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Ketamine Associated ACC GABA and Glutamate Change and Depression Remission:

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: NCT03573349
Recruitment Status : Enrolling by invitation
First Posted : June 29, 2018
Last Update Posted : September 10, 2021
Sponsor:
Information provided by (Responsible Party):
Balwinder Singh, MD, MS, Mayo Clinic

Tracking Information
First Submitted Date  ICMJE June 20, 2018
First Posted Date  ICMJE June 29, 2018
Last Update Posted Date September 10, 2021
Actual Study Start Date  ICMJE January 3, 2019
Estimated Primary Completion Date December 31, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 18, 2020)
  • To evaluate percent change in the anterior cingulate cortex (ACC) GABA and Glutamate (baseline to peak) during a 40-minute IV ketamine infusion and remission (MADRS ≤9) at 24 hour [ Time Frame: 24 hour ]
    Percent change in central metabolites and association with remission
  • To evaluate a correlation between percent change in ACC GABA and Glutamate/Glx levels (baseline to peak) with a change in MADRS (baseline to 24 hours). [ Time Frame: 24 hour ]
    Change in central metabolite and association with change in depression scores
Original Primary Outcome Measures  ICMJE
 (submitted: June 20, 2018)
Glutamate [ Time Frame: 1 day ]
Evaluate change in central glutamate and peripheral glutamate with MRS after a single 40-minute infusion of i.v. racemic ketamine
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 18, 2020)
  • To compare the percent change in peripheral GABA/Glutamate levels between remitters and non-remitters [ Time Frame: 24 hour ]
    Change in peripheral metabolites and association with remission
  • To evaluate the correlation between percent change in peripheral GABA and glutamate levels with a change in MADRS scores. [ Time Frame: 24 hour ]
    Change in peripheral metabolites and association with change in depression (MADRS) scores
Original Secondary Outcome Measures  ICMJE
 (submitted: June 20, 2018)
Mood [ Time Frame: 1 day ]
Measure the change in depression symptoms using MADRS scale in participants with treatment-resistant major depression before receiving and 24 hours after the Ketamine infusion
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Ketamine Associated ACC GABA and Glutamate Change and Depression Remission:
Official Title  ICMJE Central Versus Peripheral GABA and Glutamate Biomarkers for Treatment Response During A Single Infusion of Intravenous Ketamine for Treatment-Resistant Depression
Brief Summary

This is a feasibility study and the goal of this project is to evaluate whether peak ACC GABA and glutamate, quantified as a CSF-corrected absolute concentration percent change from baseline, is associated with clinical remission, Montgomery Asberg Depression Rating Scale (MADRS) total score of <10, to the anti-glutamatergic antidepressant ketamine.

As MRS is expensive, we also aim to study a correlation between change in peripheral metabolites (GABA and glutamate) and central GABA and glutamate levels.

Detailed Description

Aims: This feasibility study aims to better understand the neurobiology of major depression and how ketamine may therapeutically impact brain function. This research may provide important insights into the mechanism of ketamine response, thus, potentially increasing the likelihood of successful treatment interventions and decrease the number of ineffective treatments and/or risk for serious side effects.

SPECIFIC AIMS:

Utilizing novel dynamic sliding-window functional MR spectroscopy (fMRS) and liquid chromatography-mass spectrometry (LCMS), we aim to evaluate the relationship between GABA and glutamate (central-baseline to peak and peripheral-baseline to 24 hours) levels with a change in depression symptoms (baseline to 24 hours), after a single infusion of intravenous (IV) ketamine, in subjects with treatment-resistant depression (TRD).

Study Type  ICMJE Interventional
Study Phase  ICMJE Early Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Major Depressive Disorder
  • Treatment Resistant Depression
  • Bipolar Depression
Intervention  ICMJE Drug: Ketamine
We will enroll 20 adults with treatment-resistant unipolar major depression and will provide one i.v. ketamine infusions (0.5 mg/kg, infused over 40 minutes) and measure their depressive symptom responses. Adults (aged 18-65 years) with treatment-resistant depression will be included. Biomarkers will be developed using blood samples from study subjects, taken prior to (predictive biomarkers), and following ketamine treatment (change biomarkers). This will be an open-label feasibility trial.
Study Arms  ICMJE Ketamine
Open-label, non-randomized
Intervention: Drug: Ketamine
Publications * Not Provided

