DepressionGluEskNCT06432322
(GluEsk) Glutamate and Esketamine
A study testing Esketamine nasal spray in people with Depression, run by University of Oxford at 1 site in United Kingdom.
Trial summary
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… Read more about this study
- Who is it for?
- Ages 18 to 50 yearsHealthy volunteers can take part
- Conditions the study is for
- Depression
- What is being tested?
- Esketamine nasal spray
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 16 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- 14 Jun 2024to 26 Mar 2025
- Phase
- Interventional
- Are there results?
- None posted in the registry
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 50 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 14Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
United Kingdom1 site
Department of Psychiatry, University of Oxford, Warneford Hospital
Oxford, Oxfordshire, OX3 7JX
About this study
Official title: 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.
Read the 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.
- Conditions
- Depression
- Being tested
- Esketamine nasal spray, Placebo
- Keywords
- Esketamine, Brain glutamate release, fMRS, Resting state connectivity, BOLD-rs-fMRI, Neuroplasticity, Visual task, Healthy volunteers, Magnetic Resonance Spectroscopy
- Medical subject headings
- Depression
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Esketamine nasal sprayDrug
Nasal spray solution, 56mg (28mg per nostril), intranasal
PlaceboOther
Nasal spray solution, 0.9% NaCl, intranasal
| Study group | Role | What they receive |
|---|---|---|
| Esketamine | Experimental | Nasal spray solution, 56mg (28mg per nostril), intranasal Receives: Drug: Esketamine nasal spray |
| Placebo | Placebo comparator | Nasal spray solution, 0.9% NaCl, intranasal Receives: Other: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Brain Glutamate Dynamic Change
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.
Measured: Acute (40-60 minutes after nasal spray application)
Secondary outcomes (6)
Brain Glutamate Baseline Change
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).
Measured: Acute (40-60 minutes after nasal spray application)
Excitatory-Inhibitory Ratio Change
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.
Measured: Acute (40-60 minutes after nasal spray application)
Brain Resting State Connectivity
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.
Measured: Acute (40-60 minutes after nasal spray application)
Visual response
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.
Measured: Post-Acute (60-120 minutes after nasal spray application)
Exploratory Analysis of Other Metabolite Concentrations at Baseline or Changes After Stimulation
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.
Measured: Acute (40-60 minutes after nasal spray application)
Exploratory Investigation of the Influence of Age, Gender, and Questionnaire Scores on Metabolite Concentration Change
Data collected on demographic factors like age and sex and questionnaire scores will be assessed to determine if they significantly influence metabolite levels.
Measured: Acute (40-60 minutes after nasal spray application)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 May 2024
- Study start14 Jun 2024
- Primary completion26 Mar 2025
- Study completion26 Mar 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for DepressionStudies of the same condition, open and under way.
- More trials run by University of OxfordThe 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 N/A
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- Within-subject, cross-over design
- Masking
- Double blind
- Who is masked
- Participant, Outcomes assessor
- Enrolment
- 16 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Oxford
- Sponsor type
- University, hospital or other
- Collaborators
- National Institute for Health Research, United Kingdom
- Responsible party
- Sponsor
- Investigators
- Riccardo De Giorgi, MD, DPhil, MRCPsych, Principal investigator, University of Oxford, Department of Psychiatry
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06432322
- Sponsor's protocol ID
- R90468/RE001
- Acronym
- GluEsk
- Status last verified
- May 2025
- First submitted
- 21 May 2024
- Last updated
- 8 Jun 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Ip IB, Berrington A, Hess AT, Parker AJ, Emir UE, Bridge H. Combined fMRI-MRS acquires simultaneous glutamate and BOLD-fMRI signals in the human brain. Neuroimage. 2017 Jul 15;155:113-119. doi: 10.1016/j.neuroimage.2017.04.030. Epub 2017 Apr 19.
PubMed 28433623Jewett BE, Thapa B. Physiology, NMDA Receptor. 2022 Dec 11. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2026 Jan-. Available from http://www.ncbi.nlm.nih.gov/books/NBK519495/
PubMed 30137779Li CT, Yang KC, Lin WC. Glutamatergic Dysfunction and Glutamatergic Compounds for Major Psychiatric Disorders: Evidence From Clinical Neuroimaging Studies. Front Psychiatry. 2019 Jan 24;9:767. doi: 10.3389/fpsyt.2018.00767. eCollection 2018.
