What are the toxic effects of fluoxetine (selective serotonin reuptake inhibitor)?

Toxic Effects of Fluoxetine

Fluoxetine can cause potentially fatal toxic effects including seizures, QT prolongation, cardiac arrhythmias, serotonin syndrome, and death, with particular risk in CYP2D6 poor metabolizers and when combined with other serotonergic medications. 1, 2

Common Adverse Effects

• Gastrointestinal symptoms including nausea, vomiting, diarrhea, and dry mouth 1
• Neurological effects including headache, somnolence, insomnia, dizziness, and vivid dreams 1
• Autonomic effects including diaphoresis (sweating) 1
• Other common effects include fatigue, nervousness, tremor, bruxism, and changes in appetite/weight 1

Serious Toxic Effects

Cardiovascular Toxicity

• QT interval prolongation and ventricular arrhythmias, including torsades de pointes 1, 2
• FDA has issued safety warnings about QT prolongation risk, especially in patients with:
  • Congenital long QT syndrome
  • Previous history of QT prolongation
  • Family history of long QT syndrome or sudden cardiac death 1
• CYP2D6 poor metabolizers are at higher risk for cardiac complications 1
• Tachycardia and elevated blood pressure can occur in overdose 2, 3

Neurological Toxicity

• Seizures are a common manifestation in overdose 2, 3
• Tremor, movement disorders, and dyskinesias may occur 2, 4
• Behavioral activation/agitation (motor or mental restlessness, insomnia, impulsiveness, disinhibited behavior) 1
• Serotonin syndrome characterized by mental status changes, autonomic instability, and neuromuscular symptoms 5, 6

Fatal Outcomes

• Among 633 adult patients who overdosed on fluoxetine alone, 34 resulted in fatal outcomes 2
• Ingestion as low as 520 mg has been associated with lethal outcome in adults 2
• Six fatalities reported among 156 pediatric overdose cases 2
• A documented case of a 9-year-old with CYP2D6 poor metabolizer phenotype who died after high-dose fluoxetine (80-100 mg/day) treatment, experiencing seizures, status epilepticus, and cardiac arrest 1

Pharmacogenetic Considerations

• CYP2D6 poor metabolizers have significantly higher fluoxetine exposure:
  • 3.9-fold higher area under the curve (AUC) with 20 mg single dose
  • 11.5-fold higher AUC for S-fluoxetine with 60 mg single dose 1
• Long-term fluoxetine use (20 mg/day) can convert approximately 43% of extensive metabolizers to poor metabolizers through auto-inhibition 1
• FDA recommends caution when using fluoxetine in CYP2D6 poor metabolizers due to increased risk of QT prolongation and arrhythmias 1

Overdose Manifestations

• Most common signs of non-fatal overdose: seizures, somnolence, nausea, tachycardia, and vomiting 2
• Other important manifestations include coma, delirium, ECG abnormalities, hypotension, mania, neuroleptic malignant syndrome-like events, pyrexia, stupor, and syncope 2
• Sequelae after overdose can include abnormal accommodation, abnormal gait, confusion, unresponsiveness, nervousness, pulmonary dysfunction, vertigo, tremor, elevated blood pressure, impotence, movement disorder, and hypomania 2

Drug Interactions

• Potentially fatal serotonin syndrome can occur when combined with MAOIs or other serotonergic medications 6
• Documented fatal case when fluoxetine was combined with moclobemide (MAOI), resulting in hyperthermia, rhabdomyolysis, renal failure, and circulatory collapse 6
• Fluoxetine inhibits CYP2D6, potentially increasing levels of other medications metabolized by this pathway 1, 7
• Interactions with L-tryptophan, antidepressants, anxiolytics, calcium channel blockers, and lithium can increase toxicity risk 7

Management of Toxicity

• Monitor cardiac rhythm and vital signs, particularly ECG for QT prolongation 2
• Ensure adequate airway, oxygenation, and ventilation 2
• Activated charcoal may be indicated if administered soon after ingestion 2
• Benzodiazepines (e.g., diazepam) may be effective for fluoxetine-induced seizures 2
• Forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be beneficial due to large volume of distribution 2
• No specific antidotes for fluoxetine toxicity are known 2

Prevention of Toxicity

• Consider CYP2D6 genotyping in patients requiring high doses or experiencing unusual side effects 1
• Start with lower doses and titrate slowly, especially in patients with anxiety disorders 5
• Use caution when prescribing to patients with cardiac risk factors or congenital long QT syndrome 1
• Avoid combining with other serotonergic medications, particularly MAOIs 6, 7