ClinicalTrials.gg
Sign In
RecruitingNCT03065335Updated Nov 9, 2026

Neuropharmacologic Imaging and Biomarker Assessments of Response to Acute and Repeated-Dosed Ketamine Infusions in Major Depressive Disorder

A Phase 1 interventional study of Ketamine and Placebo in Healthy Volunteer, Major Depressive Disorder and Depression, sponsored by National Institute of Mental Health (NIMH). Recruiting at 1 site in United States. Open to participants aged 18 Years to 65 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2026-11-09.

Sponsored by National Institute of Mental Health (NIMH) · Phase 1, Interventional, and Treatment

From the registry’s dates

  • Started May 2017; still recruiting 9 years 5 months later.
Phase
Phase 1
Study type
Interventional
Enrollment
150
Allocation
Randomized
Ages
18 Years to 65 Years
Sex
All
01

Study summary

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

Read the detailed description

Objective

The current protocol has a two-fold purpose. In the pharmacodynamic imaging phase, we will investigate the neuropharmacodynamics of acute intravenous ketamine administration in patients with major depressive disorder (MDD) and healthy volunteers (HV) using functional MRI (fMRI) and electrophysiological modalities [electroencephalography (EEG) and magnetoencephalography (MEG)]. We will also investigate if specific signatures from functional neuroimaging, transcranial magnetic stimulation (TMS) associated evoked potentials (TMS-EP), sleep EEG (S-EEG), and psychophysiologic responses can be used to classify specific subpopulations of patients with MDD; preliminary findings from such an approach may be important in forging further studies identifying those who will respond to ketamine infusions. In the repeat-dosing phase, we will expand upon our previous findings of the immediate efficacy of glutamatergic modulators by investigating the safety and efficacy of repeated dose administrations of ketamine in MDD patients. We will include all MDD patients regardless of antidepressant response to single infusions of ketamine to allow for potential identification of patients who are able to attain and/or maintain a response over a series of infusions. To reduce any potential biases due to partial blinding, all patients will be randomized into groups to receive ketamine at either 0.5 mg/kg or 0.1 mg/kg (an active comparator).

Study Population

The study consists of 50 patients with treatment-resistant MDD between 18 and 65 years old and 50 age/gender matched HVs. Within the MDD group, 25 patients will be enrolled into each group in the repeat-dosing phase. An addition 50 HVs will participate in the Ketamine Metabolites Substudy.

Study Design

This study is a Phase I Clinical Trial that comprises four phases.

Phase I includes screening, medication taper (patients, as needed), medication-free period (patients), and baseline assessments, including optional TMS-EP, S-EEG, the None, Predictive, Unpredictive (NPU)-threat test, non-brain imaging cognitive tasks, and blood samples for plasma neurochemicals and peripheral blood biomarkers.

In Phase II, all subjects (patients with MDD and HVs) will receive an alternating series of placebo and ketamine infusions, once per week, for a total of 4 infusions (2 ketamine, 2 placebo). Concurrently with each infusion, subjects will be administered either resting-state fMRI with simultaneous EEG, or resting state MEG recording, thus each subject receives fMRI+EEG and MEG for both a placebo and ketamine infusion. Participants may also undergo optional sEEG, non-brain imaging cognitive tasks, TMS-EP, and NPU.

Phase III involves MDD patients whose depression symptoms relapsed after the final infusion in Phase II. Patients whose symptoms did not relapse may receive an additional one-week washout prior to participating in Phase III. Subjects will be randomized to receive ketamine at 0.5 or 0.1 mg/kg twice weekly for 4 weeks (total of 8 infusions). Participants may undergo optional fMRI, S-EEG, MEG, non-brain imaging cognitive tasks, TMS-EP, pupillometry, and NPU at time points between infusions. Clinical rating scales will assess depression symptomology and blood will be drawn for pharmacokinetics testing and biomarker analyses.

Phase IV includes patients who completed Phase III and who are responders. These patients will be followed up for an additional 4 weeks, or until relapse (whichever comes first), to determine durability of response. The final study day will include rating scales, medical evaluations, blood tests, and an additional sMRI to assess structural changes that may have occurred due to repeated ketamine infusions.

The protocol includes a substudy evaluating ketamine metabolites in healthy volunteers (Ketamine Metabolites Substudy). Only HVs will be enrolled in this substudy. Subjects will undergo a single infusion of ketamine concurrently with serial peripheral blood collection. Some participants may also undergo serial CSF collection during the ketamine infusion. Clinical rating scales, cognitive tasks, MEG, S-EEG, CSF and/or blood draws for pharmacokinetics testing and biomarker analyses will be done.

Outcome Measures

The primary outcome measure of Phase II is the pharmacodynamic fMRI and MEG responses to ketamine compared to placebo. Secondary outcome measures include the difference in Montgomery-Asberg Depression Rating Scale (MADRS) score from baseline to 24 hours between the placebo and ketamine infusion, correlations between an antidepressant response and TMS-EP, S-EEG, neuroimaging, cognitive, and NPU measures. In Phase II, the HVs acts as another level of control to identify a potential neuropharmacodynamic signature associated with an antidepressant response to ketamine.

