escitalopram

**Mechanism of action:** Escitalopram is the active S-enantiomer of racemic citalopram. It selectively inhibits presynaptic reuptake of serotonin via SERT, raising synaptic serotonin. It also has an allosteric binding effect at SERT that may prolong inhibition. It has minimal affinity for histaminic, muscarinic, and adrenergic receptors, so it has fewer anticholinergic, antihistaminic, and alpha-blocking effects than TCAs. Therapeutic effect is delayed (about 2-6 weeks), which is thought to reflect downstream adaptations such as 5-HT1A autoreceptor desensitization and increased BDNF/neuroplasticity, not the immediate rise in synaptic 5-HT.

**Indications:** - Major depressive disorder (adults and adolescents 12 and older) - Generalized anxiety disorder (adults and children 7 and older) - Off-label: panic disorder, social anxiety disorder, OCD, PTSD, PMDD

**Pharmacokinetics:** - Half-life about 27-32 hours, so it is dosed once daily. - Metabolized by CYP2C19 (major), CYP3A4, and CYP2D6. - It is a weak CYP2D6 inhibitor, so it has fewer interactions than fluoxetine, paroxetine, or fluvoxamine. - CYP2C19 inhibitors (omeprazole, cimetidine) raise levels. Poor CYP2C19 metabolizers need lower doses. - Typical dose is 10-20 mg/day. The maximum is 20 mg/day, and the recommended maximum is 10 mg/day in the elderly and in hepatic impairment.

**Adverse effects (common boards themes):** - GI upset (nausea, diarrhea), headache, insomnia or somnolence - Sexual dysfunction (decreased libido, anorgasmia, delayed ejaculation). This is the most common reason for noncompliance. Management options are dose reduction, switching to bupropion or mirtazapine, or adding bupropion or sildenafil. - Hyponatremia from SIADH, especially in elderly patients - Increased bleeding risk (platelet serotonin depletion), especially with NSAIDs or anticoagulants - **QT prolongation** (dose-dependent). It is less prominent than with citalopram but still present. Avoid it in congenital long QT, and use caution with other QT-prolonging drugs. - **Serotonin syndrome:** triad of altered mental status, autonomic instability (hyperthermia, tachycardia, diaphoresis), and neuromuscular hyperactivity (clonus, hyperreflexia, rigidity). It occurs with MAOIs, linezolid, tramadol, triptans, meperidine, St. John's wort, and others. Treatment is stopping the offending agents, supportive care, benzodiazepines, and cyproheptadine (a 5-HT2A antagonist) if needed. - Black box warning: increased suicidal ideation in children, adolescents, and young adults (under 25) early in treatment. - Can precipitate mania or hypomania in undiagnosed bipolar disorder. - **SSRI discontinuation syndrome** (dizziness, "brain zaps," irritability, flu-like symptoms, paresthesias) with abrupt cessation. It is less severe with long half-life agents. Paroxetine is the worst offender.

**Contraindications:** Concurrent MAOI use or use within 14 days. Wait 14 days after stopping an MAOI before starting an SSRI. Wait about 5 weeks after stopping fluoxetine before starting an MAOI. Also contraindicated with pimozide (citalopram labeling) and in congenital long QT syndrome.

**Pregnancy:** SSRIs are generally considered acceptable when benefits outweigh risks. Paroxetine is the one most associated with cardiac malformations (avoid it). Late-pregnancy exposure is associated with persistent pulmonary hypertension of the newborn (PPHN) and a neonatal adaptation syndrome.

**High-yield comparisons:** - Escitalopram and citalopram have the fewest drug interactions among SSRIs, and escitalopram is often well tolerated. - Sertraline is first-line in cardiac disease (e.g., post-MI) and has the most evidence in that setting. - Fluoxetine has the longest half-life (least discontinuation syndrome). - Paroxetine has the most anticholinergic effects, the most weight gain, and the worst discontinuation syndrome. - Fluvoxamine is a strong CYP1A2 inhibitor. - Bupropion causes no sexual dysfunction but lowers the seizure threshold.

**Clinical pearl:** A typical vignette is a patient with depression or GAD who starts an SSRI and later has sexual dysfunction or hyponatremia (confusion, seizures in an older adult). Another is a patient on an SSRI who is given a triptan, linezolid, or tramadol and develops agitation, clonus, and fever. Allow an adequate trial (4-8 weeks at a therapeutic dose) before declaring treatment failure.