Selective serotonin reuptake inhibitors (SSRIs) share the same primary mechanism — blocking the serotonin transporter (SERT) to increase synaptic serotonin — but differ significantly in secondary pharmacological properties, pharmacokinetics, drug interactions, and side effect profiles that guide individualized selection. Fluoxetine has the longest half-life (4-6 days; active metabolite norfluoxetine 4-16 days), making it the most forgiving for missed doses but requiring the longest washout before MAOI initiation (5 weeks). It is a potent CYP2D6 inhibitor, creating significant interactions with tamoxifen (blocks conversion to active endoxifen), codeine, and tramadol. Fluoxetine is mildly activating and weight-neutral, making it suitable for fatigue-predominant depression but potentially worsening insomnia and anxiety. Sertraline has mild dopamine transporter (DAT) inhibition and sigma-1 receptor agonism, with the strongest evidence base in cardiac patients (SADHART trial) and the fewest CYP interactions among SSRIs. Paroxetine is the most potent SERT inhibitor with anticholinergic properties (sedating, weight gain) and mild norepinephrine reuptake inhibition; its short half-life and lack of active metabolites cause the most severe discontinuation syndrome. Paroxetine is Category X in pregnancy (cardiac malformations). Escitalopram (S-enantiomer of citalopram) has the...