Women receiving tamoxifen for the treatment or prevention of breast cancer should be aware of possible drug-drug interactions between tamoxifen and specific antidepressant medications. Antidepressants are used widely to treat depression and anxiety disorders in midlife women. In addition, multiple studies have shown that SSRI and SNRI antidepressants are an effective non-hormonal treatment for hot flashes; over 25% of women who are experiencing hot flashes related to tamoxifen therapy are now prescribed antidepressants to manage their symptoms.
Tamoxifen is a SERM (selective estrogen receptor modulator) used in women with breast cancer; it reduces the risk of relapse and improves overall survival and 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 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.
Many antidepressants, including fluoxetine, paroxetine, and bupropion, are strong 2D6 inhibitors. 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. Data regarding the clinical consequences of this drug interaction are conflicting; however, Kelly and colleagues found an increased risk of death from breast cancer in women taking paroxetine, a potent inhibitor of CYP2D6.
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%.
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 co-administered antidepressants in order to avoid significant interactions.
- If possible, avoid antidepressants, including fluoxetine and paroxetine,that are strong inhibitors of the CPY2D6 enzyme (see list below).
- If the antidepressant is being used solely for the management of hot flashes, other agents, such as gabapentin (Neurontin), may be used instead.
- If it is not possible to avoid antidepressants which are strong 2D6 inhibitors, another option for post-menopausal women only would be to switch from tamoxifen to an aromatase inhibitor, if medically appropriate.
Strong Inhibitors (Should be avoided if possible):
Weak Inhibitors (Use not restricted by treatment with tamoxifen):
- Vilazodone (Viibryd)
- Levomilnacipran (Fetzima)
Ruta Nonacs, MD PhD
Drug-Drug Interactions, specifically with CPY2D6 enzyme: University of Indiana Division of Clinical Pharmacology
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). Free Article
I am unfamiliar with labeling citalopram/escitalopram as moderate CYP2D6 inhibitors. Review of your references suggest this may be an error as the Indiana cyp table has a green box next to them labeling them as mild inhibitors. From memory I don’t believe the FDA classifies them as moderate CYP2D6 inhibitors either for purposes of drug drug interaction study guidance.
Good pickup. It is not an error, but there is some variation in the literature regarding the classification of citalopram with regard to 2D6 inhibition. This may be related to methodology (in vivo and in vitro studies) and dosage. In clinical articles, I have seen citalopram on the list of low and moderate inhibitors. I ultimately chose to use the designation used in the studies which studied its effects in women taking tamoxifen.
Based on the clinical studies, both low and moderate 2D6 can be co-prescribed with tamoxifen.
Also, I do not believe that this information is required by the FDA.
Vortioxetine is listed as (Viibryd) and Vilazodone as (Trintellix)…that is an error