## Protocol Section
### Identification Module
**NCT ID:** NCT06432322

**Acronym:** GluEsk

**Brief Title:** (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)

#### Organization Study ID Info
**ID:** R90468/RE001
#### Organization
**Class:** OTHER
**Full Name:** University of Oxford
### Status Module
#### Completion Date
**Date:** 2025-06

**Type:** ESTIMATED

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2024-05-29

**Type:** ACTUAL

**Last Update Submit Date:** 2024-05-28

**Overall Status:** NOT_YET_RECRUITING

#### Primary Completion Date
**Date:** 2025-06

**Type:** ESTIMATED

#### Start Date
**Date:** 2024-06

**Type:** ESTIMATED

**Status Verified Date:** 2024-05

#### Study First Post Date
**Date:** 2024-05-29
**Type:** ACTUAL
**Study First Submit Date:** 2024-05-21
**Study First Submit QC Date:** 2024-05-28
### Sponsor Collaborators Module

#### Collaborators

**Class:** UNKNOWN

**Name:** NIHR Oxford Health Biomedical Research Centre

#### Lead Sponsor

**Class:** OTHER

**Name:** University of Oxford

#### Responsible Party

**Type:** SPONSOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** False

**Is US Export:** False

### Description Module

**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 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, work in our Clinical Psychopharmacology laboratory 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 can indeed produce an increase in brain glutamate release measured via this 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 neuroplasticity measured via a behavioural computerised visual task. Psychological questionnaires will also be measured to check for possible correlations with the outcomes measured.

### Conditions Module

**Conditions:**

- Depression

**Keywords:**

- Esketamine

- Brain glutamate release

- fMRS

- Resting state connectivity

- BOLD-rs-fMRI

- Neuroplasticity

- Visual task

- Healthy volunteers

- Magnetic Resonance Spectroscopy

### Design Module

#### Design Info

**Allocation:** RANDOMIZED

**Intervention Model:** CROSSOVER

**Intervention Model Description:** Within-subject, cross-over design

##### Masking Info

**Masking:** DOUBLE

**Masking Description:** 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).

**Who Masked:**

- PARTICIPANT

- OUTCOMES_ASSESSOR

**Primary Purpose:** BASIC_SCIENCE

#### Enrollment Info

**Count:** 12

**Type:** ESTIMATED

**Phases:**

- NA

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

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

**Intervention Names:**

- Drug: Esketamine nasal spray

**Label:** Esketamine

**Type:** EXPERIMENTAL

#### Arm Group 2

**Description:** Nasal spray solution, 0.9% NaCl, intranasal

**Intervention Names:**

- Other: Placebo

**Label:** Placebo

**Type:** PLACEBO_COMPARATOR

### Interventions

#### Intervention 1

**Arm Group Labels:**

- Esketamine

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

**Name:** Esketamine nasal spray

**Type:** DRUG

#### Intervention 2

**Arm Group Labels:**

- Placebo

**Description:** Nasal spray solution, 0.9% NaCl, intranasal

**Name:** Placebo

**Type:** OTHER

### Outcomes Module

#### Primary Outcomes

**Description:** Brain glutamate release change measured via functional Magnetic Resonance Spectroscopy (fMRS) 7-Tesla (7T) "flickering checkerboard", comparing drug vs placebo occasions.

**Measure:** Brain glutamate release

**Time Frame:** Acute (40-60 minutes after nasal spray application)

#### Secondary Outcomes

**Description:** Brain resting state connectivity change measured via blood oxygenation level-dependent resting-state functional Magnetic Resonance Imaging (BOLD-rs-fMRI) 7T, comparing drug vs placebo occasions.

**Measure:** Brain resting state connectivity

**Time Frame:** Acute (40-60 minutes after nasal spray application)

**Description:** Behavioural visual response measured via a computerised visual task, comparing drug vs placebo occasions.

**Measure:** Visual response

**Time Frame:** Post-Acute (60-90 minutes after nasal spray application)

### Eligibility Module

**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 (see Approved Procedure: IDREC_17 Title: Non-invasive Magnetic Resonance Investigations in Healthy Volunteers)

**Healthy Volunteers:** True

**Maximum Age:** 50 Years

**Minimum Age:** 18 Years

**Sex:** ALL

**Standard Ages:**

- ADULT

### Contacts Locations Module

#### Central Contacts

**Contact 1:**

**Email:** wendy.howard@psych.ox.ac.uk

**Name:** Wendy Howard

**Phone:** 01865 618238

**Role:** CONTACT

#### Locations

**Location 1:**

**City:** Oxford

**Country:** United Kingdom

**Facility:** Department of Psychiatry, University of Oxford

**State:** Oxfordshire

**Zip:** OX3 7JX

### IPD Sharing Statement Module

**IPD Sharing:** NO

### References Module

#### 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.

**PMID:** 28433623

**Citation:** Jewett BE, Thapa B. Physiology, NMDA Receptor. 2022 Dec 11. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from http://www.ncbi.nlm.nih.gov/books/NBK519495/

**PMID:** 30137779

**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.

**PMID:** 30733690

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

**PMID:** 29262083

#### See Also Links

**Label:** Related Info

**URL:** https://www.psych.ox.ac.uk/getinvolved/gluesk-glutamate-and-esketamine-study

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000001526

- Term: Behavioral Symptoms

### Condition Browse Module - Browse Branches

- Abbrev: BXM

- Name: Behaviors and Mental Disorders

- Abbrev: All

- Name: All Conditions

### Condition Browse Module - Browse Leaves

- ID: M7058

- Name: Depression

- Relevance: HIGH

- As Found: Depression

- ID: M7061

- Name: Depressive Disorder

- Relevance: LOW

- As Found: Unknown

- ID: M4818

- Name: Behavioral Symptoms

- Relevance: LOW

- As Found: Unknown

### Condition Browse Module - Meshes

- ID: D000003863

- Term: Depression

### Intervention Browse Module - Ancestors

- ID: D000000928

- Term: Antidepressive Agents

- ID: D000011619

- Term: Psychotropic Drugs

### Intervention Browse Module - Browse Branches

- Abbrev: PsychDr

- Name: Psychotropic Drugs

- Abbrev: All

- Name: All Drugs and Chemicals

- Abbrev: PhSol

- Name: Pharmaceutical Solutions

- Abbrev: AA

- Name: Amino Acids

### Intervention Browse Module - Browse Leaves

- ID: M271980

- Name: Esketamine

- Relevance: HIGH

- As Found: Days per week

- ID: M21860

- Name: Pharmaceutical Solutions

- Relevance: LOW

- As Found: Unknown

- ID: M4247

- Name: Antidepressive Agents

- Relevance: LOW

- As Found: Unknown

- ID: M14474

- Name: Psychotropic Drugs

- Relevance: LOW

- As Found: Unknown

- ID: T5

- Name: Glutamic Acid

- Relevance: LOW

- As Found: Unknown

### Intervention Browse Module - Meshes

- ID: C000629870

- Term: Esketamine

### Misc Info Module

- Version Holder: 2024-05-31