The primary outcome measure for Phase III is the difference or change in MADRS from baseline to the end of 4 weeks of twice-weekly infusions. Secondary outcome measures include cognitive, TMS-EP, S-EEG, and NPU-threat test measures.

The primary outcome measure for the Ketamine Metabolites Substudy are the levels of ketamine metabolites in CSF and peripheral blood.

Other outcome measures for both Phase II and III include clinical rating scales, neurocognitive tests, ketamine levels, plasma neurochemicals, and peripheral blood biomarkers. Additional outcomes in Phase III are baseline and post-repeated dose infusion MRI scans, and neurocognitive test results. Rating scales are the outcomes measures of Phase IV. Subjects will continue Phase IV for 4 weeks or until relapse (whichever comes first). Additional outcomes for the Ketamine Metabolites Substudy are metabolite levels and clinical rating scales

02

Conditions studied

  • Healthy Volunteer
  • Major Depressive Disorder
  • Depression

Keywords

  • Magnetic Resonance Imaging
  • Magnetoencephalography
  • Major Depressive Disorder
  • Ketamine
  • Neuropharmacology
03

In context

Depressive Disorder, Major

3,041 studies on the registry are indexed under Depressive Disorder, Major; 588 are open to participants now.

This study's planned enrollment of 150 is above the median of 79 across 2,530 interventional studies indexed under Depressive Disorder, Major.

Browse Depressive Disorder, Major studies →

Lead sponsor

National Institute of Mental Health (NIMH) is the lead sponsor of 367 studies on the registry; 45 are open to participants now.

Of its 25 completed or terminated interventional studies of FDA-regulated products, 24 (96%) have results posted.

Browse National Institute of Mental Health (NIMH) studies →

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
18 Years to 65 Years
Sexes eligible
All
Accepts healthy volunteers
Yes

Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.

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 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 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.

Ketamine Metabolites Substudy Inclusion Criteria: Healthy Volunteers

  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 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 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 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.
  3. abnormal laboratory tests.
  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 test
  12. Weight > 119 kg
  13. [for participants undergoing NPU Threat Test with Auditory Startle] Known history of hearing loss

Additional Exclusion Criteria: Healthy Volunteers (Main Study)

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).

Ketamine Metabolites Substudy Exclusion Criteria: Healthy Volunteers

  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.
  5. Clinically significant abnormal laboratory tests.
  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).
Terms in these criteria, in plain language(5)

Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.

Informed consent

Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.

You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.

DSM diagnostic criteria

The American Psychiatric Association’s manual of mental health diagnoses. DSM-5 (2013, revised as DSM-5-TR in 2022) replaced DSM-IV, and some studies still name the older edition. “Meets DSM criteria for …” means diagnosed by that edition’s diagnostic criteria, usually by a clinician in an interview.

Contraception

Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.

Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.

Clinically significant

Judged by the study doctor to matter for your health or for the study. It is a doctor’s decision, so ask the study team if you are unsure whether something counts.

HIV

The human immunodeficiency virus, which weakens the immune system.

Many studies now accept people whose HIV is controlled on treatment, judged by the viral load and the CD4 count. Check the limits this study sets.

05

Study design

Phase
Phase 1
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Crossover assignment
Masking
Double (Participant, Investigator)
Enrollment
150 participants (estimated)

Study arms

  • Experimental
    Metabolites Substudy

    Open-label, single dose of 0.5 mg/kg IV ketamine

    Drug: Ketamine

  • Experimental
    Phase I

    Medication taper, drug-free period, and baseline assessments

    Device: Cobot TS MV robotic arm for TMS

  • Experimental
    Phase II, Arm 1

    Double-blind, single dose of 0.5 mg/kg IV ketamine

    Drug: Ketamine · Device: Cobot TS MV robotic arm for TMS

  • Experimental
    Phase II, Arm 1b

    Double-blind, single dose of 0.5 mg/kg IV ketamine, concurrently with fMRI+EEG or MEG

    Drug: Ketamine · Device: Cobot TS MV robotic arm for TMS

  • Placebo comparator
    Phase II, Arm 2

    Double-blind, single dose of 0.5 mg/kg IV saline

    Other: Placebo · Device: Cobot TS MV robotic arm for TMS

  • Placebo comparator
    Phase II, Arm 2b

    Double-blind, single dose of 0.5 mg/kg IV saline, concurrently with fMRI+EEG or MEG.

