Antidepressants are used widely to treat depression and anxiety disorders in midlife women and may be an important intervention for managing depression and anxiety in individuals with breast cancer. In addition, SSRI and SNRI antidepressants are effective for the treatment for hot flashes.  Women taking tamoxifen for the treatment or prevention of breast cancer should be aware of possible drug-drug interactions between tamoxifen and specific antidepressant medications.  

Cytochrome P450 2D6 (CYP2D6) Enzymes Convert Tamoxifen to Active Drug  

Tamoxifen is a SERM (selective estrogen receptor modulator) used in women with certain types of hormone receptor-positive breast cancer; it reduces the risk of relapse and improves overall survival.  It is also used to reduce risk for breast cancer in women at high risk for the disease. In order to be fully effective, tamoxifen must be metabolized to an active metabolite, endoxifen, by the liver enzyme cytochrome P450 2D6 (CYP2D6). Consequently, any co-administered medications that inhibit this enzyme will reduce the conversion of tamoxifen to endoxifen and may potentially reduce the efficacy of tamoxifen as a breast cancer therapy.

Over the last few decades, there has been concern about the use of antidepressants in women taking tamoxifen.  This is because many commonly used antidepressants, including fluoxetine, paroxetine, and bupropion, are strong 2D6 inhibitors.  These concerns have resulted in guidelines recommending that antidepressants be avoided or used with caution in women taking tamoxifen. However, there have been few studies examining whether this drug-drug interaction is clinically significant.

In general, it is difficult to assess the clinical impact of this drug interaction.  In several studies (most notably Jin et al, 2005), concurrent use of tamoxifen with the potent CYP2D6-inhibitor antidepressants paroxetine and fluoxetine was associated with a significant reduction in circulating endoxifen levels in some women.  While there is evidence that concurrent administration may lower levels of endoxifen, data regarding the clinical consequences of this drug interaction have yielded conflicting results.  

The clinical impact of any reduction in endoxifen levels cannot be seen immediately.  Reduced efficacy may increase the risk of breast cancer recurrence; however, this outcome may be evident  many decades in the future. Understanding the impact of tamoxifen-antidepressant interactions is further complicated by the fact that adherence to long-term tamoxifen therapy  is often suboptimal, ranging from 53% to 86%.

Other Studies Documenting Clinical Outcomes

In another study, Woolpert and colleagues analyzed 4493 premenopausal women with estrogen receptor-positive breast cancer and examined the impact of combined use of tamoxifen and CYP2D6, CYP2C19, and CYP3A4 inhibiting drugs (antidepressants, as well as other medications) on recurrence.  Bayesian joint modeling was used to generate a more accurate picture of any association between ongoing medication use and recurrence risk by modeling both the treatment patterns and clinical outcomes simultaneously.

During tamoxifen therapy, 13% of the cohort used strong CYP2D6 inhibitors, 31% weak CYP2D6 inhibitors, 37% CYP2C19 inhibitors, and 12% CYP3A4/5 inhibitors. 

Use of CYP2C19 and CYP3A4 inhibiting medications during tamoxifen treatment was not associated with breast cancer recurrence.  Bayesian joint modeling demonstrated that women with more than 50% overlap between tamoxifen and any CYP2D6 inhibitor had increased recurrence risk compared to women with 0% overlap (HR: 1.24, 95% CrI: 0.96, 1.58).  While the authors report a “small increase in risk”, it is important to note that the observed hazard ratio does not reach statistical significance because the confidence interval crosses 1, meaning there is no clear evidence of increased recurrence risk in this analysis.  

Making Sense of The Data    

Depression is relatively common among women diagnosed with breast cancer, and there is a growing body of literature indicating that women with depression experience worse outcomes, including about a 25% increased risk of breast cancer recurrence (Wang et al, 2025). Given this finding, and the fact that untreated depression can have a profound impact on quality of life, we would not recommend withholding treatment for depression.

While pharmacokinetically plausible that some antidepressants may affect levels of tamoxifen’s active metabolites, Bradbury and colleagues note that the concurrent use of antidepressants and tamoxifen does not appear to result in negative outcomes in data analyzed in a systematic review of nearly 100,000 breast cancer patients.  Given the risks associated with avoiding or switching either tamoxifen or antidepressants, Bradbury and colleagues recommend that evidence-based guidelines should be updated to reflect the low risk of adverse events in women combining antidepressants and tamoxifen.

Before and since the publication of the Bradbury study, there have also been some studies suggesting a small increase in risk of breast cancer recurrence in those treated with CYP2D6 inhibitors.  In studies demonstrating an association, the increase in risk has been small, and, in some cases, not statistically significant.  It is plausible that some of the increase in risk seen here is not necessarily related to the antidepressant itself but may reflect the impact of underlying depression or anxiety on risk of recurrence.  Additionally, it is likely that the individuals that use antidepressants are those with more severe symptoms, which may further amplify this association.

So it’s complicated.  The bulk of the information we have regarding the concurrent use of tamoxifen and  CYP2D6 inhibitors is reassuring; however, there are a few studies which may indicate a small risk. Future research may help to clarify and quantify risk, but at the present time, the picture is a bit hazy, with some researchers claiming that the risk is overblown, and others urging caution regarding the use of CYP2D6 inhibitors in women on tamoxifen.

Selection of Antidepressants in Individuals Taking Tamoxifen

As is the case with any treatment decision, one must weigh the risks of the treatment (using antidepressant) with the risks of withholding treatment.  Because untreated depression is associated with worse outcomes in individuals with breast cancer, avoiding antidepressants may not actually be the safest option.  

Overall the data regarding strong CYP2D6 inhibiting antidepressants in women taking tamoxifen is reassuring.  Thus, 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 should be considered.

Given previous recommendations regarding the avoidance of certain antidepressants, it is likely that some patients and clinicians will hesitate to use strong CYP2D6 inhibitors (fluoxetine, paroxetine, bupropion) in conjunction with tamoxifen.  In this setting, using antidepressants that are weak (e.g., venlafaxine, desvenlafaxine, fluvoxamine) or moderate (e.g., citalopram, escitalopram, sertraline, duloxetine) CPY2D6 inhibitors might be preferable.

If the antidepressant is being used solely for the management of hot flashes, other agents, such as gabapentin (Neurontin), which has not impact on the metabolism of tamoxifen, may be used instead.  

Ruta Nonacs, MD PhD

References

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. 

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.

Woolpert KM, Cronin-Fenton DP, Damkier P, Kjærsgaard A, Hamilton-Dutoit S, Ejlertsen B, MacLehose RF, Christiansen P, Silliman RA, Lash TL, Ahern TP, Collin LJ. Drug Interactions With Tamoxifen and Treatment Effectiveness in Premenopausal Breast Cancer Patients: A Bayesian Joint Modeling Approach. Pharmacoepidemiol Drug Saf. 2025 May;34(5):e70157.