Individual Agent Profiles
All six selective serotonin reuptake inhibitors work by the same primary mechanism, but they differ enough in their pharmacokinetic profiles, drug interaction potential, and secondary receptor activity to make agent selection clinically meaningful. These differences — not the shared mechanism — are what Step 1 tests.
Fluoxetine is unique among selective serotonin reuptake inhibitors for its exceptionally long effective duration. The parent drug has a long half-life, and its active metabolite norfluoxetine has a half-life of one to two weeks. This extended active metabolite produces three clinically critical consequences. First, abrupt discontinuation of fluoxetine causes minimal or no discontinuation syndrome — norfluoxetine self-tapers over weeks. Second, a five-week washout period is required before starting a monoamine oxidase inhibitor after stopping fluoxetine (versus two weeks for all other selective serotonin reuptake inhibitors). Third, cytochrome P450 2D6 inhibition by fluoxetine and norfluoxetine persists for weeks after the last dose.
Fluoxetine is a potent inhibitor of cytochrome P450 2D6 and a moderate inhibitor of cytochrome P450 3A4 and cytochrome P450 2C19. It is approved for major depressive disorder, obsessive-compulsive disorder, panic disorder, bulimia nervosa, premenstrual dysphoric disorder, and bipolar depression (combined with olanzapine). It is the only selective serotonin reuptake inhibitor approved for depression in children age 8 and older.
Sertraline has the broadest Food and Drug Administration approval profile of the class — covering major depressive disorder, obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder, social anxiety disorder, and premenstrual dysphoric disorder. It has a moderate half-life (no long active metabolite), weak cytochrome P450 2D6 inhibition at standard doses, and minimal effects on other cytochrome P450 isoforms. This clean interaction profile, combined with evidence of cardiac safety, makes sertraline the preferred selective serotonin reuptake inhibitor in cardiac patients and a common first choice in primary care. It is also among the most studied agents in pregnancy.
Paroxetine carries the highest clinical caution burden of any selective serotonin reuptake inhibitor for several compounding reasons. Its half-life is short and it has no active metabolites, making it the selective serotonin reuptake inhibitor most prone to discontinuation syndrome — abrupt cessation frequently produces flu-like symptoms, insomnia, nausea, sensory disturbances (electric-shock sensations), and irritability. It is the most potent cytochrome P450 2D6 inhibitor in the class, effectively converting normal metabolizers to poor metabolizer phenotype, with significant consequences for co-administered drugs including tricyclic antidepressants, antipsychotics, and tamoxifen.
Uniquely among selective serotonin reuptake inhibitors, paroxetine has clinically significant muscarinic receptor antagonism, producing anticholinergic adverse effects — dry mouth, constipation, urinary hesitancy, and cognitive effects — that are not seen with other class members. Paroxetine is also of concern in pregnancy due to signals of cardiovascular malformation in neonates with first-trimester exposure, making it the selective serotonin reuptake inhibitor most avoided during pregnancy.
Escitalopram is the S-enantiomer of citalopram and is pharmacokinetically the cleanest selective serotonin reuptake inhibitor in terms of drug interactions. It has minimal inhibition of all major cytochrome P450 isoforms, making it the preferred choice when a patient is on multiple medications and drug interactions are a primary concern. It carries a Food and Drug Administration warning for QTc prolongation at higher doses, with a maximum recommended dose of 20 mg per day in elderly patients, those with liver disease, and cytochrome P450 2C19 poor metabolizers. Escitalopram is approved for major depressive disorder and generalized anxiety disorder, and has additional off-label use across anxiety disorders. It is approved for depression in adolescents age 12 and older.
Citalopram is a racemic mixture. It has minimal cytochrome P450 inhibition and a relatively clean receptor profile, but carries the most significant QTc prolongation concern of the class. The Food and Drug Administration caps citalopram at 40 mg per day in most patients and at 20 mg per day in patients over age 60, those with hepatic impairment, and cytochrome P450 2C19 poor metabolizers. It is not recommended above these doses for any indication. When QTc prolongation is a particular concern, escitalopram or sertraline are preferred over citalopram.
Fluvoxamine is used primarily for obsessive-compulsive disorder and social anxiety disorder rather than major depressive disorder, and its use in other settings is limited by its drug interaction burden. It is the most potent cytochrome P450 1A2 inhibitor in the class and also inhibits cytochrome P450 2C19 and cytochrome P450 3A4. The cytochrome P450 1A2 inhibition is particularly consequential: fluvoxamine can raise plasma concentrations of clozapine dramatically, risking clozapine toxicity. It also significantly raises theophylline, olanzapine, and tizanidine levels — the tizanidine combination is contraindicated due to severe hypotension. In patients on clozapine or complex psychiatric regimens, fluvoxamine is generally avoided.
Discontinuation syndrome risk: paroxetine (highest — short half-life, no active metabolite) versus fluoxetine (lowest — norfluoxetine self-tapers). Cytochrome P450 2D6 inhibition: paroxetine and fluoxetine (potent) versus escitalopram and citalopram (minimal). Monoamine oxidase inhibitor washout: fluoxetine requires five weeks; all others require two weeks. QTc prolongation: citalopram (most significant — dose cap 40 mg) and escitalopram (lesser but real — dose cap 20 mg in high-risk patients).
