A patient with major depressive disorder on fluoxetine (SSRI) for 3 years develops migraine. The physician considers prescribing sumatriptan. What is the primary concern with this combination?

• A Increased risk of QT prolongation and torsades de pointes
• B Sumatriptan inhibits CYP2D6, causing fluoxetine toxicity
• C Fluoxetine antagonizes 5-HT1B/1D receptors, reducing sumatriptan efficacy
• D Increased risk of serotonin syndrome due to additive serotonergic activity ✓

Explanation

Sumatriptan is a 5-HT1B/1A agonist and fluoxetine increases synaptic serotonin by blocking reuptake. Their combination can theoretically cause serotonin syndrome (clonus, hyperthermia, agitation). While the absolute risk is low, FDA labeling warns against combining triptans with SSRIs/SNRIs. The clinically significant concern is additive serotonergic activity, not pharmacokinetic interactions.

Reference: Katzung Basic and Clinical Pharmacology, 14th ed.

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Written and medically reviewed by the StethoPrep medical team.