Intravenous Ketamine for Treatment-Resistant Depression (G2K)

October 9, 2025 updated by: Balwinder Singh, MD, MS, Mayo Clinic

Central and Peripheral GABA and Glutamate Modulation With Intravenous Ketamine for Treatment-Resistant Depression (G2K): A Randomized, Double-Blind, Placebo-Controlled Study

The purpose of this study is to to evaluate the relationships between peak (% change from baseline) central GABA and Glu levels during a 40-min IV ketamine or normal saline infusion utilizing fMRS, and change in peripheral GABA and Glu levels from baseline to 24-hr postinfusion utilizing LCMS, with baseline to 24-hr post-infusion change in depression (MADRS) in 30 TRD adults.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

This will be a randomized, double-blind, placebo-controlled, parallel-group study where adult subjects with treatment refractory major depressive disorder (MDD) will receive 1:1 single IV racemic ketamine (n=15) or normal saline (placebo) (n=15) infusion in an MRI scanner, followed by an optional open-label ketamine infusion. In this innovative comparative study utilizing novel dynamic sliding-window fMRS and liquid chromatography-mass spectrometry (LCMS), we will investigate the dynamic relationship between GABA and Glu levels measured centrally and peripherally, respectively, with change in depression symptoms utilizing the Montgomery Asberg Depression Rating Scale (MADRS).12 Given preclinical models of reduced ACs and glutamatergic function in depression, we will also include an exploratory analysis of ACs metabolomic markers associated with ketamine treatment response.

Study Type

Interventional

Enrollment (Estimated)

30

Phase

  • Phase 2

Contacts and Locations

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

Study Contact

Study Locations

  • United States
    • Minnesota
      • Rochester, Minnesota, United States, 55905
        • Recruiting
        • Mayo Clinic in Rochester
        • Principal Investigator:
          • Balwinder Singh

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

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Ability to provide informed consent
  • Meets diagnostic criteria for major depressive disorder without psychotic features per the SCID DSM-IV-TR
  • PHQ-9 total score ≥ 15 at screening
  • Treatment-resistant depression, 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, trial of transcranial magnetic stimulation (TMS) or an acute series of at least 6 administrations of electroconvulsive therapy (ECT)
  • Ability to pass a comprehension assessment test related to effects of ketamine and trial objectives and criteria

Exclusion Criteria:

  • Inability to speak English
  • Inability to provide consent or have a legal guardian
  • Patients with a BMI > 40 kg/m2.
  • Personality disorder being the primary diagnosis
  • Diagnosis of schizophrenia, schizoaffective disorder, bipolar disorder, or active psychotic symptoms
  • Active post-traumatic stress disorder symptoms based on clinical assessment
  • Ongoing prescription of > 2 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 and at least 24 hours after last dose of study drug
  • Monoamine Oxidase Inhibitors (MAOIs) are prohibited two weeks prior to administration of study drug
  • Opioid antagonists (naltrexone, naloxone, nalmefene, methylnaltrexone, buprenorphine and naloxone combination) are prohibited within two weeks prior to administration of study drug and at least 24 hours after last dose of study drug
  • CYP3A4 inducers carbamazepine and modafinil are prohibited within two weeks prior to administration of study drug and at least 24 hours after 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 6 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
  • A history of bleeding in the brain
  • Arteriovenous malformation or a history of aneurysm
  • 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 with brain bleeding
  • History of tonic-clonic (grand mal) seizures
  • Developmental delay, intellectual disability, or intellectual disorder
  • Clinical or self-reported diagnosis of delirium, encephalopathy, or related clinical diagnosis within the prior 12 months
  • Minor or Major Neurocognitive disorder
  • 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
  • History of hypothyroidism unless taking a stable dose of thyroid medication and asymptomatic for 3 months
  • Hepatic insufficiency (2.5 X ULN for AST or ALT) within 3 months of consent, past liver transplant recipient, and/or clinical diagnosis of cirrhosis of the liver
  • Gastroesophageal reflux disease that is poorly managed
  • A diagnosis of Complex Regional Pain Syndrome (CRPS)
  • Pregnancy, or nursing
  • History of claustrophobia with active symptoms that would interfere with the MRI
  • Any contraindication to MRI safety questionnaire
  • Poorly controlled hypertension.

