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

NCT03065335 | Recruiting Phase 1 FDA Drug FDA Device

• 2 other identifiers: 17006017-M-0060
• Study Type: interventional
• Target: 150
• Locations: 1 country
• Sites: 1

Brief 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

Conditions

Healthy Volunteer; Major Depressive Disorder; Depression

Keywords

Magnetic Resonance Imaging; Magnetoencephalography; Major Depressive Disorder; Ketamine; Neuropharmacology

Outcome Measures

Primary Outcomes (2)

• 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

  Multiple

• 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)

  Multiple

Secondary Outcomes (5)

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

  Multiple

• 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.

  Baseline to 24-hours post-ketamine infusion

• 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.

  Multiple

• Ketamine Metabolites Substudy: To correlate metabolite levels in periphery and CSF with changes in clinical rating scales.

  Multiple

• 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).

  Multiple

Study Arms (8)

Metabolites Substudy

EXPERIMENTAL

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

Drug: Ketamine

Phase I

EXPERIMENTAL

Medication taper, drug-free period, and baseline assessments

Device: Cobot TS MV robotic arm for TMS

Phase II, Arm 1

EXPERIMENTAL

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

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

Phase II, Arm 1b

EXPERIMENTAL

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

Phase II, Arm 2

PLACEBO COMPARATOR

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

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

Phase II, Arm 2b

PLACEBO COMPARATOR

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

Phase III

EXPERIMENTAL

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

Drug: Ketamine; Device: NeurOptics PLRTM-30000 Pupillometer

Phase IV

NO INTERVENTION

Follow-up evaluations

Interventions

Ketamine DRUG

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

Metabolites Substudy; Phase II, Arm 1; Phase II, Arm 1b; Phase III

Placebo OTHER

Placebo comparator

Phase II, Arm 2; Phase II, Arm 2b

Cobot TS MV robotic arm for TMS DEVICE

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

Phase I; Phase II, Arm 1; Phase II, Arm 1b; Phase II, Arm 2; Phase II, Arm 2b

NeurOptics PLRTM-30000 Pupillometer DEVICE

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

Phase III

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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.
• 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.
• 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.
• 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 17-M-0181 ("Recruitment and Characterization of Research Volunteers for NIMH Intramural Studies").
• Agree to be hospitalized.

You may not qualify if:

• 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.
• Subjects who, in the investigator s judgment, pose a current serious suicidal or homicidal risk.
• 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.
• 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.
• Clinically significant abnormal laboratory tests.
• 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.
• 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.
• Any use of opioid medication in the past 3 months
• Presence of metallic (ferromagnetic) implants (e.g, heart pacemaker, aneurysm clip) (for subjects doing imaging component of the study only).
• Presence of any medical illness likely to alter brain morphology and/or physiology (e.g., hypertension, diabetes) even if controlled by medications.
• Subjects who have hearing loss that has been clinically evaluated and diagnosed
• 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).

Sponsors & Collaborators

• National Institute of Mental Health (NIMH): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

RECRUITING

Related Publications (1)

• 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.

  PMID: 35501309 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Depressive Disorder, Major; Depression

Interventions

Ketamine; Transcranial Magnetic Stimulation

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders; Behavioral Symptoms; Behavior

Intervention Hierarchy (Ancestors)

Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Magnetic Field Therapy; Therapeutics

Study Officials

• Carlos A Zarate, M.D.

  National Institute of Mental Health (NIMH)

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Laura R Waldman, L.C.S.W.

CONTACT

(877) 646-3644; moodresearch@mail.nih.gov

Carlos A Zarate, M.D.

CONTACT

(301) 326-5836; zaratec@mail.nih.gov

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 24, 2017
• First Posted: February 27, 2017
• Study Start: May 25, 2017
• Primary Completion (Estimated): January 1, 2027
• Study Completion (Estimated): January 1, 2028
• Last Updated: April 24, 2026

Record last verified: 2025-10-24

Data Sharing

• IPD Sharing: Will share
• Shared Documents: SAP
• 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.

Locations

US (1)