests * Blood and urine tests * Sleep test: Monitors on the skin record brain waves, breathing, heart rate, and movement during sleep. * Transcranial magnetic stimulation: A coil on the scalp gives an electrical current that affects brain activity. * Stress tests: Electrodes on the skin measure reactions to loud noises or electric shocks.
Phase I tests are repeated in Phases II and III and in the final visit.
Phase II (4-5 weeks):
* 4 weekly IV infusions of ketamine or a placebo during an MRI or MEG. For the MEG, a cone over the head records brain activity.
Phase III (optional):
* 8 infusions of ketamine over 4 weeks
Phase IV (optional):
* Symptoms monitoring for 4 weeks * Participants will have a final visit. They will be offered standard treatment at NIH for up to 2 months.
Ketamine Metabolites Substudy:
Participants will be screened in another study, with:
* Medical and psychiatric history * Psychiatric and physical exam * Blood, urine, and heart tests
Participants will be inpatients at NIH for 4 days.
Study Procedures:
Mood and thinking tests
Blood and urine tests
1 infusion of ketamine
Spinal tap and spinal catheter: Used to get samples of cerebrospinal fluid (CSF). This is a fluid that moves around and within the brain and spinal cord. Studying CSF will help us learn how ketamine effects brain chemistry
18 to 65 years of age.
Each subject must have a level of understanding sufficient to agree to all required tests and examinations and sign an informed consent document.
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").
Agree to be hospitalized
Current diagnosis of Bipolar Disorder including Bipolar I, Bipolar II, or Bipolar NOS diagnoses.
Current psychotic features or a diagnosis of Schizophrenia or any other psychotic disorder as defined in the DSM-IV or DSM-5.
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.
Treatment with a reversible MAOI within two weeks prior to Phase II.
Crossover
Ketamine
DrugN-methyl-D-aspartate (NMDA) glutamate receptor (NMDA-R) antagonist
Placebo
Other interventionPlacebo comparator
Cobot TS MV robotic arm for TMS
DeviceTMS-Cobot TS MV \[Axilum Robotics\] robotic arm for spatial positioning and orientation of the TMS coil
NeurOptics PLRTM-30000 Pupillometer
DeviceThe Neu-rOptics PLRTM-3000 Pupillometer will use quantitative infrared technology to objectively and accurately measure pupil size and dynamics.
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Treatment groupsSee each treatment group below.
To demonstrate more robust neuropharmacodynamic effects measured by neuropharmacodynamic imaging (fMRI+EEG and MEG) of ketamine 0.5 mg/kg as compared to placebo administered over 40 minutes.
Magnetoencephalography (MEG) data
Ketamine Metabolites Substudy: To determine if ketamine metabolites cross the blood brain barrier and enter the brain during ketamine IV administration.
Data from peripheral blood and CSF (in some participants)
To profile ketamine s opioid action based on the PLR using video pupillometry.
Pupil diameter, amplitude of constriction, and constriction velocity
To identify baseline peripheral measures associated with response to the administration of ketamine 0.5 mg/kg, as potential biomarkers of acute (24 hour) treatment response.
Plasma/serum biomarkers
To determine if increases in synaptic plasticity, using electrophysiological measures in response to TMS and in association with sleep (i.e. slow wave sleep EEG activity) are associated with better antidepressant response to 0.5 mg/kg ketamine.
Transcranial Magnetic Stimulation (TMS) and Polysomnography (PSG)/Electroencephalography (EEG) data
Ketamine Metabolites Substudy: To correlate metabolite levels in periphery and CSF with changes in clinical rating scales.
CSF and peripheral blood data, clinical rating scale of depression
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