(GluEsk) Glutamate and Esketamine (GluEsk)

June 3, 2025 updated by: University of Oxford

Effects of Esketamine Challenge on Brain Glutamate Release (fMRS), Resting State Connectivity (BOLD-rs-fMRI), and Neuroplasticity (Visual Task)

Esketamine is the S-enantiomer of racemic ketamine, a N-methyl-D-aspartate (NMDA) receptor antagonist. Esketamine and other antidepressant NMDA receptor antagonists are hypothesised to act by producing a rapid increase in brain glutamate release, which then stimulates α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. This activity in turn is thought to restore synaptic functioning, neuroplasticity, and connectivity in brain regions involved in mood regulation, which would be ultimately responsible for the antidepressant effect of esketamine. However, the effect of esketamine on glutamate release in humans has not previously been studied. In this study we therefore aim to ascertain the effect of esketamine on dynamic brain glutamate release, resting state connectivity, and neuroplasticity as measured via fMRS, BOLD-rs-fMRI, and a behavioural computerised visual task respectively.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

There is growing interest in the use of antagonists at the glutamate N-methyl-D-aspartate (NMDA) receptor in patients with treatment-resistant depression (TRD). Work in animal studies suggests that NMDA receptor antagonists act initially by increasing brain glutamate release, but whether such an action occurs in humans is not established.

Esketamine is the S-enantiomer of racemic ketamine: a non-selective, non-competitive, antagonist of the ionotropic glutamate NMDA receptor. It is the only NMDA receptor antagonist licensed in the UK for the treatment of patients with TRD. Esketamine is administered intranasally: it is rapidly absorbed by the nasal mucosa following nasal administration and can be measured in plasma within 7 minutes following a 28 mg dose. The time to reach maximum plasma concentration (tmax) is typically 20 to 40 minutes after the last nasal spray of a treatment session. It is hypothesised that through NMDA receptor antagonism, esketamine produces a transient increase in glutamate release leading to increases in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor stimulation and subsequently to increases in neurotrophic signalling which may contribute to the restoration of synaptic function, neuroplasticity, and connectivity in brain regions involved with the regulation of mood.

Glutamate is the primary excitatory neurotransmitter in the brain and has been implicated in several neuropsychiatric disorders. "Gold-standard" methods to assess glutamate activity in the living human brain are expensive and involve radioactive injections and invasive blood sampling. More recently, preliminary work in our Clinical Psychopharmacology laboratory (Department of Psychiatry, University of Oxford) has shown that 7T fMRS (a more widely available, non-invasive, safe technique) that uses a visual stimulus ("flickering checkerboard") can reliably and sensitively measure changes in brain glutamate release. No prior study however has shown whether this effect is susceptible to pharmacological challenge. We therefore propose to assess whether through its NMDA/AMPA-mediated activity, esketamine induced glutamate increase can be measured via this fMRS technique.

The aims of this study are to investigate the effect of esketamine on brain glutamate release and resting state connectivity, and on vision. Therefore, the primary objective of this study is to assess the effect of a single dose of esketamine 56mg intranasal vs placebo on brain glutamate release changes measured via 7T fMRS "flickering checkerboard" stimulus. Secondary objectives include the investigation of the effects of esketamine on brain resting state connectivity changes measured via 7T BOLD-rs-fMRI, and on vision measured via a behavioural computerised visual task. Psychological questionnaires will also be measured to check for possible correlations with the outcomes measured.

Study Type

Interventional

Enrollment (Actual)

16

Phase

  • Not Applicable

Contacts and Locations

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

Study Locations

  • United Kingdom
    • Oxfordshire
      • Oxford, Oxfordshire, United Kingdom, OX3 7JX
        • Department of Psychiatry, University of Oxford, Warneford Hospital

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

Accepts Healthy Volunteers

Yes

Description

Inclusion Criteria:

  • Aged 18 to 50 years
  • Body Mass Index in the range of 18-30
  • Sufficiently fluent in English to understand the study instructions
  • Willing and able to give informed consent for participation in the research

Exclusion Criteria:

