Depressive Disorder, Treatment-ResistantPhase 2G2KNCT06668571
Intravenous Ketamine for Treatment-Resistant Depression
A Phase 2 study testing Ketamine and Normal Saline in people with Depressive Disorder, Treatment-Resistant and Treatment Resistant Depression (TRD), run by Mayo Clinic at 1 site in United States.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Depressive Disorder, Treatment-Resistant, Treatment Resistant Depression (TRD)
- What is being tested?
- Ketamine and Normal Saline
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 30 participants
- Where
- 1 siteUnited States
- Study dates
- 10 Feb 2025to 31 Dec 2027
- Phase
- Phase 2
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
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- 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.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site, 1 recruiting
- Recruiting
Mayo Clinic in Rochester
Rochester, Minnesota, 55905
Balwinder Singh
About this study
Official title: 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.
Read the 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.
- Being tested
- Ketamine, Normal Saline
- Keywords
- Major Depression, Depressive Disorder, Treatment-Resistant, MDD, TRD, Treatment-Resistant Depression, Treatment-Resistant Major Depression, Ketamine, Intravenous Ketamine
- Medical subject headings
- Depressive Disorder, Treatment-Resistant, Depressive Disorder, Major
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
KetamineDrug
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 SalineDrug
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
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: Drug: Ketamine |
| Normal Saline/Placebo Group | Placebo comparator | Subjects will receive an IV infusion of normal saline over a duration of 40 minutes Receives: Drug: Normal Saline |
What is being measured
The primary outcome is the main question the study is designed to answer.
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)
Measured: 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
Measured: 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.
Measured: 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).
Measured: 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).
Measured: 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
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.
Measured: Baseline to up to 24 hours post-infusion
Change in Quick Inventory of Depressive Symptomatology (Self-Report)
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.
Measured: Baseline to up to 24 hours post-infusion
Changes in short chain acylcarnitine levels
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).
Measured: Baseline to up to 24 hours post-infusion.
Changes in short-chain acylcarnitine levels and ketamine-related remission
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.
Measured: Baseline to up to 24 hours post-infusion.
Changes in mTOR (mechanistic Target of Rapamycin)
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.
Measured: Baseline to the end of 40-minute infusion
Change in the Snaith-Hamilton Pleasure Scale
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.
Measured: Baseline to up to 24 hours post-infusion
Changes in neurocognitive functioning
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.
Measured: Baseline to 24 hours post-infusion
Change in Beck Scale for Suicidal Ideation
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.
Measured: Baseline to up to 24 hours post-infusion
Changes in Dimensional Anhedonia Rating Scale
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.
Measured: Baseline to up to 24 hours post-infusion
Change in Clinical Global Impression
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.
Measured: Baseline to up to 24 hours post-infusion
Perceived Stress
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
Measured: Baseline to up to 24 hours post-infusion
Resilience
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.
Measured: Baseline to 24 hours post-infusion
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted31 Oct 2024
- Study start10 Feb 2025
- Primary completion31 Dec 2027 (estimated)
- Study completion31 Dec 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (15)Papers the sponsor has linked to this study.
- Other trials for Depressive Disorder, Treatment-ResistantStudies of the same condition, open and under way.
- More trials run by Mayo ClinicThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 30 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Mayo Clinic
- Sponsor type
- University, hospital or other
- Collaborators
- National Center for Advancing Translational Sciences (NCATS)
- Responsible party
- Principal investigator, Balwinder Singh, MD, MS, Mayo Clinic
- Investigators
- Balwinder Singh, M.D., M.S., Principal investigator, Mayo Clinic
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06668571
- Sponsor's protocol ID
- 24-005249
- Other IDs
- 5KL2TR002379, 5KL2TR002379-08
- Acronym
- G2K
- Status last verified
- Oct 2026
- First submitted
- 16 Oct 2024
- Last updated
- 16 Oct 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: 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.
Publications
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.
PubMed 38302067Singh 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.
PubMed 31721482Frye 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.
PubMed 25928701Singh 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.
PubMed 38479192Parikh 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.
PubMed 38142892Singh 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.
PubMed 36724113Vande 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.
PubMed 27656788Brix 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.
PubMed 28205280Dubin 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.
PubMed 26900793Port 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 &amp; SMRT Virtual Conference &amp; Exhibition; 2020; Virtual https://www.ismrm.org/20/program_files/DP01-09.htm#044
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.
PubMed 36707268Rotroff 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.
PubMed 27648916Singh 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.
PubMed 33933839Singh 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.
PubMed 34973601Singh 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.
PubMed 35738038