Tamoxifen is a medication commonly prescribed for the treatment or prevention of hormone receptor-positive breast cancer. It is often administered after surgery and/or chemotherapy to reduce the risk of cancer recurrence. Typically, tamoxifen is taken daily for five to ten years, depending on the specific circumstances and medical recommendations.

Women taking tamoxifen must be aware of important drug-drug interactions between tamoxifen and specific antidepressant medications.  Antidepressants are used widely to treat depression and anxiety disorders in women with breast cancer. In addition, multiple studies have shown that SSRI and SNRI antidepressants are an effective non-hormonal treatment for hot flashes.  As hot flashes are a common side effect experienced by women taking tamoxifen, SSRIs and SNRIs are commonly prescribed in this population to manage side effects.

Tamoxifen is a “pro-drug”. In order to be fully effective, tamoxifen must be metabolized to its active metabolite, endoxifen, by the liver enzyme cytochrome P450 2D6 (CYP2D6). Consequently, any co-administered agent that inhibits this enzyme will reduce the conversion of tamoxifen to endoxifen, thereby potentially reducing the efficacy of tamoxifen as a breast cancer therapy.

Antidepressants and Tamoxifen

Many antidepressants, including fluoxetine, paroxetine, and bupropion, are strong 2D6 inhibitors.  Concerns about the use of antidepressants in conjunction with tamoxifen were first raised when several studies (most notably Jin et al, 2005) indicated that in some women taking tamoxifen, the concurrent use of the antidepressants fluoxetine or paroxetine, which are potent CYP2D6 inhibitors, was associated with a significant reduction in circulating endoxifen levels.  

Data regarding the clinical significance of this drug interaction have been conflicting.  Kelly and colleagues found an increased risk of death from breast cancer in women taking paroxetine, a potent inhibitor of CYP2D6.

However, more recent studies have not demonstrated an increase in risk of recurrent breast cancer in women taking tamoxifen along with antidepressants.  

 The largest study to date included 16,887 breast cancer survivors receiving treatment with tamoxifen (Haque et al, 2016).  About half of the women (n = 8099) used antidepressants and 2946 women developed subsequent breast cancer during the 14-year study period.  This study did not observe an increased risk of subsequent breast cancer in women who used tamoxifen and antidepressants, including paroxetine.

In general, it is difficult to assess the clinical impact of this drug interaction.  We can measure levels of endoxifen; however, the clinical impact of any reduction in endoxifen cannot be seen immediately.  The recurrence of breast cancer or cancer-related mortality may occur many decades in the future. This is complicated by the fact that adherence to long-term tamoxifen therapy for early-stage breast cancer is often suboptimal, ranging from 53% to 86%.

In a systematic review, Bradbury and colleagues (2022) included 15 studies (2 randomized controlled trials , 10 retrospective cohort studies, and 3 case-control studies.  Differences in clinical populations and methodology (including analysis of confounding variables) precluded a formal meta-analysis; however, this systematic review, including data from nearly 100,000 patients, observed that the concurrent use of tamoxifen and antidepressants showed no consistent negative effects on clinical outcomes.  The authors note that, given the recognized risks associated with avoiding or switching either endocrine therapy or antidepressants to avoid concurrent use, evidence-based guidelines should be updated to reflect the low risk of adverse events in women combining antidepressants and tamoxifen.

Clinical Recommendations for the Treatment of Depression

Depression is common among women being treated for breast cancer and may be more common in those receiving tamoxifen.  Depression should not be ignored in this situation; a conservative approach to its management would emphasize the careful selection of antidepressants in order to avoid significant interactions.

Certainly we do not recommend the avoidance of antidepressants in women with breast cancer who are taking tamoxifen.  If antidepressants are indicated, we would first consider the patient’s treatment history.  If there is an antidepressant that has been effective for a particular patient in the past, this antidepressant would be a good choice.

Nonetheless, while the findings are reassuring, it is likely that patients and clinicians will hesitate to use strong CYP2D6 inhibitors (fluoxetine, paroxetine, bupropion) in conjunction with tamoxifen.  Thus, we might prefer to use antidepressants that are weak or moderate CYP2D6 inhibitors in this setting. However, the more recent studies are reassuring.  If we find ourselves in a situation where the only effective or tolerable antidepressant happens to be a strong CYP2D6 inhibitor, we can consider the use of these medications, as there is not a consistent pattern of adverse outcomes associated with concurrent use of antidepressants and tamoxifen.

  1. If possible, avoid antidepressants, including fluoxetine, paroxetine, and bupropion, that are strong inhibitors of the CPY2D6 enzyme (see list below).
  2. Antidepressants that are weak (e.g., venlafaxine, desvenlafaxine) or moderate (e.g., citalopram, duloxetine) CPY2D6 inhibitors are preferred.
  3. If the antidepressant is being used solely for the management of hot flashes, other agents, such as gabapentin (Neurontin), may be used instead.  

Antidepressants: Strength of CPY2D6 Inhibition

Strong Inhibitors (Should be avoided if possible):

  • Paroxetine
  • Fluoxetine
  • Bupropion

Moderate Inhibitors:

  • Duloxetine
  • Sertraline
  • Citalopram/Escitalopram
  • Doxepin

Weak Inhibitors (Use not restricted by treatment with tamoxifen):

  • Venlafaxine
  • Desvenlafaxine
  • Fluvoxamine
  • Vortioxetine (Trintellix)
  • Vilazodone (Viibryd)
  • Levomilnacipran (Fetzima)


Read More:

Bradbury M, Hutton B, Beltran-Bless AA, Alzahrani M, Lariviere T, Fernandes R, Ibrahim MF, Cole K, Hilton J, Vandermeer L, Shorr R, Larocque G, Clemons M. Time to Update Evidence-Based Guideline Recommendations About Concurrent Tamoxifen and Antidepressant Use? A Systematic Review. Clin Breast Cancer. 2022 Apr;22(3):e362-e373. 

Flockhart DA, Thacker, D., McDonald, C., Desta, Z. The Flockhart Cytochrome P450 Drug-Drug Interaction Table. Division of Clinical Pharmacology, Indiana University School of Medicine (Updated 2021). 

Cicali EJ, Smith DM, Duong BQ, Kovar LG, Cavallari LH, Johnson JA. A Scoping Review of the Evidence Behind Cytochrome P450 2D6 Isoenzyme Inhibitor Classifications. Clin Pharmacol Ther. 2020 Jul;108(1):116-125. 

Desmarais JE, Looper KJ.  Interactions between tamoxifen and antidepressants via cytochrome P450 2D6.  J Clin Psychiatry. 2009 Dec;70(12):1688-97. 

Haque R, Shi J, Schottinger JE, Ahmed SA, et al. Tamoxifen and Antidepressant Drug Interaction in a Cohort of 16,887 Breast Cancer Survivors.  J Natl Cancer Inst. 2015 Dec 1;108(3).

Nahid NA, Johnson JA. CYP2D6 pharmacogenetics and phenoconversion in personalized medicine. Expert Opin Drug Metab Toxicol. 2022 Nov;18(11):769-785.

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