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Ketamine in the Treatment of Depression

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01558063
Recruitment Status : Completed
First Posted : March 20, 2012
Results First Posted : July 16, 2019
Last Update Posted : December 10, 2019
Sponsor:
Collaborator:
National Institute of Mental Health (NIMH)
Information provided by (Responsible Party):
Columbia University

Tracking Information
First Submitted Date  ICMJE March 16, 2012
First Posted Date  ICMJE March 20, 2012
Results First Submitted Date  ICMJE April 11, 2019
Results First Posted Date  ICMJE July 16, 2019
Last Update Posted Date December 10, 2019
Study Start Date  ICMJE February 2012
Actual Primary Completion Date May 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 16, 2019)
Number of Responders 24-hours Post-ketamine Infusion [ Time Frame: Day 1 (post ketamine) ]
The quantitative depressive symptom ratings were collected at Baseline, Day 1 (post ketamine), Day 3 using HDRS-24 (a 24-item questionnaire used to provide an indication of depression, and as a guide to evaluate recovery). The total score can range from 0 to a maximum score of 15 with a higher score indicating a worse outcome. A "responder" was defined as an individual exhibiting a reduction in the HDRS score from baseline to 24 hours (day 1) post-treatment, and all other individuals were classified as non-responders.
Original Primary Outcome Measures  ICMJE
 (submitted: March 19, 2012)
Ketamine Dose-Response Curve [ Time Frame: Baseline and Day 1 (post ketamine) ]
The primary outcome is the dose-response curve as it refers to ketamine inducing a dose-dependent reduction in the 24-item Hamilton Depression Rating Scale (HDRS-24) scores of patients with major depressive disorder.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 20, 2016)
  • Change in Glutamate Levels [ Time Frame: Baseline and 120 minutes after infusion ]
    The dose-response curve as it refers to ketamine inducing a dose-dependent increase in glutamate levels with 1H Magnetic Resonance Spectroscopy (MRS) will be analyzed.
  • Change in Gamma-Amino Butyric Acid (GABA) Levels [ Time Frame: Baseline and 120 minutes after infusion ]
    The dose-response curve as it refers to ketamine inducing a dose-dependent increase in GABA levels measured with 1H Magnetic Resonance Spectroscopy (MRS) will be analyzed.
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Ketamine in the Treatment of Depression
Official Title  ICMJE The Antidepressant Action of Ketamine: Brain Chemistry
Brief Summary

Depressed patients will be offered experimental treatment with a new, potentially fast-acting antidepressant called ketamine while being scanned by magnetic resonance imaging (MRI) to measure the chemical effect of the drug. Ketamine will be given in a dose of 0.0 (placebo), 0.1, 0.2, 0.3, 0.4, or 0.5 mg/kg. If a patient does not respond to ketamine after the first infusion, it may be because s/he received ketamine placebo or the dose of ketamine was too low. In that case, an optional second scan and infusion of active ketamine (0.5 mg/kg) will be offered. This second scan will occur no later than weeks after the first scan/infusion (as scheduling permits). There is no guarantee that the patient will respond to the second ketamine infusion. Patients enrolled in the study are eligible for up to 6 months treatment with their study psychiatrist after the ketamine infusion(s).

Healthy Volunteers: Healthy controls will receive an infusion of ketamine at a single dose (0.5 mg/kg). Volunteers will only receive one MRI scan and infusion.

Detailed Description Major depressive disorder (MDD) is a common illness, affecting over 14 million American adults each year. MDD is a leading cause of disability worldwide, and is responsible for huge workplace and healthcare costs. The several week delay between onset of treatment and improvement in MDD symptoms with currently available treatments further increases the burden of the disorder. Shortening this delay is a major unmet challenge in the treatment of MDD. Studies report that a single intravenous low dose of a drug called ketamine can bring about substantial improvement in depression in hours, even in patients that have not improved with other antidepressant treatments. Certain aspects of ketamine's drug action are fairly well understood, but the question remains of how these properties relate to antidepressant effect. The investigator's preliminary data support the rapid antidepressant benefit from ketamine. The investigators have used a scanner to measure the effects of ketamine on two major brain chemical transmitters and found that it causes a significant increase (more than 60%) in glutamate (Glu) and gamma aminobutyric acid (GABA) levels in the front of the brain. The investigators hypothesize that this increase in Glu and GABA levels, is responsible for the antidepressant action of the medication. Knowing how ketamine works could help to develop better medications that can be used orally and used for maintenance of the improvement seen with ketamine. The objective of the proposed dose finding study is to examine the relationship between the ketamine-induced improvement of MDD and the Glu and GABA responses to ketamine and to compare the Glu and GABA responses to ketamine in MDD and healthy subjects to better understand the pathophysiology of MDD. To achieve these aims this the investigators propose a randomized, placebo-controlled, double blind study with several different doses of ketamine. The investigators will conduct MRI scans to measure Glu and GABA before and during the ketamine treatment.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Major Depressive Disorder
Intervention  ICMJE
  • Drug: Ketamine
    Single dose of 0.1, 0.2, 0.3, 0.4 or 0.5 mg/kg of ketamine given intravenously over 40 minutes.
    Other Name: Ketalar
  • Drug: Saline
    Single infusion of saline given intravenously over 40 minutes.
    Other Name: Saline solution
  • Procedure: Magnetic Resonance Imaging (MRI)
    90-minute scan during the 40-minute infusion.
Study Arms  ICMJE
  • Active Comparator: Ketamine Dose 1
    0.1 mg/kg, IV (in the vein) of Ketamine and MRI scan
    Interventions:
    • Drug: Ketamine
    • Procedure: Magnetic Resonance Imaging (MRI)
  • Active Comparator: Ketamine Dose 2
    0.2 mg/kg, IV (in the vein) of Ketamine and MRI scan
    Interventions:
    • Drug: Ketamine
    • Procedure: Magnetic Resonance Imaging (MRI)
  • Active Comparator: Ketamine Dose 3
    0.3 mg/kg, IV (in the vein) of Ketamine and MRI scan
    Interventions:
    • Drug: Ketamine
    • Procedure: Magnetic Resonance Imaging (MRI)
  • Active Comparator: Ketamine Dose 4
    0.4 mg/kg, IV (in the vein) of Ketamine and MRI scan
    Interventions:
    • Drug: Ketamine
    • Procedure: Magnetic Resonance Imaging (MRI)
  • Active Comparator: Ketamine Dose 5
    0.5 mg/kg, IV (in the vein) of Ketamine and MRI scan
    Interventions:
    • Drug: Ketamine
    • Procedure: Magnetic Resonance Imaging (MRI)
  • Placebo Comparator: Saline Solution
    Saline infused over 40 minutes and MRI scan
    Interventions:
    • Drug: Saline
    • Procedure: Magnetic Resonance Imaging (MRI)
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: April 8, 2019)
38
Original Estimated Enrollment  ICMJE
 (submitted: March 19, 2012)
76
Actual Study Completion Date  ICMJE October 2019
Actual Primary Completion Date May 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Patient Inclusion Criteria:

  • Patient suffering from a major depressive episode (MDE) as part of an major depressive disorder (MDD). Patients may be psychiatric medication-free or, if on psychiatric medications, not responding adequately.
  • Patient scores at least 22 on the Montgomery-Åsberg Depression Rating Scale (MADRS)
  • Age range 18-65 years
  • Patient is off all psychotropic and other types of drugs likely to interact with glutamate for at least 14 days before starting the study with an exception of chloral hydrate or short acting benzodiazepines for distressing anxiety or insomnia
  • Subject is likely to be able to tolerate a medication washout
  • Female subjects of child-bearing potential must be using an acceptable method of birth control throughout the study.
  • Must be enrolled in New York Psychiatric Institute (NYSPI) study #4815

Patient Exclusion Criteria:

  • Lifetime history of schizophrenia,schizoaffective illness, Bipolar Disorder, or psychosis.
  • First-degree relative with schizophrenia, schizoaffective disorder, or bipolar disorder if the subject is less than 33 years old
  • Significant uncontrolled physical illness particularly if it may affect the brain or glutamatergic system including blood dyscrasias lymphomas, hypersplenism, endocrinopathies, renal failure or severe chronic obstructive lung disease, autonomic neuropathies and active malignancy.
  • Subjects will be excluded for baseline hypertension (BP>140/90) or significant history of cardiovascular illness
  • Significant ECG abnormalities
  • Lacks capacity to consent
  • Patients who are actively suicidal as defined by a suicidal ideation score of 4 or 5 or suicidal behavior score > 0 on the Columbia Suicide Severity Rating Scale (C-SSRS) at in-person screening interview will be excluded from participating as outpatients and may only participate as inpatients if the independent inpatient treatment team agrees with the plan to enroll the patient.
  • Electroconvulsive therapy (ECT) within the last 3 months for this episode
  • Pregnancy or plans to conceive during the course of study participation
  • Heart pacemaker, body implant or other metal in body
  • A neurological disease or prior head trauma with evidence of cognitive impairment.
  • Patients who are responding satisfactorily to antidepressant medications because they will not be washed-out for purposes of this study
  • Claustrophobia sufficient to preclude MRI
  • Irremovable medicinal patch
  • Prior ineffective trial of, or adverse effect to, ketamine
  • Subjects judged unlikely to be able to tolerate a psychoactive medication washout of 14 days
  • Inadequate understanding of English
  • IV drug use or history of ketamine use as a recreational drug ≥ 2 times or an adverse reaction to ketamine

Control Inclusion Criteria:

  • Age 18-65
  • Physically healthy
  • Absence of an Axis I diagnosis (specific phobia acceptable). Absence of Borderline Personality Disorder and Antisocial Personality Disorder.
  • Not on any medications known to affect glutamatergic functioning
  • Female subjects of child-bearing potential must be using an acceptable method of birth control throughout the study.
  • Must be enrolled in NYSPI protocol #4815

Control Exclusion Criteria:

  • First degree relative with MDD; first degree relative with Schizophrenia, Schizoaffective Disorder, Bipolar disorder, if the subject is less than 33 years old, and therefore still at significant risk
  • Significant active physical illness particularly if it may affect the brain or glutamatergic system including blood dyscrasias lymphomas, hypersplenism, endocrinopathies, renal failure or severe chronic obstructive lung disease,autonomic neuropathies and active malignancy.
  • Subjects will be excluded for baseline hypertension (BP>140/90) or significant history of cardiovascular illness.
  • Significant ECG abnormalities
  • Pregnancy or plans to conceive during the course of study participation
  • Heart pacemaker, body implant or other metal in body
  • A neurological disease or prior head trauma with evidence of cognitive impairment.
  • Claustrophobia sufficient to preclude MRI
  • Irremovable Medicinal patch
  • Inadequate understanding of English
  • Lifetime history of substance dependence,current or past substance abuse will be excluded; IV drug use or history of ketamine use as a recreational drug ≥ 2 times or an adverse reaction to ketamine will be excluded.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01558063
Other Study ID Numbers  ICMJE NYSPI 6460
5R01MH093637-03 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Columbia University
Study Sponsor  ICMJE Columbia University
Collaborators  ICMJE National Institute of Mental Health (NIMH)
Investigators  ICMJE
Principal Investigator: Michael F. Grunebaum, M.D. Columbia University
PRS Account Columbia University
Verification Date December 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP