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

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ClinicalTrials.gov Identifier: NCT03065335
Recruitment Status : Recruiting
First Posted : February 27, 2017
Last Update Posted : July 16, 2018
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Mental Health (NIMH) )

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


Condition or disease Intervention/treatment Phase
Healthy Volunteer Major Depressive Disorder Depression Drug: Ketamine Other: Placebo Phase 1

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 120 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: Neuropharmacologic Imaging and Biomarker Assessments of Response to Acute and Repeated-Dosed Ketamine Infusions in Major Depressive Disorder
Actual Study Start Date : May 25, 2017
Estimated Primary Completion Date : July 1, 2020
Estimated Study Completion Date : July 1, 2020

Resource links provided by the National Library of Medicine

Drug Information available for: Ketamine

Arm Intervention/treatment
Placebo Comparator: Phase II Arm 2a
Double-blind, single dose of 0.5 mg/kg IV saline
Other: Placebo
0.5 mg/kg IV saline

Experimental: Phase II Arm 1a
Double-blind, single dose of 0.5 mg/kg IV ketamine concurrently with MEG
Drug: Ketamine
N-methyl-D-aspartate (NMDA) glutamate receptor (NMDA-R) antagonist

Experimental: Phase III
Double-blind, repeated dose of 0.5 mg/kg or 0.1 mg/kg IV ketamine
Drug: Ketamine
N-methyl-D-aspartate (NMDA) glutamate receptor (NMDA-R) antagonist

No Intervention: Phase IV
Follow-up evaluations
No Intervention: Phase I
Medication taper, drug-free period, and baseline assessments
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
0.5 mg/kg IV saline

Experimental: Phase II Arm 1b
Double-blind, single dose of 0.5 mg/kg IV ketamine, concurrently with fMRI+EEG
Drug: Ketamine
N-methyl-D-aspartate (NMDA) glutamate receptor (NMDA-R) antagonist

Experimental: Metabolites Substudy
Open-label, single dose of 0.5 mg/kg IV ketamine
Drug: Ketamine
N-methyl-D-aspartate (NMDA) glutamate receptor (NMDA-R) antagonist




Primary Outcome Measures :
  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. [ Time Frame: Ongoing ]
  2. Ketamine Metabolites Substudy: To determine if ketamine metabolites cross the blood brain barrier and enter the brain during ketamine IV administration. [ Time Frame: Ongoing ]

Secondary Outcome Measures :
  1. 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. [ Time Frame: Ongoing ]
  2. 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). [ Time Frame: Ongoing ]
  3. 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. [ Time Frame: Ongoing ]
  4. Ketamine Metabolites Substudy: To correlate metabolite levels in periphery and CSF with changes in clinical rating scales. [ Time Frame: Ongoing ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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 protocol 01-M-0254, "The Evaluation of Patients with Mood and Anxiety Disorders and Healthy Volunteers".
  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-V 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 greater than or equal to 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 protocol 01-M-0254, "The Evaluation of Patients with Mood and Anxiety Disorders and Healthy Volunteers".
  4. Agree to be hospitalized.

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-V.
  3. Subjects with a history of DSM-IV or DSM-V 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.
  3. Clinically significant 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.
  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. A current NIMH employee/staff or their immediate family member

Additional Exclusion Criteria: Healthy Volunteers (Main Study)

  1. Current or past history of any DSM-IV or DSM-V Axis I disorder based on clinical assessment and confirmed by a structured diagnostic interview (SCID).
  2. First-degree relative with a history of any DSM-IV or DSM-V Axis I disorder.

Ketamine Metabolites Substudy Exclusion Criteria: Healthy Volunteers

  1. Current or past history of any DSM-IV or DSM-V 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. First-degree relative with a history of any DSM-IV or DSM-V Axis I disorder.
  4. 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.
  5. 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. Clinically significant abnormal laboratory tests.
  7. Subjects with one or more seizures without a clear and resolved etiology or current use of medication known to lower seizure threshold.
  8. Treatment with any other concomitant medication.
  9. Any use of opioid medication in the past 3 months
  10. Positive HIV test
  11. Weight > 119 kg
  12. A current NIMH employee/staff or their immediate family member

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03065335


Contacts
Contact: Libby Jolkovsky (877) 646-3644 libby_jolkovsky@nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)    800-411-1222 ext TTY8664111010    prpl@cc.nih.gov   
Sponsors and Collaborators
National Institute of Mental Health (NIMH)
Investigators
Principal Investigator: Carlos A Zarate, M.D. National Institute of Mental Health (NIMH)

Additional Information:
Responsible Party: National Institute of Mental Health (NIMH)
ClinicalTrials.gov Identifier: NCT03065335     History of Changes
Other Study ID Numbers: 170060
17-M-0060
First Posted: February 27, 2017    Key Record Dates
Last Update Posted: July 16, 2018
Last Verified: July 3, 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute of Mental Health (NIMH) ):
Magnetic Resonance Imaging
Magnetoencephalography
Major Depressive Disorder
Ketamine
NEUROPHARMACOLOGY

Additional relevant MeSH terms:
Disease
Depressive Disorder
Depression
Depressive Disorder, Major
Mood Disorders
Mental Disorders
Pathologic Processes
Behavioral Symptoms
Ketamine
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anesthetics, Dissociative
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
Central Nervous System Depressants
Excitatory Amino Acid Antagonists
Excitatory Amino Acid Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action