    Other: Placebo · Device: Cobot TS MV robotic arm for TMS

  • Experimental
    Phase III

    Double-blind, repeated dose of 0.5 mg/kg or 0.1 mg/kg IV ketamine

    Drug: Ketamine · Device: NeurOptics PLRTM-30000 Pupillometer

  • No intervention
    Phase IV

    Follow-up evaluations

Interventions

  • DrugKetamine

    N-methyl-D-aspartate (NMDA) glutamate receptor (NMDA-R) antagonist

  • OtherPlacebo

    Placebo comparator

  • DeviceCobot TS MV robotic arm for TMS

    TMS-Cobot TS MV \[Axilum Robotics\] robotic arm for spatial positioning and orientation of the TMS coil

  • DeviceNeurOptics PLRTM-30000 Pupillometer

    The Neu-rOptics PLRTM-3000 Pupillometer will use quantitative infrared technology to objectively and accurately measure pupil size and dynamics.

06

What researchers measure

Primary outcomes

  1. 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

    Time frame: Multiple

  2. 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)

    Time frame: Multiple

Secondary outcomes

  1. To profile ketamine s opioid action based on the PLR using video pupillometry.

    Pupil diameter, amplitude of constriction, and constriction velocity

    Time frame: Multiple

  2. 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

    Time frame: Baseline to 24-hours post-ketamine infusion

  3. 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

    Time frame: Multiple

  4. 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

    Time frame: Multiple

  5. To demonstrate enhanced efficacy, as measured by the MADRS, of IV ketamine 0.5 mg/kg in participants with MDD using a psychophysiological technique (i.e. NPU-threat test).

    Clinical rating scale of depression

    Time frame: Multiple

07

Study locations

1 of 1 sites recruiting
  • National Institutes of Health Clinical Center
    Bethesda, Maryland 20892, United States
    Recruiting
    • NIH Clinical Center Office of Patient Recruitment (OPR) · Contactccopr@nih.gov · 800-411-1222
08

References and documents

Publications

  • Moaddel R, Zanos P, Farmer CA, Kadriu B, Morris PJ, Lovett J, Acevedo-Diaz EE, Cavanaugh GW, Yuan P, Yavi M, Thomas CJ, Park LT, Ferrucci L, Gould TD, Zarate CA Jr. Comparative metabolomic analysis in plasma and cerebrospinal fluid of humans and in plasma and brain of mice following antidepressant-dose ketamine administration. Transl Psychiatry. 2022 May 2;12(1):179. doi: 10.1038/s41398-022-01941-x. PubMed 35501309 ↗

Individual participant data

Plan to share: Yes — Clinical and demographic and biomarker participant data collected during the trial, after deidentification

Supporting information: Statistical analysis plan

Time frame: Starting within 1 year of completion of the study

Access criteria: The Branch Chief will review requests and obtain approval by the NIMH/DIRP offices of the Scientific and Clinical Directors and/or the NIH IRB.

09

Updates

7 registry updates since Sep 25, 2026
Minor edits
Nothing that changes what the study is or who can join. Edited: description and verification date
7 updates, last Nov 9, 2026
Show all 7 updates
  1. Nov 9, 2026
    Minor edits only
    + 1 other change: description
  2. Oct 29, 2026
    Minor edits only
    + 1 other change: description
  3. Oct 26, 2026
    Minor edits only
    + 1 other change: verification date
  4. Oct 20, 2026
    Minor edits only
    + 1 other change: verification date
  5. Oct 16, 2026
    Minor edits only
    + 1 other change: description
  6. Oct 13, 2026
    Minor edits only
    + 1 other change: verification date
  7. Oct 8, 2026
    Minor edits only
    + 1 other change: description

From the registry record's own update history. This site started tracking changes on Sep 25, 2026; for anything earlier, see the record history on ClinicalTrials.gov ↗

10

Registry details

Key details

Study ID
NCT03065335
Lead sponsor
National Institute of Mental Health (NIMH)
Responsible party
Sponsor
First posted
Feb 27, 2017
Start date
May 25, 2017
Primary completion
Jan 1, 2027 (estimated)
Completion
Jan 1, 2028 (estimated)
Last update
Nov 9, 2026

Study contacts

Adilah M Kirton
Contact
adilah.meredith-kirton@nih.gov
(301) 549-0315
Carlos A Zarate, M.D.
principal investigator · National Institute of Mental Health (NIMH)

Oversight

FDA-regulated drug
Yes
FDA-regulated device
Yes
View the source record on ClinicalTrials.gov ↗

Interested in this study?

Eligibility is decided by the study team. Share this record with your doctor or contact the team directly.

Contact study team

Follow this study

Get an email when the registry record changes — status, dates, results — or when someone posts here.

Sign in to follow

Discussion

Questions and observations about this study, from anyone following it. Not medical advice, and not a channel to the study team — their contact details are on the registry record.

Sign in to join the discussion. Reading takes no account; posting does. You choose a display name, and a pseudonym is the default.

Nothing here yet. If you are running this trial, taking part in it, or weighing whether to, this is the place to say so.

Studies of the drug tested here: Ketamine

Other studies in this condition

Depressive Disorder, Major →

Other studies from this sponsor

National Institute of Mental Health (NIMH) →

Start the discussion