Which antidepressant mechanism best explains why mirtazapine causes weight gain and sedation more than most SSRIs?

• A Inhibition of serotonin and noradrenaline reuptake transporters
• B Irreversible inhibition of monoamine oxidase A
• C Blockade of dopamine D2 receptors in the mesolimbic pathway
• D Blockade of alpha-2 auto/hetero-receptors plus potent H1 and 5-HT2C receptor antagonism ✓

Explanation

Mirtazapine is a noradrenergic and specific serotonergic antidepressant (NaSSA) that blocks presynaptic alpha-2 autoreceptors and heteroceptors, increasing noradrenaline and serotonin release. Its potent H1 (histamine-1) antagonism causes sedation and weight gain, while 5-HT2C antagonism also promotes appetite stimulation and weight gain—properties that can be therapeutically useful in depressed, underweight, or insomnia-prominent patients. SSRIs lack significant H1 and 5-HT2C blockade, explaining the difference.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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