*   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 Enrolling by invitation
Estimated Enrollment  ICMJE
 (submitted: October 8, 2019)
20
Original Estimated Enrollment  ICMJE
 (submitted: June 20, 2018)
10
Estimated Study Completion Date  ICMJE December 2024
Estimated Primary Completion Date December 31, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

For inclusion in this study, the following will be required:

  • Ability to provide informed consent;
  • Current psychiatric inpatient (voluntary only) or outpatient treatment;
  • Male or female;
  • Age 18-65 years;
  • Meets clinical DSM-5 diagnostic criteria for major depressive disorder/bipolar depression without psychotic features;
  • PHQ-9 total score ≥ 15 at screening and at baseline (just prior to first acute phase ketamine infusion);
  • Treatment-resistant depression (TRD), as defined by failure of at least two previous antidepressant treatments within the current depressive episode. Failed antidepressant treatments can include pharmacotherapy for depression at an adequate dose for at least 8 weeks, or an acute series of at least 6 administrations of electroconvulsive therapy (ECT) or an acute series of Transcranial magnetic stimulation (TMS);
  • Ability to pass a comprehension assessment test related to effects of ketamine and trial objectives and criteria.

Exclusion Criteria: Based on ketamine's known difficulties with the induction of perceptual/psychomimetic symptoms, the exclusion criteria for this study will be as follows:

  • Inability to speak English
  • Patients with a BMI >40.
  • Any current psychiatric diagnosis other than anxiety disorders needing concurrent antidepressant therapy
  • Personality disorder being the primary diagnosis
  • Diagnosis of schizophrenia, schizoaffective disorder, post-traumatic stress disorder, or active psychotic symptoms;
  • Ongoing prescription of > 4 mg lorazepam equivalents (total) daily, or morning dosing of any benzodiazepine at the time of assessment;
  • On current medications known to affect glutamate (i.e., riluzole, carbamazepine) or GABA (zaleplon, zolpidem, zopiclone, valproate, gabapentin, pregabalin, tiagabine, and vigabatrin);
  • Antidepressant Monoamine Oxidase Inhibitors (MAOIs) are prohibited two weeks prior to the administration of the study drug.
  • CYP3A4 inducers carbamazepine and modafinil are prohibited within two weeks prior to administration of the study drug and at least 24 hours after the last dose of study drug.
  • Currently undergoing TMS, vagal nerve stimulation, or deep brain stimulation as either an acute or maintenance treatment of depression;
  • ECT in the past 12 months;
  • Any active or unstable medical condition judged by the study psychiatrist as conferring too great a level of medical risk to allow inclusion in the study;
  • Use of methamphetamine, cocaine, or cannabis. Abuse of stimulant(s) within the prior 12 months;
  • Any current substance use disorder (excluding nicotine and caffeine). Note: Persons will be allowed to enroll in this study if their substance use is in complete (not partial) and sustained (> 1 year) remission;
  • History of traumatic brain injury that resulted in loss of consciousness;
  • Developmental delay, intellectual disability, or intellectual disorder;
  • Clinical or self-reported diagnosis of delirium, encephalopathy, or related clinical diagnosis within the prior 12 months;
  • Cognitive disorder (mild and major categories, per DSM-);
  • Received ketamine treatment for depression within the prior 2 months;
  • History of either poor antidepressive response to or poor tolerability of ketamine (any route of administration) when previously administered for treating symptoms of depression;
  • History of hypothyroidism unless taking a stable dose of thyroid medication and asymptomatic for 6 months;
  • Hepatic insufficiency (2.5 X ULN for AST or ALT) within 1 year of consent, past liver transplant recipient, and/or clinical diagnosis of cirrhosis of the liver;
  • Gastroesophageal reflux disease
  • A diagnosis of Complex Regional Pain Syndrome (CRPS);
  • Pregnancy, or nursing;
  • History of claustrophobia
  • Any contraindication to MRI safety questionnaire
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
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 NCT03573349
Other Study ID Numbers  ICMJE 17-011373
Has Data Monitoring Committee No
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Balwinder Singh, MD, MS, Mayo Clinic
Study Sponsor  ICMJE Mayo Clinic
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Balwinder Singh Mayo Clinic
PRS Account Mayo Clinic
Verification Date September 2021

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