Ketamine Associated ACC GABA and Glutamate Change and Depression Remission:

March 21, 2024 updated by: Balwinder Singh, MD, MS, Mayo Clinic

Central Versus Peripheral GABA and Glutamate Biomarkers for Treatment Response During Two Infusions of Intravenous Ketamine for Treatment-Resistant Depression

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.

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

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

Interventional

Enrollment (Estimated)

18

Phase

  • Early Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Minnesota
      • Rochester, Minnesota, United States, 55905
        • Mayo Clinic in Rochester

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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 diagnostic criteria for major depressive disorder/bipolar depression without psychotic features per the SCID DSM-IV-TR;
  • 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;
  • Medications known to affect glutamate (i.e., riluzole, carbamazepine) or GABA (zaleplon, zolpidem, zopiclone, valproate, gabapentin, pregabalin, tiagabine, and vigabatrin) are prohibited within two weeks prior to administration of study drug;
  • 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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Other: Ketamine
Open-label, non-randomized
Drug: Ketamine
We will enroll 20 adults (aged 18-65 years) with treatment-resistant depression and will provide two i.v. ketamine infusions (0.5 mg/kg, infused over 40 minutes) and measure their depressive symptom responses. 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
24 hour
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
24 hour

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
24 hour
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
24 hour

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Mayo Clinic

Investigators

  • Principal Investigator: Balwinder Singh, Mayo Clinic

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 3, 2019

Primary Completion (Estimated)

May 1, 2024

Study Completion (Estimated)

May 1, 2024

Study Registration Dates

First Submitted

June 20, 2018

First Submitted That Met QC Criteria

June 20, 2018

First Posted (Actual)

June 29, 2018

Study Record Updates

Last Update Posted (Actual)

March 22, 2024

Last Update Submitted That Met QC Criteria

March 21, 2024

Last Verified

March 1, 2024

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 17-011373

Drug and device information, study documents

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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