Intravenous Ketamine for Treatment-Resistant Depression

NCT06668571 | Recruiting Phase 2 FDA Drug

• 3 other identifiers: 24-0052495KL2TR0023795KL2TR002379-08
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

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)

Keywords

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

Outcome Measures

Primary Outcomes (5)

• Peak (% change from baseline) Anterior Cingulate Cortex metabolites (Gamma-Aminobutyric Acid and Glutamate)

  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

  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

  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

  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

  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 Outcomes (12)

• Change in McIntyre And Rosenblat Rapid Response Scale

  Baseline to up to 24 hours post-infusion

• Change in Quick Inventory of Depressive Symptomatology (Self-Report)

  Baseline to up to 24 hours post-infusion

• Changes in short chain acylcarnitine levels

  Baseline to up to 24 hours post-infusion.

• Changes in short-chain acylcarnitine levels and ketamine-related remission

  Baseline to up to 24 hours post-infusion.

• Changes in mTOR (mechanistic Target of Rapamycin)

  Baseline to the end of 40-minute infusion

Study Arms (2)

Ketamine Group

EXPERIMENTAL

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

Normal Saline/Placebo Group

PLACEBO COMPARATOR

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

Drug: Normal Saline

Interventions

Ketamine DRUG

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

Ketamine Group

Normal Saline DRUG

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

Normal Saline/Placebo Group

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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
• A history of bleeding in the brain
• Arteriovenous malformation or a history of aneurysm

Sponsors & Collaborators

• Mayo Clinic: lead
• National Center for Advancing Translational Sciences (NCATS): collaborator

Study Sites (1)

Mayo Clinic in Rochester

Rochester, Minnesota, 55905, United States

RECRUITING

Related Publications (15)

• Singh B, Vande Voort JL, Pazdernik VK, Frye MA, Kung S. Treatment-resistant depression patients with baseline suicidal ideation required more treatments to achieve therapeutic response with ketamine/esketamine. J Affect Disord. 2024 Apr 15;351:534-540. doi: 10.1016/j.jad.2024.01.262. Epub 2024 Jan 30.

  PMID: 38302067 BACKGROUND

• Singh B, Bobo WV, Rasmussen KG, Stoppel CJ, Rico JA Jr, Schak KM, Biernacka JM, Frye MA, Vande Voort JL. The Association Between Body Mass Index and Remission Rates in Patients With Treatment-Resistant Depression Who Received Intravenous Ketamine. J Clin Psychiatry. 2019 Nov 12;80(6):19l12852. doi: 10.4088/JCP.19l12852. No abstract available.

  PMID: 31721482 BACKGROUND

• Frye MA, Blier P, Tye SJ. Concomitant benzodiazepine use attenuates ketamine response: implications for large scale study design and clinical development. J Clin Psychopharmacol. 2015 Jun;35(3):334-6. doi: 10.1097/JCP.0000000000000316. No abstract available.

  PMID: 25928701 BACKGROUND

• Singh B, Parikh SV, Voort JLV, Pazdernik VK, Achtyes ED, Goes FS, Yocum AK, Nykamp L, Becerra A, Smart L, Greden JF, Bobo WV, Frye MA, Burdick KE, Ryan KA. Change in neurocognitive functioning in patients with treatment-resistant depression with serial intravenous ketamine infusions: The Bio-K multicenter trial. Psychiatry Res. 2024 May;335:115829. doi: 10.1016/j.psychres.2024.115829. Epub 2024 Feb 28.

  PMID: 38479192 BACKGROUND

• Parikh SV, Vande Voort JL, Yocum AK, Achtyes E, Goes FS, Nykamp L, Singh B, Lopez-Vives D, Sera CE, Maixner D, Tarnal V, Severe J, Bartek S, Tye SJ, Rico J, Stoppel CJ, Becerra A, Smart L, Miller CR, Frye MA, Greden JF, Bobo WV. Clinical outcomes in the biomarkers of ketamine (Bio-K) study of open-label IV ketamine for refractory depression. J Affect Disord. 2024 Mar 1;348:143-151. doi: 10.1016/j.jad.2023.12.033. Epub 2023 Dec 22.

  PMID: 38142892 BACKGROUND

• Singh B, Kung S, Pazdernik V, Schak KM, Geske J, Schulte PJ, Frye MA, Vande Voort JL. Comparative Effectiveness of Intravenous Ketamine and Intranasal Esketamine in Clinical Practice Among Patients With Treatment-Refractory Depression: An Observational Study. J Clin Psychiatry. 2023 Feb 1;84(2):22m14548. doi: 10.4088/JCP.22m14548.

