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Esketamine mechanism — MRCPsych Paper A MCQ

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HardPsychopharmacologyEsketamine mechanismMRCPsych Paper A

A 43-year-old woman with major depressive disorder that has not responded to two adequate antidepressant trials receives intranasal esketamine under direct supervision in a specialist programme. Its antidepressant effect is associated with a transient increase in glutamate release, subsequent AMPA-receptor stimulation and increased neurotrophic signalling. Which primary pharmacological action initiates this cascade?

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Correct answer: C — Non-selective, non-competitive antagonism at NMDA glutamate receptors

Explanation lettering: B = shown as A · D = shown as B · E = shown as C · A = shown as D · C = shown as E

E is correct. Esketamine, the S-enantiomer of racemic ketamine, is a non-selective, non-competitive antagonist at the ionotropic NMDA glutamate receptor. NMDA-receptor antagonism produces a transient increase in glutamate release, leading to increased AMPA-receptor stimulation and neurotrophic signalling that may restore synaptic function in mood-related brain regions. AMPA activation is therefore downstream rather than direct, excluding A. Dopamine D2/D3 partial agonism is associated with some antipsychotics, while GABA-A positive allosteric modulation is characteristic of drugs such as benzodiazepines. Irreversible monoamine oxidase inhibition is the mechanism of older MAO inhibitor antidepressants and does not account for esketamine's pharmacology.

Reference: Electronic Medicines Compendium. Spravato 28 mg nasal spray, solution: Summary of Product Characteristics, section 5.1, Pharmacodynamic properties—Mechanism of action. Updated 24 July 2025. https://www.medicines.org.uk/emc/product/10977/smpc