Selective Serotonin Reuptake Inhibitors

Module 2 — Chapter 17: Antidepressant Drugs

The Six Selective Serotonin Reuptake Inhibitors — Key Distinctions
Agent Half-Life Tier Cytochrome P450 Inhibition Key Distinguishing Feature
Fluoxetine Very long (norfluoxetine) Potent 2D6; moderate 3A4, 2C19 Active metabolite norfluoxetine — minimal discontinuation syndrome; 5-week monoamine oxidase inhibitor washout; approved for children age 8 and older
Sertraline Moderate Weak 2D6 at standard doses Broadest Food and Drug Administration approval; preferred in cardiac patients and pregnancy; cleanest interaction profile after escitalopram
Paroxetine Short — no active metabolite Potent 2D6 (most potent in class) Highest discontinuation syndrome risk; anticholinergic (muscarinic blockade); avoid in pregnancy and with tamoxifen
Escitalopram Moderate Minimal — all isoforms Cleanest interaction profile — preferred in polypharmacy; QTc risk at high doses (cap 20 mg in elderly/hepatic); approved age 12 and older
Citalopram Moderate Minimal 2D6 Greatest QTc prolongation risk — Food and Drug Administration dose cap 40 mg; 20 mg in elderly/hepatic/cytochrome P450 2C19 poor metabolizers
Fluvoxamine Moderate-short Potent 1A2, 2C19; moderate 3A4 Primary indication: obsessive-compulsive disorder; avoid with clozapine (dramatic level increase) and tizanidine (contraindicated)
High-Yield Drug Interactions
Cytochrome P450 2D6 Inhibitors
Paroxetine and Fluoxetine
  • Tricyclic antidepressants: levels double or triple → toxicity
  • Tamoxifen: reduced activation to endoxifen → reduced anticancer efficacy (avoid both agents)
  • Antipsychotics (haloperidol, risperidone): elevated levels
  • Codeine: reduced conversion to morphine → reduced analgesia
Cytochrome P450 1A2 Inhibitor
Fluvoxamine Only
  • Clozapine: 5- to 10-fold level increase → toxicity
  • Theophylline: narrow therapeutic index → toxicity risk
  • Olanzapine: 2- to 3-fold level increase
  • Tizanidine: contraindicated — severe hypotension
Serotonin Syndrome — Clinical Recognition
Clinical Triad
Serotonin Syndrome
  • Neuromuscular: clonus (key finding), hyperreflexia, myoclonus, tremor
  • Autonomic: hyperthermia, diaphoresis, tachycardia, hypertension
  • Mental status: agitation, confusion, anxiety
  • Onset: within 24 hours of precipitant
  • Treatment: stop all serotonergic drugs; cyproheptadine; benzodiazepines
Comparison
Neuroleptic Malignant Syndrome
  • Neuromuscular: lead-pipe rigidity, bradyreflexia (no clonus)
  • Autonomic: hyperthermia, diaphoresis, labile blood pressure
  • Mental status: confusion, stupor
  • Onset: 24 to 72 hours or more; caused by dopamine antagonists
  • Treatment: stop offending drug; bromocriptine; dantrolene
Monoamine Oxidase Inhibitor Washout Rules

Before starting monoamine oxidase inhibitor after selective serotonin reuptake inhibitor: wait 2 weeks for most agents — wait 5 weeks after fluoxetine (norfluoxetine active metabolite). Before starting any selective serotonin reuptake inhibitor after monoamine oxidase inhibitor: always wait 2 weeks. Combining a selective serotonin reuptake inhibitor with a monoamine oxidase inhibitor is absolutely contraindicated.