Ketamine Associated ACC GABA and Glutamate Change and Depression Remission:

Sponsor

Mayo Clinic (Other)

Overall Status

Enrolling by invitation

CT.gov ID

NCT03573349

Collaborator

(none)

Enrollment

Location

Arm

70.9

Anticipated Duration (Months)

0.3

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Major Depressive Disorder Treatment Resistant Depression Bipolar Depression	Drug: Ketamine	Early Phase 1

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 Design

Study Type:

Interventional

Anticipated Enrollment :

20 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Central Versus Peripheral GABA and Glutamate Biomarkers for Treatment Response During A Single Infusion of Intravenous Ketamine for Treatment-Resistant Depression

Actual Study Start Date :

Jan 3, 2019

Anticipated Primary Completion Date :

Dec 31, 2023

Anticipated Study Completion Date :

Dec 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Other: Ketamine Open-label, non-randomized	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.

Arm

Intervention/Treatment

Other: Ketamine

Open-label, non-randomized

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.

Outcome Measures

Primary Outcome Measures

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 [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). [24 hour]
Change in central metabolite and association with change in depression scores

Secondary Outcome Measures

To compare the percent change in peripheral GABA/Glutamate levels between remitters and non-remitters [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. [24 hour]
Change in peripheral metabolites and association with change in depression (MADRS) scores

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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