Does fluoxetine affect the metabolism of amitriptyline?

Does Fluoxetine Affect Amitriptyline Metabolism?

Yes, fluoxetine significantly inhibits the metabolism of amitriptyline and can increase amitriptyline plasma concentrations 3- to 4-fold, creating substantial risk for toxicity. 1, 2

Mechanism of Interaction

Fluoxetine is a potent inhibitor of CYP2D6, the primary enzyme responsible for metabolizing amitriptyline to its active metabolite nortriptyline. 3, 1 This inhibition occurs through competitive binding, with fluoxetine demonstrating an inhibition constant (Ki) of 0.60 μM against CYP2D6 substrates. 4

• Fluoxetine converts approximately 43% of extensive metabolizers into functional poor metabolizers at doses as low as 20 mg/day, meaning nearly half of patients on fluoxetine will have dramatically reduced CYP2D6 activity. 3, 5

• Both fluoxetine and its active metabolite norfluoxetine are potent CYP2D6 inhibitors, with norfluoxetine showing a Ki of 0.43 μM—actually more potent than the parent compound. 4, 2

• Amitriptyline is metabolized by CYP2D6 and CYP2C19, with CYP2C19 handling N-demethylation of this tertiary amine. 6 Fluoxetine inhibits both pathways, compounding the interaction risk. 7, 8

Clinical Magnitude of the Interaction

When amitriptyline (or its metabolite desipramine) is coadministered with fluoxetine 60 mg/day, plasma concentrations increase approximately 3- to 4-fold. 2 This represents a clinically significant elevation that substantially increases the risk of tricyclic toxicity, including:

• Cardiac arrhythmias and QT prolongation 1
• Anticholinergic toxicity (confusion, urinary retention, tachycardia)
• Seizures
• Sedation and cognitive impairment

Critical Timing Considerations

The interaction persists for approximately 3 weeks after fluoxetine discontinuation due to norfluoxetine's exceptionally long half-life of 4-16 days. 2, 9

• Fluoxetine itself has a half-life of 1-3 days, but norfluoxetine requires 5-7 weeks to reach steady-state and an equivalent time to be eliminated. 9, 3

• If fluoxetine is added to a patient already taking amitriptyline, elevated tricyclic levels will develop gradually over weeks as fluoxetine and norfluoxetine accumulate. 1

• If fluoxetine is discontinued in a patient on amitriptyline, the inhibitory effect will persist for weeks, requiring continued vigilance for tricyclic toxicity. 2

Management Algorithm

If this combination cannot be avoided, reduce the amitriptyline dose by at least 50-75% when initiating fluoxetine, and monitor closely with therapeutic drug monitoring (TDM). 1

1. Before combining: The FDA label explicitly states that therapy with medications predominantly metabolized by CYP2D6 with narrow therapeutic indices (including tricyclic antidepressants) should be initiated at the low end of the dose range if fluoxetine is given concurrently or within the previous 5 weeks. 1

2. If fluoxetine is added to existing amitriptyline: Consider reducing the amitriptyline dose by 50-75% immediately and obtain baseline amitriptyline/nortriptyline levels, then recheck in 2-3 weeks. 1, 2

3. If amitriptyline is added to existing fluoxetine: Start amitriptyline at 25% of the usual starting dose (e.g., 10-12.5 mg instead of 50 mg) and titrate very slowly with TDM guidance. 1

4. Monitor for toxicity: Watch for anticholinergic symptoms, cardiac conduction abnormalities (obtain ECG), sedation, and confusion—especially in the first 4-6 weeks as norfluoxetine accumulates. 1, 2

5. Consider alternatives: Given the magnitude and duration of this interaction, strongly consider using an antidepressant with minimal CYP2D6 inhibition (such as sertraline, citalopram, or escitalopram) instead of fluoxetine when tricyclic coadministration is necessary. 5, 2

Pharmacogenetic Considerations

Patients who are genetically CYP2D6 poor metabolizers face the highest risk, as they already have impaired amitriptyline clearance before fluoxetine is added. 6

• Approximately 5-8% of Caucasians are CYP2D6 poor metabolizers and will have markedly elevated amitriptyline levels even without fluoxetine. 6

• Adding fluoxetine to a CYP2D6 poor metabolizer on amitriptyline creates extreme toxicity risk and should generally be avoided. 3

• If unexpected toxicity occurs at standard doses, consider CYP2D6 genotyping to identify poor metabolizer status. 6, 3

Common Pitfalls

• Underestimating the duration of interaction: Clinicians often fail to recognize that the interaction persists for 3+ weeks after fluoxetine discontinuation due to norfluoxetine's prolonged half-life. 2, 9

• Failure to use TDM: Therapeutic drug monitoring is classified as "useful" for both fluoxetine and tricyclics and should be employed when combining these agents. 6

• Ignoring multiple enzyme inhibition: Fluoxetine also inhibits CYP2C19 (which demethylates amitriptyline) and CYP3A4 to a lesser extent, compounding the interaction beyond CYP2D6 alone. 7, 8