Can rasagiline be combined with fluoxetine (selective serotonin reuptake inhibitor)?

Combining Rasagiline with Fluoxetine: Serious Risk of Serotonin Syndrome

Rasagiline should not be combined with fluoxetine due to the significant risk of potentially life-threatening serotonin syndrome. 1

Mechanism and Risk

Rasagiline is a selective MAO-B inhibitor at recommended doses (0.5-1mg daily), but this selectivity diminishes as doses increase. The FDA label explicitly warns about serotonin syndrome when combining rasagiline with SSRIs like fluoxetine 1. This dangerous drug interaction occurs because:

• Rasagiline inhibits the breakdown of serotonin by blocking MAO-B
• Fluoxetine increases serotonin levels by blocking its reuptake
• The combination leads to excessive serotonergic activity in the CNS

Evidence of Harm

Case reports document serious adverse outcomes when combining MAO-B inhibitors with SSRIs:

• A 77-year-old man developed serotonin syndrome with high-grade fever, confusion, agitation, hallucinations, and acute kidney injury just two days after adding rasagiline to ongoing escitalopram treatment 2
• A recent 2024 case report describes serotonin syndrome in a Parkinson's patient triggered by the interaction between rasagiline and buspirone (another serotonergic agent) 3

Clinical Manifestations of Serotonin Syndrome

If serotonin syndrome occurs, patients may experience:

• Behavioral/cognitive changes: confusion, agitation, hallucinations, delirium, headache, coma
• Autonomic effects: syncope, shivering, sweating, hyperthermia, hypertension, tachycardia, nausea, diarrhea
• Somatic effects: muscular rigidity, myoclonus, muscle twitching, hyperreflexia, tremor 1

Alternative Approaches

For patients requiring both Parkinson's disease and depression treatment:

1. For Parkinson's disease: Consider alternative antiparkinsonian medications that don't have MAO-inhibiting properties

2. For depression/OCD treatment:

   • CBT is recommended as first-line treatment for anxiety disorders 4
   • If medication is necessary, consider non-SSRI antidepressants with lower serotonergic activity

Important Precautions

If transitioning between these medications:

• Allow at least 14 days between discontinuing rasagiline and starting fluoxetine 1
• Allow at least 5 weeks between discontinuing fluoxetine (due to its long half-life) and starting rasagiline 1

Research Considerations

While one retrospective study (STACCATO) found no cases of serotonin syndrome among patients taking rasagiline with antidepressants 5, and animal studies suggest rasagiline may have less risk than selegiline 6, the FDA label contraindication and documented case reports of serious adverse events outweigh these findings.

The potential consequences of serotonin syndrome are severe and can be fatal. Given the availability of alternative treatment options for both conditions, the combination of rasagiline and fluoxetine should be avoided in clinical practice.