  • Currently on any regular prescribed medications (except the contraceptive pill), unless unlikely to compromise safety or affect data quality in the opinion of the Investigator
  • Known hypersensitivity to the study drug (i.e., esketamine)
  • History of, or current significant alcohol or substance misuse disorder
  • Any use of recreational drugs over the last 3 months
  • Any lifetime use of ketamine or phencyclidine (PCP)
  • Currently smoking >/=20 cigarettes/day
  • History of, or current significant cardiovascular disorder (e.g., hypertension, myocardial infarction)
  • History of, or current significant neurological disorder (e.g., epilepsy, migraine) or cerebrovascular disorder (e.g., haemorrhagic or ischemic stroke, aneurysmal vascular disease, raised intracranial pressure)
  • History of, or current significant respiratory, hepatic, urinary tract, or thyroid disorders
  • History of, or current acute porphyria
  • History of, or current significant psychiatric disorder (e.g., psychosis, mania, depression)
  • History of, or current eye disorder, not including refractive error that can be corrected with glasses or contact lenses)
  • Pregnant, breast feeding, women of child-bearing potential not using appropriate contraceptive measures
  • Any contraindication to 7T MRI

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: Basic Science
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Esketamine
Nasal spray solution, 56mg (28mg per nostril), intranasal
Drug: Esketamine nasal spray
Nasal spray solution, 56mg (28mg per nostril), intranasal
Placebo Comparator: Placebo
Nasal spray solution, 0.9% NaCl, intranasal
Other: Placebo
Nasal spray solution, 0.9% NaCl, intranasal

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Brain Glutamate Dynamic Change
Time Frame: Acute (40-60 minutes after nasal spray application)
From the functional magnetic resonance spectroscopy (fMRS), calculating the glutamate concentration change in response to flickering checkerboard stimulation (by the difference in the rest concentrations to the stimulation concentrations). This dynamic glutamate change will be compared between individuals on ketamine and placebo, in a within subject cross over design.
Acute (40-60 minutes after nasal spray application)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Brain Glutamate Baseline Change
Time Frame: Acute (40-60 minutes after nasal spray application)
Determining if the baseline glutamate concentration levels in the rest condition is different between individuals on ketamine and placebo (without the influence of a functional task to produce a dynamic change).
Acute (40-60 minutes after nasal spray application)
Excitatory-Inhibitory Ratio Change
Time Frame: Acute (40-60 minutes after nasal spray application)
Using the glutamate and GABA concentrations quantified from the fMRS data, we will calculate the glu-GABA ratio to assess the excitatory-inhibitory ratio, and determine whether this ratio is different between the ketamine and placebo conditions.
Acute (40-60 minutes after nasal spray application)
Brain Resting State Connectivity
Time Frame: Acute (40-60 minutes after nasal spray application)
Brain resting state connectivity change measured via blood oxygenation level-dependent resting-state functional Magnetic Resonance Imaging (BOLD-rs-fMRI) 7T, comparing ketamine and placebo conditions.
Acute (40-60 minutes after nasal spray application)
Visual response
Time Frame: Post-Acute (60-120 minutes after nasal spray application)
Behavioural visual response measured via a computerised visual task, in both the ketamine and placebo conditions we will be comparing differences in the binocular rivalry perceptual suppression, differences in orientation discrimination thresholds and differences in stereopsis thresholds.
Post-Acute (60-120 minutes after nasal spray application)
Exploratory Analysis of Other Metabolite Concentrations at Baseline or Changes After Stimulation
Time Frame: Acute (40-60 minutes after nasal spray application)
Other metabolites captured from the fMRS STEAM sequence will be analysed to assess whether there are differences between the concentrations in the ketamine and placebo conditions, whether that be dynamic or baseline concentration changes.
Acute (40-60 minutes after nasal spray application)
Exploratory Investigation of the Influence of Age, Gender, and Questionnaire Scores on Metabolite Concentration Change
Time Frame: Acute (40-60 minutes after nasal spray application)
Data collected on demographic factors like age and sex and questionnaire scores will be assessed to determine if they significantly influence metabolite levels.
Acute (40-60 minutes after nasal spray application)

Collaborators and Investigators

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

Sponsor

University of Oxford

Collaborators

NIHR Oxford Health Biomedical Research Centre

Investigators

  • Principal Investigator: Riccardo De Giorgi, MD, DPhil, MRCPsych, University of Oxford, Department of Psychiatry

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

Helpful Links

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)

June 14, 2024

Primary Completion (Actual)

March 26, 2025

Study Completion (Actual)

March 26, 2025

Study Registration Dates

First Submitted

May 21, 2024

First Submitted That Met QC Criteria

May 28, 2024

First Posted (Actual)

May 29, 2024

Study Record Updates

Last Update Posted (Actual)

June 8, 2025

Last Update Submitted That Met QC Criteria

June 3, 2025

Last Verified

May 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • R90468/RE001

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

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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