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Mirtazapine Pharmacology — MRCPsych Paper B MCQ

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HardMood DisordersMirtazapine PharmacologyMRCPsych Paper B

A 43-year-old woman with a depressive episode starts mirtazapine 15 mg at night and develops marked morning somnolence. Which pairing correctly identifies the receptor action most directly responsible for this sedation and the separate action by which mirtazapine enhances central noradrenergic transmission?

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Correct answer: C — Histamine H1 antagonism; presynaptic alpha-2 antagonism

Mirtazapine’s sedative effect is most directly attributable to potent histamine H1-receptor antagonism. Its enhancement of central noradrenergic transmission results from blockade of presynaptic alpha-2 adrenergic autoreceptors; blockade of alpha-2 heteroreceptors also contributes to its serotonergic effects. It does not inhibit the noradrenaline or serotonin transporters or monoamine oxidase. Mirtazapine antagonises rather than stimulates 5-HT3 receptors and has little clinically relevant muscarinic activity. Although lower doses are often said to be more sedating because H1 blockade supposedly predominates over noradrenergic activation, a reliable inverse dose-sedation relationship has not been established. The original dose-paradox wording therefore asserted a mechanistic hypothesis more strongly than the evidence permits.

Reference: Mirtazapine 15 mg Tablets, Summary of Product Characteristics, sections 4.8 and 5.1, revised 2024. https://www.medicines.org.uk/emc/product/531/smpc