(GluEsk) Glutamate and Esketamine

NCT06432322 | Completed

• 1 other identifier: R90468/RE001
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

Brief 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 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.

Conditions

Depression

Keywords

Esketamine; Brain glutamate release; fMRS; Resting state connectivity; BOLD-rs-fMRI; Neuroplasticity; Visual task; Healthy volunteers; Magnetic Resonance Spectroscopy

Outcome Measures

Primary Outcomes (1)

• 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.

  Acute (40-60 minutes after nasal spray application)

Secondary Outcomes (6)

• Brain Glutamate Baseline Change

  Acute (40-60 minutes after nasal spray application)

• Excitatory-Inhibitory Ratio Change

  Acute (40-60 minutes after nasal spray application)

• Brain Resting State Connectivity

  Acute (40-60 minutes after nasal spray application)

• Visual response

  Post-Acute (60-120 minutes after nasal spray application)

• Exploratory Analysis of Other Metabolite Concentrations at Baseline or Changes After Stimulation

  Acute (40-60 minutes after nasal spray application)

Study Arms (2)

Esketamine

EXPERIMENTAL

Nasal spray solution, 56mg (28mg per nostril), intranasal

Drug: Esketamine nasal spray

Placebo

PLACEBO COMPARATOR

Nasal spray solution, 0.9% NaCl, intranasal

Other: Placebo

Interventions

Esketamine nasal spray DRUG

Nasal spray solution, 56mg (28mg per nostril), intranasal

Esketamine

Placebo OTHER

Nasal spray solution, 0.9% NaCl, intranasal

Placebo

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Oxford: lead
• National Institute for Health Research, United Kingdom: collaborator

Study Sites (1)

Department of Psychiatry, University of Oxford, Warneford Hospital

Oxford, Oxfordshire, OX3 7JX, United Kingdom

Location

Related Publications (4)

• 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.

  PMID: 28433623 BACKGROUND

• Jewett BE, Thapa B. Physiology, NMDA Receptor. 2022 Dec 11. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from http://www.ncbi.nlm.nih.gov/books/NBK519495/

  PMID: 30137779 BACKGROUND

• Li 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.

  PMID: 30733690 BACKGROUND

• Rosenbaum SB, Gupta V, Patel P, Palacios JL. Ketamine. 2024 Jan 30. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from http://www.ncbi.nlm.nih.gov/books/NBK470357/

  PMID: 29262083 BACKGROUND

MeSH Terms

Conditions

Depression

Condition Hierarchy (Ancestors)

Behavioral Symptoms; Behavior

Study Officials

• Riccardo De Giorgi, MD, DPhil, MRCPsych

  University of Oxford, Department of Psychiatry

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, OUTCOMES ASSESSOR
• Masking Details: Self-administered by the participant wearing an eye mask, following instructions and under supervision of appropriately trained medical staff where resuscitation facilities are available, via a single-use device delivering 28 mg as two sprays (i.e., one spray per nostril).
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Within-subject, cross-over design

Study Record Dates

• First Submitted: May 21, 2024
• First Posted: May 29, 2024
• Study Start: June 14, 2024
• Primary Completion: March 26, 2025
• Study Completion: March 26, 2025
• Last Updated: June 8, 2025

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)