SSRI Selection and Differences

Selective serotonin reuptake inhibitors (SSRIs) are the first-line pharmacotherapy for major depressive disorder and most anxiety disorders. All SSRIs share the same primary mechanism — selective inhibition of the serotonin transporter (SERT) — but each has unique pharmacological properties that guide clinical selection. Fluoxetine: longest half-life (4-6 days; active metabolite norfluoxetine 4-16 days), potent CYP2D6 inhibitor; best for patients with adherence concerns (missed doses less problematic); only SSRI FDA-approved for children with depression; available in weekly formulation. Sertraline: mild dopamine reuptake inhibition; preferred in cardiac patients (SADHART trial safety data); lowest protein binding → fewest drug interactions overall; preferred in breastfeeding (lowest breast milk transfer). Paroxetine: most potent SERT inhibitor; anticholinergic properties (unique among SSRIs); most weight gain, most sexual dysfunction, worst discontinuation syndrome (short half-life ~21 hours); pregnancy category D (cardiac malformations). Citalopram: dose-dependent QT prolongation (FDA limit 40 mg/day; 20 mg/day in patients >60, hepatic impairment, CYP2C19 poor metabolizers); most serotonin-selective (fewest off-target effects). Escitalopram: S-enantiomer of citalopram; more potent at SERT with fewer off-target effects; best tolerability profile; start at therapeutic dose (10 mg). Fluvoxamine: primarily used...