Recruiting
Phase 2

Ketamine

Sponsor:

Mayo Clinic

Code:

NCT06668571

Conditions

Depressive Disorder, Treatment-Resistant

Treatment Resistant Depression (TRD)

Eligibility Criteria

Sex: All

Age: 18 - 65

Healthy Volunteers: Not accepted

Interventions

Ketamine

Normal Saline

Study Details

Brief summary:

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.

Conditions

Depressive Disorder, Treatment-Resistant

Treatment Resistant Depression (TRD)

Study ID

NCT06668571

Start date

Feb 10, 2025

Status verified date

Oct, 2025

Completion date

Dec 31, 2027

Anticipated

Primary completion date

Dec 31, 2027

Anticipated

Eligibility Criteria

Eligibility Criteria

Sex: All

Age: 18 - 65

Healthy Volunteers: Not accepted

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 Design

Enrollment

30 participants

Anticipated

Allocation

Randomized

Intervention Model

Parallel Assignment

Primary purpose

Treatment

Interventions and Outcome Measures

Arms

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.

placebo comparator: Normal Saline/Placebo Group

Subjects will receive an IV infusion of normal saline over a duration of 40 minutes

Interventions

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

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

Primary outcome measure

  • Peak (% change from baseline) Anterior Cingulate Cortex metabolites (Gamma-Aminobutyric Acid and Glutamate) [ Time Frame: 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 the Montgomery Asberg Depression Rating Scale [ Time Frame: 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 ]
  • 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 ]

Central Contacts and Locations

Central contacts

Nicole Reinicke

507-422-1835reinicke.nicole@mayo.edu

Locations

Mayo Clinic in Rochester

Recruiting

Rochester, Minnesota, United States, 55905

Principal Investigator:

Balwinder Singh

More Information

Sponsor

Mayo Clinic

Last update posted

Oct 14, 2025

Last verified

Oct, 2025

Keywords

  • Major Depression
  • Depressive Disorder, Treatment-Resistant
  • MDD
  • TRD
  • Treatment-Resistant Depression
  • Treatment-Resistant Major Depression
  • Ketamine
  • Intravenous Ketamine

Trial information was received from ClinicalTrials.gov and was last updated on 2026-09-10. This information was provided to ClinicalTrials.gov by Mayo Clinic on 2025-10-14.