Which antidepressants inhibit the cytochrome P450 2D6 (CYP2D6) enzyme?

Antidepressants That Inhibit CYP2D6

Fluoxetine and paroxetine are the most potent CYP2D6 inhibitors among antidepressants, while sertraline is a moderate inhibitor, and citalopram and escitalopram have minimal inhibitory effects on CYP2D6. 1, 2

Strong CYP2D6 Inhibitors

• Paroxetine - Potent CYP2D6 inhibitor that can significantly increase plasma concentrations of CYP2D6 substrates 3, 2
• Fluoxetine - Potent CYP2D6 inhibitor with a long-acting metabolite (norfluoxetine) that prolongs the inhibitory effect for weeks after discontinuation 2, 4

Moderate CYP2D6 Inhibitors

• Sertraline - Moderate inhibitor of CYP2D6, with less pronounced effects than fluoxetine or paroxetine 2, 5
• Fluvoxamine - Moderate CYP2D6 inhibitor, though it more potently inhibits CYP1A2 and CYP2C19 2, 6

Minimal CYP2D6 Inhibitors

• Citalopram/Escitalopram - Minimal effect on CYP2D6, making them preferred choices when CYP2D6 interactions are a concern 2, 6
• Desvenlafaxine - SNRI with the least interaction with CYP2D6 7

Clinical Significance of CYP2D6 Inhibition

Impact on Drug Metabolism

CYP2D6 is responsible for metabolizing approximately 25% of all prescribed medications 7. When CYP2D6 inhibitors are co-administered with CYP2D6 substrates, they can:

1. Increase plasma concentrations of the substrate drug
2. Enhance therapeutic effects or increase risk of adverse effects
3. Alter pharmacokinetic profiles of the substrate drug

Specific Drug Interactions

When prescribing antidepressants that inhibit CYP2D6, be cautious with co-administration of:

• Tricyclic antidepressants - Plasma TCA concentrations may need monitoring and dose reduction 3, 4
• Antipsychotics - Risperidone concentrations can increase approximately 4-fold with paroxetine 3
• Tamoxifen - Reduced efficacy due to decreased conversion to active metabolite endoxifen 7, 3
• Type 1C antiarrhythmics (propafenone, flecainide) - Increased risk of toxicity 3
• Beta-blockers - Metoprolol levels can increase two-fold with citalopram 8

Potential Serious Consequences

In extreme cases, CYP2D6 inhibition has been associated with:

• QT prolongation
• Cardiac arrhythmias
• Seizures
• Fatalities due to drug accumulation 1, 7

Clinical Recommendations

1. When CYP2D6 interactions are a concern:

   • Choose antidepressants with minimal CYP2D6 inhibition (citalopram, escitalopram, desvenlafaxine)
   • For patients on tamoxifen, avoid strong CYP2D6 inhibitors (paroxetine, fluoxetine) 7

2. When prescribing strong CYP2D6 inhibitors:

   • Consider dose adjustments for co-administered CYP2D6 substrates
   • Monitor for increased side effects or altered efficacy
   • Be aware that fluoxetine's inhibitory effects can persist for weeks after discontinuation due to its long half-life 2, 4

3. For patients with known CYP2D6 poor metabolizer status:

   • Avoid high-dose fluoxetine or paroxetine due to risk of metabolic toxicity 1
   • Consider preferentially using desvenlafaxine 7

Common Pitfalls to Avoid

1. Overlooking the duration of inhibition - Fluoxetine's inhibitory effects can persist for approximately 3 weeks after discontinuation due to its active metabolite norfluoxetine 4

2. Ignoring the clinical context - The significance of CYP2D6 inhibition depends on the therapeutic index of the co-administered drug and the extent of inhibition 4

3. Failing to recognize "phenocopying" - Long-term high-dose fluoxetine can produce an auto-phenocopy that further inhibits CYP2D6, potentially contributing to toxicity 1

By understanding the differential effects of antidepressants on CYP2D6, clinicians can make more informed decisions to minimize the risk of drug interactions and optimize treatment outcomes.