Tamoxifen is a selective estrogen receptor modulator (or SERM) which is used for the treatment and prevention of breast cancer. Tamoxifen’s effects in the breast depend on its ability to antagonize estrogen, and this anti-estrogenic activity is generated when tamoxifen is metabolized to its active metabolite, endoxifen, by the liver enzyme CYP2D6. Consequently, any co-administered agent that inhibits this enzyme may reduce the conversion of tamoxifen to endoxifen, thereby potentially reducing the efficacy of tamoxifen as a breast cancer therapy (Jin et al, 2005).

Many commonly used antidepressants are CYP2D6 inhibitors and are used widely to treat depression and anxiety disorders in women with breast cancer. In addition, multiple studies have shown that serotonin reuptake inhibitor (SRI) antidepressants are an effective non-hormonal treatment for the hot flashes which commonly occur in women taking tamoxifen.

In 2006, an FDA advisory committee recommended that the product label for tamoxifen should be updated to reflect an increased risk of treatment failure when tamoxifen is co-administered with potent CYP2D6 inhibitors. This recommendation was based on data from several studies (notably Jin et al, 2005), which concluded when tamoxifen was co-administered with strong CYP2D6-inhibitor antidepressants, specifically paroxetine and fluoxetine, there was a significant reduction in circulating endoxifen levels in some women.  These earlier studies, however, did not assess long-term clinical outcomes.

A recent study looked at rates of breast cancer recurrence in women taking antidepressants.  The study included 16,887 women with early stage breast cancer who took tamoxifen for an average of three years. Nearly half (n=8089) of the women also took antidepressants.  During the 14-year follow-up period, breast cancer recurred in 2946 women. Recurrence rates were similar in women who took antidepressants versus those who did not.  Recurrence rates were similar across all types of antidepressant used, including the potent CYP2D6 inhibitors, paroxetine and fluoxetine.

This is the largest study to date assessing clinical outcomes in women taking tamoxifen and antidepressants concurrently.  While the findings of this study are very reassuring, a previous study demonstrated an increased risk of death from breast cancer in women treated with tamoxifen and paroxetine (Kelly et al, 2010).  Given the inconsistencies among these clinical studies and the fact that we have many antidepressants to choose from, I am inclined to be cautious in this setting and to follow the original recommendations, which suggested avoiding strong CYP2D6 inhibitors: paroxetine, fluoxetine, bupropion, and duloxetine. However, one must acknowledge that there may be situations where a woman responds better to one of the potent CYP2D6 inhibitors than to other antidepressants.

Ruta Nonacs, MD PhD

Haque R, Shi J, Schottinger JE, et al.  Tamoxifen and Antidepressant Drug Interaction in a Cohort of 16887 Breast Cancer Survivors.  J Natl Cancer Inst. 2016; 108(3).