PubMed 30733690Rosenbaum SB, Gupta V, Patel P, Palacios JL. Ketamine. 2024 Jan 30. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2026 Jan-. Available from http://www.ncbi.nlm.nih.gov/books/NBK470357/
PubMed 29262083
Study at a glance
From the registry record, last updated by the sponsor on 8 Jun 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Effects of Esketamine Challenge on Brain Glutamate Release (fMRS), Resting State Connectivity (BOLD-rs-fMRI), and Neuroplasticity (Visual Task)
- ClinicalTrials.gov ID
- NCT06432322
- Acronym / sponsor ID
- GluEsk / R90468/RE001
- Conditions
- Depression
- Keywords
- Esketamine, Brain glutamate release, fMRS, Resting state connectivity, BOLD-rs-fMRI, Neuroplasticity, Visual task, Healthy volunteers
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 16 participants (actual)
- Lead sponsor
- University of OxfordUniversity, hospital or other
- Collaborators
- National Institute for Health Research, United Kingdom
- Study start
- 14 Jun 2024 (actual)
- Primary completion
- 26 Mar 2025 (actual)
- Study completion
- 26 Mar 2025 (actual)
- First posted
- 29 May 2024 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Double blind (participant, outcomes assessor)
- Number of arms
- 2
- Model description
- Within-subject, cross-over design
| Arm | Type | Receives |
|---|---|---|
| Esketamine | Experimental | Drug: Esketamine nasal sprayNasal spray solution, 56mg (28mg per nostril), intranasal |
| Placebo | Placebo comparator | Other: PlaceboNasal spray solution, 0.9% NaCl, intranasal |
Who may qualify
- Ages
- 18 to 50 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (4 listed)
- 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
Key exclusion criteria (14 listed)
- 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)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Esketamine nasal sprayNasal spray solution, 56mg (28mg per nostril), intranasal | Drug | Esketamine |
| PlaceboNasal spray solution, 0.9% NaCl, intranasal | Other | Placebo |
Primary outcome
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.
6 secondary outcomes
Brain Glutamate Baseline Change
Time frame: Acute (40-60 minutes after nasal spray application)
Excitatory-Inhibitory Ratio Change
Time frame: Acute (40-60 minutes after nasal spray application)
Brain Resting State Connectivity
Time frame: Acute (40-60 minutes after nasal spray application)
Visual response
Time frame: 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)
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)
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 8 Jun 2025.
- Background: PubMed 28433623Ip IB, Berrington A, Hess AT, Parker AJ, Emir UE, Bridge H. Combined fMRI-MRS acquires simultaneous glutamate and BOLD-fMRI signals in the human brain. Neuroimage. 2017 Jul 15;155:113-119. doi: 10.1016/j.neuroimage.2017.04.030. Epub 2017 Apr 19.
- Background: PubMed 30137779Jewett BE, Thapa B. Physiology, NMDA Receptor. 2022 Dec 11. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2026 Jan-. Available from http://www.ncbi.nlm.nih.gov/books/NBK519495/
- Background: PubMed 30733690Li CT, Yang KC, Lin WC. Glutamatergic Dysfunction and Glutamatergic Compounds for Major Psychiatric Disorders: Evidence From Clinical Neuroimaging Studies. Front Psychiatry. 2019 Jan 24;9:767. doi: 10.3389/fpsyt.2018.00767. eCollection 2018.
- Background: PubMed 29262083Rosenbaum SB, Gupta V, Patel P, Palacios JL. Ketamine. 2024 Jan 30. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2026 Jan-. Available from http://www.ncbi.nlm.nih.gov/books/NBK470357/
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Riccardo De Giorgi, MD, DPhil, MRCPsych principal investigator
University of Oxford, Department of Psychiatry
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Esketamine nasal spray in people with Depression, run by University of Oxford at 1 site in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 8 Jun 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Brain Glutamate Dynamic Change (time frame: Acute (40-60 minutes after nasal spray application)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT06432322, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 Jun 2025.