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: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Ketamine Group
Subjects will receive IV racemic ketamine at a dose of 0.5 mg per kg of the participant's actual body weight, with a maximum dose of 50 mg for individuals weighing over 100 kg.
Drug: Ketamine
The subjects will receive 1:1 single IV racemic ketamine (dosed @0.5 mg/kg actual body weight) (n=15) 40-min infusion in an MRI scanner, followed by an optional open-label ketamine infusion (available to everyone) 1-7 days after the initial treatment
Placebo Comparator: Normal Saline/Placebo Group
Subjects will receive an IV infusion of normal saline over a duration of 40 minutes
Drug: Normal Saline
The subjects will receive 1:1 single IV normal saline/placebo (n=15) 40-min infusion in an MRI scanner, followed by an optional open-label ketamine infusion (available to everyone) 1-7 days after the initial treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Peak (% change from baseline) Anterior Cingulate Cortex metabolites (Gamma-Aminobutyric Acid and Glutamate)
Time Frame: Baseline to the end of 40-minute infusion
To measure peak (% change from baseline) Anterior Cingulate Cortex (ACC) Gamma-Aminobutyric Acid (GABA) and Glutamate (Glu) levels during a 40-minute IV ketamine or normal saline (0.9% sodium chloride) infusion utilizing fMRS (functional Magnetic Resonance Spectroscopy)
Baseline to the end of 40-minute infusion
Change in peripheral Gamma-Aminobutyric Acid and Glutamate levels
Time Frame: Baseline to the end of 40-minute infusion
Change in peripheral Gamma-Aminobutyric Acid (GABA) and Glutamate (Glu) levels measured utilizing liquid chromatography-mass spectrometry (LCMS) at baseline and the end of 40-minute infusion
Baseline to the end of 40-minute infusion
Change in the Montgomery Asberg Depression Rating Scale
Time Frame: Baseline to 24-hours post-infusion
Montgomery Asberg Depression Rating Scale (MADRS) is a 10-item clinician rating of depressive symptoms used in the previous ketamine research studies. Higher scores represent higher levels of depression.
Baseline to 24-hours post-infusion
Correlation between the percent change in central (anterior cingulate cortex) Gamma-Aminobutyric Acid and Glutamate levels and the change in depression severity measured using the Montgomery-Åsberg Depression Rating Scale
Time Frame: Baseline to the end of 40-minute infusion for GABA and Glu. Baseline to 24 hours post-infusion for MADRS

Outcome measure: Changes in the total Montgomery-Asberg Depression Rating Scale (MADRS) scale from baseline (pre-infusion) to 24 hours post-infusion. MADRS will be compared by randomized arm as a continuous variable as well as defined by remission status (MADRS≤9). The total MADRS score can range from 0 to 60, with higher scores indicating a worse outcome.

We aim to evaluate the correlation between the percent change in anterior cingulate cortex (ACC) Gamma-Aminobutyric Acid (GABA) and Glutamate (Glu) levels (from baseline to peak) during a 40-minute IV infusion of ketamine or normal saline (0.9% sodium chloride) using functional magnetic resonance spectroscopy (fMRS) and the change in MADRS scores (from baseline to 24 hours).
Baseline to the end of 40-minute infusion for GABA and Glu. Baseline to 24 hours post-infusion for MADRS
Correlation between the percent change in serum Gamma-Aminobutyric Acid and Glutamate levels and the change in depression severity measured using the Montgomery-Åsberg Depression Rating Scale
Time Frame: Baseline to the end of 40-minute infusion for serum GABA and Glu. Baseline to 24 hours post-infusion for MADRS

Outcome measure: Changes in the total Montgomery-Asberg Depression Rating Scale (MADRS) scale from baseline (pre-infusion) to 24 hours post-infusion. MADRS scores will be compared by randomized arm as a continuous variable as well as defined by remission status (MADRS≤9). The total MADRS score can range from 0 to 60, with higher scores indicating a worse outcome.

