What is the recommended protocol for switching a patient from fluoxetine (Prozac) 60 mg to vortioxetine (Trintellix)?

Switching from Fluoxetine 60 mg to Vortioxetine

Due to fluoxetine's exceptionally long half-life (4-16 days for the active metabolite norfluoxetine), you must implement a conservative taper-and-washout strategy rather than direct cross-titration to avoid serotonin syndrome and drug interactions. 1, 2

Recommended Switching Protocol

Step 1: Reduce Fluoxetine Dose

• Decrease fluoxetine from 60 mg to 40 mg daily for 1 week 3
• Then reduce to 20 mg daily for an additional 1-2 weeks 3, 2
• This gradual taper minimizes discontinuation symptoms including headache, dizziness, anxiety, and irritability 3

Step 2: Washout Period

• After the final fluoxetine dose, wait a minimum of 14 days (preferably 21 days) before initiating vortioxetine 1, 2
• This washout is critical because fluoxetine is a potent CYP2D6 inhibitor that will significantly elevate vortioxetine levels if co-administered 1, 4
• The FDA label explicitly states that when switching FROM fluoxetine to another antidepressant, at least 21 days should elapse to avoid drug interactions 1

Step 3: Initiate Vortioxetine

• Start vortioxetine at 10 mg once daily 1
• After 1 week, increase to 20 mg daily as tolerated, which is the target therapeutic dose for most patients 1, 5
• Vortioxetine reaches steady-state within 2 weeks at a given dose 4

Critical Drug Interaction Consideration

The FDA label for vortioxetine specifically identifies fluoxetine as a strong CYP2D6 inhibitor requiring dose reduction of vortioxetine by one-half if co-administered. 1 This is why direct cross-titration is contraindicated—fluoxetine's persistent CYP2D6 inhibition (lasting weeks after discontinuation due to the long half-life) will cause vortioxetine levels to approximately double, increasing adverse effects including nausea, vomiting, and serotonin syndrome risk. 1, 4

Monitoring During the Switch

• Assess for discontinuation syndrome weekly during the fluoxetine taper, particularly dizziness, anxiety, irritability, sensory disturbances, and headache 3
• Monitor for depressive symptom exacerbation during the washout period, as this represents 3-5 weeks without active antidepressant coverage 2
• Evaluate for serotonin syndrome symptoms in the first 2 weeks after starting vortioxetine, including mental status changes, neuromuscular hyperactivity, and autonomic instability 3, 2
• Use standardized rating scales (PHQ-9, HAM-D) every 2 weeks to objectively track symptom changes 6

Special Consideration for CYP2D6 Poor Metabolizers

If the patient is a known CYP2D6 poor metabolizer (or develops unexpected adverse effects suggesting this phenotype), limit vortioxetine to a maximum dose of 10 mg daily rather than increasing to 20 mg. 1 Poor metabolizers have 3.9 to 11.5-fold higher fluoxetine levels, and this genetic variant also affects vortioxetine metabolism. 3, 1

Common Pitfalls to Avoid

• Do not attempt direct cross-titration or overlap the medications—the combination of fluoxetine and vortioxetine creates unacceptable serotonin syndrome risk and will double vortioxetine exposure 1, 2
• Do not shorten the washout period below 14 days—fluoxetine's active metabolite persists for weeks and continues to inhibit CYP2D6 1, 4
• Do not abruptly discontinue fluoxetine 60 mg—this high dose requires gradual taper to minimize withdrawal symptoms 3, 2

Expected Timeline

The complete switch will require 4-6 weeks total: 2-3 weeks for fluoxetine taper, 2-3 weeks washout, then vortioxetine initiation. 1, 2 While this prolonged timeline increases the risk of symptom exacerbation during the washout period, it is necessary to ensure patient safety and avoid serious drug interactions. 2