Clinical trial NCT06432322: (GluEsk) Glutamate and Esketamine
Official title: Effects of Esketamine Challenge on Brain Glutamate Release (fMRS), Resting State Connectivity (BOLD-rs-fMRI), and Neuroplasticity (Visual Task)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Depression
Keywords: Esketamine
Brain glutamate release
fMRS
Resting state connectivity
BOLD-rs-fMRI
Neuroplasticity
Visual task
Healthy volunteers
Magnetic Resonance Spectroscopy
Lead sponsor: University of Oxford
Sponsor class: OTHER
Collaborators: name: NIHR Oxford Health Biomedical Research Centre
First posted: 2024-05-29
Enrollment: 16
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Within-subject, cross-over design
Primary purpose: BASIC_SCIENCE

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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Brain Glutamate Dynamic Change
timeFrame: Acute (40-60 minutes after nasal spray application)
Secondary outcomes:
measure: Brain Glutamate Baseline Change
timeFrame: Acute (40-60 minutes after nasal spray application)
measure: Excitatory-Inhibitory Ratio Change
timeFrame: Acute (40-60 minutes after nasal spray application)
measure: Brain Resting State Connectivity
timeFrame: Acute (40-60 minutes after nasal spray application)
measure: Visual response
timeFrame: Post-Acute (60-120 minutes after nasal spray application)
measure: Exploratory Analysis of Other Metabolite Concentrations at Baseline or Changes After Stimulation
timeFrame: Acute (40-60 minutes after nasal spray application)
measure: Exploratory Investigation of the Influence of Age, Gender, and Questionnaire Scores on Metabolite Concentration Change
timeFrame: Acute (40-60 minutes after nasal spray application)
Other outcomes:
Locations:
city: Oxford
country: United Kingdom
facility: Department of Psychiatry, University of Oxford, Warneford Hospital
state: Oxfordshire
Study officials:
affiliation: University of Oxford, Department of Psychiatry
name: Riccardo De Giorgi, MD, DPhil, MRCPsych
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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/
citation: 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.
citation: 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/