We aim to evaluate the correlation between the percent change in serum Gamma-Aminobutyric Acid (GABA) and Glutamate (Glu) levels during a 40-minute IV infusion of ketamine or normal saline (0.9% sodium chloride) using Liquid Chromatography-Mass Spectrometry (LCMS) and the change in MADRS scores (from baseline to 24 hours).
Baseline to the end of 40-minute infusion for serum GABA and Glu. Baseline to 24 hours post-infusion for MADRS

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in McIntyre And Rosenblat Rapid Response Scale
Time Frame: Baseline to up to 24 hours post-infusion
The McIntyre and Rosenblat Rapid Response Scale (MARRRS) is a validated self-report instrument designed to assess rapid treatment response in the context of rapid-acting antidepressant drugs (RAADs), such as ketamine. The scale comprises 14 items and has shown promising psychometric properties, including high internal consistency and significant convergent validity. Each item is scored on a 4-point ordinal scale, where 0 indicates the absence of symptoms and 3 signifies the highest severity of symptoms. The total score ranges from 0 to 42, with higher scores indicating a more severe state of depression.
Baseline to up to 24 hours post-infusion
Change in Quick Inventory of Depressive Symptomatology (Self-Report)
Time Frame: Baseline to up to 24 hours post-infusion
The Quick Inventory of Depressive Symptomatology (QIDS-SR-16) is a depression scale that assesses the symptom domains of major depressive disorder, with scores ranging from 0 to 27. Higher scores indicate more severe depressive symptoms. The individual items evaluate key aspects such as sadness, anhedonia (the loss of pleasure), and sleep disturbances, which may manifest as insomnia or hypersomnia. Additionally, the scale addresses changes in appetite or weight and includes assessments of psychomotor agitation or retardation. It also measures fatigue or loss of energy, feelings of worthlessness or excessive guilt, and difficulties in concentration. Furthermore, the scale incorporates items related to suicidal ideation, offering a comprehensive overview of both the emotional and physical symptoms experienced by individuals with depression.
Baseline to up to 24 hours post-infusion
Changes in short chain acylcarnitine levels
Time Frame: Baseline to up to 24 hours post-infusion.
Changes in short-chain acylcarnitine (AC) levels-early change (baseline to 40 minutes) and late change (100 minutes to 24 hours)-among patients who received a 40-minute IV infusion of either ketamine or normal saline (0.9% sodium chloride).
Baseline to up to 24 hours post-infusion.
Changes in short-chain acylcarnitine levels and ketamine-related remission
Time Frame: Baseline to up to 24 hours post-infusion.
To evaluate the relationship between changes in short-chain AC levels-early change (baseline to 40 minutes) and late change (100 minutes to 24 hours)-among remitters and non-remitters (MADRS < 10) at 24 hours.
Baseline to up to 24 hours post-infusion.
Changes in mTOR (mechanistic Target of Rapamycin)
Time Frame: Baseline to the end of 40-minute infusion
To investigate the changes in mTOR from baseline to the end of infusion with IV ketamine compared to normal saline. To investigate the correlation between anhedonia phenotypes (baseline) and the percent change in mTOR from baseline. Anhedonia phenotypes will be assessed using the MADRS and the SHAPS.
Baseline to the end of 40-minute infusion
Change in the Snaith-Hamilton Pleasure Scale
Time Frame: Baseline to up to 24 hours post-infusion
The Snaith-Hamilton Pleasure Scale (SHAPS) is a 14-item scale that measures anhedonia, the inability to experience pleasure. The items cover the domains of: social interaction, food and drink, sensory experience, and interest/pastimes. A score of 2 or less constitutes a "normal" score, while an "abnormal" score is defined as 3 or more. A higher total score indicates greater levels of anhedonia.
Baseline to up to 24 hours post-infusion
Changes in neurocognitive functioning
Time Frame: Baseline to 24 hours post-infusion
The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)is a brief, standardized, individually administered battery to measure cognitive change in immediate memory, visuospatial/constructional orientation, language (naming, fluency), attention, and delayed memory. The 12 subtests that comprise the RBANS require approximately 30 minutes to administer.
