An updated version of this post can be found HERE.
Tamoxifen is a SERM (selective estrogen receptor modulator) used in women with breast cancer; it reduces the risk of relapse and improves overall survival. Tamoxifen may also be used to reduce the risk of 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 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, but not all, commonly used antidepressants are CYP2D6 inhibitors. Many women with breast cancer take antidepressants to treat mood and anxiety disorders; in addition, SSRI and SNRI antidepressants are also used widely as non-hormonal treatments for hot flashes. Over 25% of women who are experiencing hot flashes related to tamoxifen therapy are now prescribed antidepressants to manage their symptoms.
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 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 published in the British Medical Journal provides evidence that antidepressants which are potent inhibitors of CYP2D6 enzymes may decrease the effectiveness of tamoxifen and may result in worse outcomes.
In this retrospective, population-based study, Kelly and colleagues analyzed data from a total of 24,430 women (66 years or older) treated for breast cancer with tamoxifen over a 13-year period (1993 to 2005). Of these women, 30.6% received at least one antidepressant during the time they were taking tamoxifen. The most commonly prescribed antidepressant was paroxetine (in 25.9%), followed by sertraline (22.3%), citalopram (19.2%), venlafaxine (15%), fluoxetine (10.4%), and fluvoxamine (7.2%). