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The Role of HNKs in the Antidepressant Effect of Ketamine

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ClinicalTrials.gov Identifier: NCT03977675
Recruitment Status : Recruiting
First Posted : June 6, 2019
Last Update Posted : July 10, 2019
Sponsor:
Information provided by (Responsible Party):
Columbia University

Brief Summary:
The objective of the proposed study is to examine the relationship between serum concentrations of HNK and changes in the Hamilton Depression Rating Scale (HDRS), Beck Depression Inventory (BDI), and the Profile of Mood States (POMS), as well as glutamatergic/GABAergic response. To achieve these aims the investigators propose a double-blind, uncontrolled (no placebo, no healthy control subjects) study with several different doses of ketamine. The investigators will conduct MRI scans to measure Glu and GABA before and during the ketamine treatment.

Condition or disease Intervention/treatment Phase
Major Depressive Disorder Drug: Ketamine Phase 1

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.

Preliminary data support the rapid antidepressant benefit from ketamine but do not show a relationship between clinical improvement and the amount of ketamine, norketamine or dehydronorketamine (DHNK)(two of ketamine's metabolites) in the blood. The investigators hypothesize that a different metabolite of ketamine, hydroxynorketamine (HNK), produces the antidepressant effect of ketamine. The investigators have also 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 drug. 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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Basic Science
Official Title: The Role of HNKs in the Antidepressant Effect of Ketamine
Actual Study Start Date : May 15, 2019
Estimated Primary Completion Date : September 2020
Estimated Study Completion Date : September 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Antidepressants
Drug Information available for: Ketamine

Arm Intervention/treatment
Experimental: Ketamine 0.3 mg/kg
Subjects are assigned to receive a dose of 0.3 mg/kg of Ketamine.
Drug: Ketamine
Patients are assigned to one of three ketamine doses (0.3, 0.5, or 0.7 mg/kg) that will be administered intravenously.

Experimental: Ketamine 0.5 mg/kg
Subjects are assigned to receive a dose of 0.5 mg/kg of Ketamine.
Drug: Ketamine
Patients are assigned to one of three ketamine doses (0.3, 0.5, or 0.7 mg/kg) that will be administered intravenously.

Experimental: Ketamine 0.7 mg/kg
Subjects are assigned to receive a dose of 0.7 mg/kg of Ketamine.
Drug: Ketamine
Patients are assigned to one of three ketamine doses (0.3, 0.5, or 0.7 mg/kg) that will be administered intravenously.




Primary Outcome Measures :
  1. Change in HNK Plasma Concentration [ Time Frame: Baseline and 80 minutes post-infusion ]
    HNK levels will be measured after ketamine administration.

  2. Change in DHNK Plasma Concentration [ Time Frame: Baseline and 80 minutes post-infusion ]
    DHNK levels will be measured after ketamine administration.



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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Current major depressive episode (MDE) as part of major depressive disorder (MDD). May be psychiatric medication-free or, if on psychiatric medications, not responding adequately.
  • Off all psychotropic and other types of drugs likely to interact with glutamate for at least 14 days before starting the study OR likely able to tolerate a medication washout.
  • Female subjects of child-bearing potential must be using an acceptable method of birth control throughout the study.

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.
  • Electroconvulsive therapy (ECT) within the last 3 months for current MDE.
  • Pregnancy or plans to conceive during the course of study participation.
  • Heart pacemaker, body implant or other metal in body.
  • Neurological disease or prior head trauma with evidence of cognitive impairment.
  • Claustrophobia sufficient to preclude MRI.
  • Prior ineffective trial of, or adverse effect to, ketamine.
  • IV drug use or history of ketamine use as a recreational drug ≥ 2 times or an adverse reaction to ketamine; any other drug or alcohol dependence within past 6 months.

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): NCT03977675


Contacts
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Contact: Study Coordinator 6467747594 rr3110@cumc.columbia.edu

Locations
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United States, New York
New York State Psychiatric Institute Recruiting
New York, New York, United States, 10032
Contact: Study Coordinator    646-774-7594    rr3110@cumc.columbia.edu   
Sponsors and Collaborators
Columbia University
Investigators
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Principal Investigator: Michael Grunebaum, MD New York Psychiatric Institute

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Responsible Party: Columbia University
ClinicalTrials.gov Identifier: NCT03977675     History of Changes
Other Study ID Numbers: NYSPI 7558
First Posted: June 6, 2019    Key Record Dates
Last Update Posted: July 10, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Columbia University:
Magnetic Resonance Spectroscopy
Ketamine
Additional relevant MeSH terms:
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Depressive Disorder
Depressive Disorder, Major
Mood Disorders
Mental Disorders
Ketamine
Antidepressive Agents
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
Psychotropic Drugs