sertraline

MECHANISM: Selectively inhibits presynaptic reuptake of serotonin (5-HT) via SERT, raising synaptic serotonin. Therapeutic effect takes ~4-6 weeks (downstream receptor desensitization/downregulation, e.g., 5-HT1A autoreceptors, and increased BDNF/neuroplasticity).

INDICATIONS: Major depressive disorder (first-line), OCD, PTSD (sertraline and paroxetine are FDA-approved), panic disorder, social anxiety disorder, PMDD, and generalized anxiety (off-label/commonly used). Considered one of the safest SSRIs in pregnancy/lactation and in cardiac disease (e.g., post-MI; SADHART trial) because of low transfer into breast milk and minimal QT effect compared with citalopram/escitalopram.

PHARMACOKINETICS: Hepatic metabolism, mainly CYP2B6 and CYP2C19 (with contributions from 2C9, 3A4, 2D6). It's a mild-to-moderate CYP2D6 inhibitor at higher doses. Half-life ~26 hours (active metabolite desmethylsertraline is weaker). Steady state ~1 week. Taking with food increases absorption.

ADVERSE EFFECTS: - GI: nausea, diarrhea (sertraline has the highest rate of GI side effects among SSRIs). - Sexual dysfunction: decreased libido, anorgasmia, delayed ejaculation (common cause of nonadherence). - Insomnia or somnolence, tremor, headache, anxiety/jitteriness early in treatment. - SIADH → hyponatremia (especially in elderly). - Increased bleeding risk (platelet serotonin depletion), especially with NSAIDs/anticoagulants. - Activation of mania/hypomania in undiagnosed bipolar disorder. - Black box warning: increased suicidal thoughts/behavior in children, adolescents, and young adults (<25). - Serotonin syndrome: with MAOIs, linezolid, tramadol, meperidine, triptans, St. John's wort, MDMA, dextromethorphan, other serotonergic drugs. Triad: altered mental status, autonomic instability (hyperthermia, tachycardia, diaphoresis), neuromuscular hyperactivity (clonus, hyperreflexia, rigidity, tremor); diarrhea and mydriasis. Treat: stop offending agent, supportive care, benzodiazepines, cyproheptadine (5-HT2A antagonist). - Discontinuation syndrome with abrupt cessation (dizziness, "brain zaps," irritability, flu-like symptoms, paresthesias); less severe with long-half-life agents (fluoxetine lowest risk; paroxetine highest). - Neonatal risks: third-trimester exposure → neonatal adaptation syndrome and a small risk of persistent pulmonary hypertension of the newborn (PPHN). (Paroxetine is most associated with fetal cardiac malformations and is avoided in pregnancy.)

INTERACTIONS/CONTRAINDICATIONS: Contraindicated with MAOIs (need 14-day washout; 5 weeks after fluoxetine). Caution with warfarin, NSAIDs, and other serotonergic drugs. Pimozide is contraindicated with sertraline.

HIGH-YIELD COMPARISONS: - Fluoxetine: longest half-life, activating, least discontinuation syndrome, strong CYP2D6 inhibitor. - Paroxetine: most anticholinergic, weight gain, worst discontinuation syndrome, teratogenic risk. - Citalopram/escitalopram: dose-dependent QT prolongation. - Fluvoxamine: strong CYP1A2/2C19 inhibitor; used for OCD. - Sertraline: GI effects, relatively few drug interactions, favored in cardiac disease and pregnancy/lactation.

BOARD PEARLS: SSRIs are first-line for depression and anxiety disorders. Depressed patient on SSRI who develops confusion/low sodium → think SIADH. Patient on SSRI + tramadol/linezolid with fever, clonus, agitation → serotonin syndrome. Young patient started on SSRI who becomes more agitated/suicidal → black box warning; monitor closely in first weeks. Switching from an SSRI to an MAOI requires an adequate washout.