Baseline to 24 hours post-infusion
Change in Beck Scale for Suicidal Ideation
Time Frame: Baseline to up to 24 hours post-infusion
The Beck Scale for Suicidal Ideation consists of 19 items which can be used to evaluate a patient's suicidal intentions. It can also be used to monitor a patient's response to interventions over time. Each of the 19 items is rated on a 0-3 point scale (range 0-38, with higher scores indicating greater suicidal ideations or risk), and includes specific items that assess wish to live, wish to die, desire to make an active suicide attempt, passive suicidal desire, duration of suicidal ideations, frequency of suicidal ideations, and subjective level of control over suicidal actions.
Baseline to up to 24 hours post-infusion
Changes in Dimensional Anhedonia Rating Scale
Time Frame: Baseline to up to 24 hours post-infusion
The Dimensional Anhedonia Rating Scale (DARS) measures anhedonia, including facets of desire, motivation, effort, and consummatory pleasure. The scale has demonstrated high internal consistency, reliability, and validity across studies. It has shown superiority in distinguishing MDD subgroups. The DARS total score ranges from 0 to 68. A lower DARS score reflects more severe anhedonia, while a higher score indicates lower anhedonia.
Baseline to up to 24 hours post-infusion
Change in Clinical Global Impression
Time Frame: Baseline to up to 24 hours post-infusion
The Clinical Global Impression (CGI) is assessed using a 7-point scale. The CGI-Severity (CGI-S) of Illness measures the severity of the patient's condition, ranging from 1 (normal) to 7 (among the most severely ill patients). In addition, the CGI-Improvement (CGI-I) scale evaluates changes in the patient's condition from baseline, which is prior to the ketamine infusion. The CGI-I scale is rated as follows: 1 indicates "very much improved" since the initiation of treatment, 2 signifies "much improved," 3 denotes "minimally improved," 4 represents "no change from baseline," 5 means "minimally worse," 6 indicates "much worse," and 7 reflects "very much worse" since the initiation of treatment.
Baseline to up to 24 hours post-infusion
Perceived Stress
Time Frame: Baseline to up to 24 hours post-infusion
The Perceived Stress Scale is a 10-item self-rated tool that measures the frequency of an individual's perception of stress over the last month
Baseline to up to 24 hours post-infusion
Resilience
Time Frame: Baseline to 24 hours post-infusion
The Brief Resilience Scale (BRS) is a reliable tool for assessing resilience, specifically focused on an individual's ability to bounce back or recover from stress. The BRS ranges from 1 to 5, with higher scores indicating greater resilience-that is, a stronger ability to bounce back from stress.
Baseline to 24 hours post-infusion

Collaborators and Investigators

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

Sponsor

Mayo Clinic

Collaborators

National Center for Advancing Translational Sciences (NCATS)

Investigators

  • Principal Investigator: Balwinder Singh, M.D., M.S., 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

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)

February 10, 2025

Primary Completion (Estimated)

December 31, 2027

Study Completion (Estimated)

December 31, 2027

Study Registration Dates

First Submitted

October 16, 2024

First Submitted That Met QC Criteria

October 30, 2024

First Posted (Actual)

October 31, 2024

Study Record Updates

Last Update Posted (Estimated)

October 14, 2025

Last Update Submitted That Met QC Criteria

October 9, 2025

Last Verified

October 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 24-005249
  • 5KL2TR002379 (U.S. NIH Grant/Contract)
  • 5KL2TR002379-08 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

The study results will be uploaded to the website after the completion of the study. All related research findings will be published or submitted to the NIH.

IPD Sharing Time Frame

2027

IPD Sharing Access Criteria

The study results will be uploaded to the website after the completion of the study.

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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