A 35-year-old man on phenelzine for depression develops a migraine and takes sumatriptan. He develops hyperthermia, clonus, agitation, and hyperreflexia. The diagnosis is serotonin syndrome. The mechanism of this interaction is:

• A Phenelzine inhibits CYP3A4, reducing sumatriptan metabolism
• B Both drugs block serotonin reuptake at the synapse
• C Sumatriptan displaces phenelzine from plasma protein binding
• D MAO-A inhibition increases presynaptic serotonin, and sumatriptan adds serotonergic stimulation ✓

Explanation

Phenelzine is a monoamine oxidase inhibitor (MAOI) that blocks MAO-A, the enzyme that metabolises serotonin in presynaptic neurons, increasing serotonin stores. Sumatriptan is a 5-HT1D/1B agonist with some serotonergic activity. The combination can produce excessive serotonergic stimulation causing serotonin syndrome. Sumatriptan is not a reuptake inhibitor. The interaction is pharmacodynamic, not primarily pharmacokinetic.

Reference: Goodman and Gilman's The Pharmacological Basis of Therapeutics, 14th ed.

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