A patient who abruptly stops her antidepressant develops dizziness, electric shock sensations, insomnia, nausea, and irritability after 48 hours. Among SSRIs, this discontinuation syndrome is most frequent and severe with which agent, and why?

• A Fluoxetine, because its metabolite norfluoxetine accumulates in fat
• B Escitalopram, because it has the highest serotonin transporter affinity
• C Sertraline, because it is the strongest CYP2D6 inhibitor
• D Paroxetine, because it has the shortest half-life and lacks active metabolites among SSRIs ✓

Explanation

Discontinuation syndrome severity correlates inversely with half-life. Paroxetine has a half-life near 21 hours with no long-lived active metabolite, so receptor-level serotonergic changes emerge rapidly after stopping. Fluoxetine, with a parent plus norfluoxetine half-life approaching one to two weeks, rarely causes the syndrome and is sometimes used as a taper bridge. Potency at the transporter and CYP inhibition do not determine this outcome.

Reference: Katzung Basic and Clinical Pharmacology, 15th ed.

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Written and medically reviewed by the StethoPrep medical team.