  PMID: 36724113 BACKGROUND

• Vande Voort JL, Morgan RJ, Kung S, Rasmussen KG, Rico J, Palmer BA, Schak KM, Tye SJ, Ritter MJ, Frye MA, Bobo WV. Continuation phase intravenous ketamine in adults with treatment-resistant depression. J Affect Disord. 2016 Dec;206:300-304. doi: 10.1016/j.jad.2016.09.008. Epub 2016 Sep 12.

  PMID: 27656788 BACKGROUND

• Brix MK, Ersland L, Hugdahl K, Dwyer GE, Gruner R, Noeske R, Beyer MK, Craven AR. Within- and between-session reproducibility of GABA measurements with MR spectroscopy. J Magn Reson Imaging. 2017 Aug;46(2):421-430. doi: 10.1002/jmri.25588. Epub 2017 Feb 15.

  PMID: 28205280 BACKGROUND

• Dubin MJ, Mao X, Banerjee S, Goodman Z, Lapidus KA, Kang G, Liston C, Shungu DC. Elevated prefrontal cortex GABA in patients with major depressive disorder after TMS treatment measured with proton magnetic resonance spectroscopy. J Psychiatry Neurosci. 2016 Apr;41(3):E37-45. doi: 10.1503/jpn.150223.

  PMID: 26900793 BACKGROUND

• Port JD, Singh B, Frye MA. Dynamic Sliding-Window MRS Method for Measuring Changes in Glutamate and GABA in Patients with Major Depressive Disorder. presented at: ISMRM & SMRT Virtual Conference & Exhibition; 2020; Virtual https://www.ismrm.org/20/program_files/DP01-09.htm#044

  BACKGROUND

• Singh B, Vande Voort JL, Riva-Posse P, Pazdernik VM, Frye MA, Tye SJ. Ketamine-Associated Change in Anhedonia and mTOR Expression in Treatment-Resistant Depression. Biol Psychiatry. 2023 Jun 15;93(12):e65-e68. doi: 10.1016/j.biopsych.2022.10.007. Epub 2023 Jan 25. No abstract available.

  PMID: 36707268 BACKGROUND

• Rotroff DM, Corum DG, Motsinger-Reif A, Fiehn O, Bottrel N, Drevets WC, Singh J, Salvadore G, Kaddurah-Daouk R. Metabolomic signatures of drug response phenotypes for ketamine and esketamine in subjects with refractory major depressive disorder: new mechanistic insights for rapid acting antidepressants. Transl Psychiatry. 2016 Sep 20;6(9):e894. doi: 10.1038/tp.2016.145.

  PMID: 27648916 BACKGROUND

• Singh B, Port JD, Voort JLV, Coombes BJ, Geske JR, Lanza IR, Morgan RJ, Frye MA. A preliminary study of the association of increased anterior cingulate gamma-aminobutyric acid with remission of depression after ketamine administration. Psychiatry Res. 2021 Jul;301:113953. doi: 10.1016/j.psychres.2021.113953. Epub 2021 Apr 20.

  PMID: 33933839 BACKGROUND

• Singh B, Port JD, Pazdernik V, Coombes BJ, Vande Voort JL, Frye MA. Racemic ketamine treatment attenuates anterior cingulate cortex GABA deficits among remitters in treatment-resistant depression: A pilot study. Psychiatry Res Neuroimaging. 2022 Mar;320:111432. doi: 10.1016/j.pscychresns.2021.111432. Epub 2021 Dec 24. No abstract available.

  PMID: 34973601 BACKGROUND

• Singh B, MahmoudianDehkordi S, Voort JLV, Han X, Port JD, Frye MA, Kaddurah-Daouk R; Mood Disorders Precision Medicine Consortium (MDPMC). Metabolomic signatures of intravenous racemic ketamine associated remission in treatment-resistant depression: A pilot hypothesis generating study. Psychiatry Res. 2022 Aug;314:114655. doi: 10.1016/j.psychres.2022.114655. Epub 2022 May 28.

  PMID: 35738038 BACKGROUND

MeSH Terms

Conditions

Depressive Disorder, Treatment-Resistant; Depressive Disorder, Major

Interventions

Ketamine; Saline Solution

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Study Officials

• Balwinder Singh, M.D., M.S.

  Mayo Clinic

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Nicole Reinicke

CONTACT

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

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: MRI-tech, Radiologist, and Clinical Research Trial Unit Nurses. Any staff involved in the ratings will be blinded to the treatment of the subject for infusion. Only the study investigator present during infusion in the MRI will be unblinded for safety precautions during the infusion.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: October 16, 2024
• First Posted: October 31, 2024
• Study Start: February 10, 2025
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2027
• Last Updated: October 14, 2025

Record last verified: 2025-10

Data Sharing

• IPD Sharing: Will share
• Time Frame: 2027
• Access Criteria: The study results will be uploaded to the website after the completion of the study.

Locations

US (1)