What is the interaction between Tamoxifen and Selective Serotonin Reuptake Inhibitors (SSRIs)?

From the Guidelines

Tamoxifen and certain SSRIs, such as paroxetine and fluoxetine, should not be used together due to potential drug interactions that can reduce tamoxifen's effectiveness in breast cancer treatment. The most recent and highest quality study, published in 2024 1, suggests that strong CYP2D6 inhibitors like paroxetine and fluoxetine can decrease conversion of tamoxifen to its active metabolite endoxifen, potentially limiting tamoxifen efficacy.

Key Considerations

• If an antidepressant is needed for a patient on tamoxifen, prefer SSRIs with minimal CYP2D6 inhibition such as citalopram, escitalopram, or non-SSRI alternatives like venlafaxine, desvenlafaxine, or mirtazapine.
• For patients experiencing hot flashes from tamoxifen who might otherwise receive an SSRI, consider gabapentin (300-900 mg daily) or venlafaxine (37.5-75 mg daily) as safer alternatives.
• The interaction between tamoxifen and SSRIs occurs because tamoxifen is a prodrug that requires metabolic activation through the CYP2D6 enzyme system, and strong inhibitors of this pathway can significantly reduce the clinical benefit of tamoxifen therapy, potentially increasing cancer recurrence risk.

Management Recommendations

• Always consult with both the patient's oncologist and psychiatrist when managing these medication combinations to ensure optimal cancer treatment while addressing mental health needs.
• Avoid potent and intermediate CYP2D6 inhibiting agents, particularly paroxetine and fluoxetine, if an appropriate alternative exists 1.
• Consider the use of mild CYP2D6 inhibitors such as citalopram, escitalopram, sertraline, and venlafaxine, which appear to have no or only minimal effect on tamoxifen metabolism 1.

From the Research

Tamoxifen and SSRI Use

• The use of selective serotonin reuptake inhibitors (SSRIs) with tamoxifen has been a topic of discussion due to the potential interaction between the two medications 2, 3, 4, 5, 6.
• Tamoxifen is metabolized by the cytochrome P450 2D6 (CYP2D6) enzyme to its active form, endoxifen, and some SSRIs can inhibit this enzyme, potentially reducing the effectiveness of tamoxifen 3, 4, 5.
• Studies have shown that certain SSRIs, such as paroxetine and fluoxetine, should be avoided in patients taking tamoxifen due to their strong inhibition of CYP2D6 3, 4, 5.
• Other SSRIs, such as citalopram, desvenlafaxine, escitalopram, milnacipran, and venlafaxine, are recommended as they do not significantly inhibit CYP2D6 and are less likely to interact with tamoxifen 2, 4, 5.
• A large cohort study of 16,887 breast cancer survivors found no significant increased risk of subsequent breast cancer in women who concurrently used paroxetine and tamoxifen 6.
• The study also found that the use of other antidepressants, including other SSRIs, did not increase the risk of subsequent breast cancer in women taking tamoxifen 6.

Recommendations for SSRI Use with Tamoxifen

• Patients taking tamoxifen should be carefully evaluated for the need for SSRI therapy, and alternative medications should be considered if possible 3, 4, 5.
• If SSRI therapy is necessary, medications that are less likely to inhibit CYP2D6, such as citalopram or venlafaxine, should be chosen 2, 4, 5.
• Patients should be closely monitored for signs of reduced tamoxifen efficacy, such as increased risk of breast cancer recurrence, if they are taking SSRIs that inhibit CYP2D6 3, 4, 5.