(GluEsk) Glutamate and Esketamine

Depression

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

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.

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.

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United Kingdom