Clinical trial NCT06668571: Intravenous Ketamine for Treatment-Resistant Depression
Official title: Central and Peripheral GABA and Glutamate Modulation With Intravenous Ketamine for Treatment-Resistant Depression (G2K): A Randomized, Double-Blind, Placebo-Controlled Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
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
Lead sponsor: Mayo Clinic
Sponsor class: OTHER
Collaborators: name: National Center for Advancing Translational Sciences (NCATS)
First posted: 2024-10-31
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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 (\&gt; 1 year) remission
* History of traumatic brain injury that resulted in loss of consciousness
* 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 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 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

Primary outcomes:
measure: Peak (% change from baseline) Anterior Cingulate Cortex metabolites (Gamma-Aminobutyric Acid and Glutamate)
timeFrame: Baseline to the end of 40-minute infusion
measure: Change in peripheral Gamma-Aminobutyric Acid and Glutamate levels
timeFrame: Baseline to the end of 40-minute infusion
measure: Change in the Montgomery Asberg Depression Rating Scale
timeFrame: Baseline to 24-hours post-infusion
measure: 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
timeFrame: Baseline to the end of 40-minute infusion for GABA and Glu. Baseline to 24 hours post-infusion for MADRS
measure: 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
timeFrame: Baseline to the end of 40-minute infusion for serum GABA and Glu. Baseline to 24 hours post-infusion for MADRS
Secondary outcomes:
measure: Change in McIntyre And Rosenblat Rapid Response Scale
timeFrame: Baseline to up to 24 hours post-infusion
measure: Change in Quick Inventory of Depressive Symptomatology (Self-Report)
timeFrame: Baseline to up to 24 hours post-infusion
measure: Changes in short chain acylcarnitine levels
timeFrame: Baseline to up to 24 hours post-infusion.
measure: Changes in short-chain acylcarnitine levels and ketamine-related remission
timeFrame: Baseline to up to 24 hours post-infusion.
measure: Changes in mTOR (mechanistic Target of Rapamycin)
timeFrame: Baseline to the end of 40-minute infusion
measure: Change in the Snaith-Hamilton Pleasure Scale
timeFrame: Baseline to up to 24 hours post-infusion
measure: Changes in neurocognitive functioning
timeFrame: Baseline to 24 hours post-infusion
measure: Change in Beck Scale for Suicidal Ideation
timeFrame: Baseline to up to 24 hours post-infusion
measure: Changes in Dimensional Anhedonia Rating Scale
timeFrame: Baseline to up to 24 hours post-infusion
measure: Change in Clinical Global Impression
timeFrame: Baseline to up to 24 hours post-infusion
measure: Perceived Stress
timeFrame: Baseline to up to 24 hours post-infusion
measure: Resilience
timeFrame: Baseline to 24 hours post-infusion
Other outcomes:
Locations:
city: Rochester
country: United States
facility: Mayo Clinic in Rochester
state: Minnesota
Study officials:
affiliation: Mayo Clinic
name: Balwinder Singh, M.D., M.S.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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 &amp;amp; SMRT Virtual Conference &amp;amp; Exhibition; 2020; Virtual https://www.ismrm.org/20/program_files/DP01-09.htm#044
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.