Which SSRI produces the most severe discontinuation syndrome when stopped abruptly, and which feature of its pharmacokinetics explains this?
- A Fluoxetine, because of active metabolite accumulation
- B Sertraline, because of irreversible receptor binding
- C Paroxetine, because of its short half-life and lack of active metabolites ✓
- D Citalopram, because of strong CYP2D6 inhibition
Correct answer: C. Paroxetine, because of its short half-life and lack of active metabolites
Explanation
Paroxetine has a half-life of about 21 hours with no active metabolite, so levels fall rapidly and cholinergic rebound plus dizziness, insomnia, and flu-like symptoms appear within days. Fluoxetine, with a half-life of days plus norfluoxetine lasting weeks, virtually never causes significant discontinuation symptoms, which is why it is used for gradual cross-tapering off other SSRIs.
Reference: Katzung Basic and Clinical Pharmacology, 15th ed.
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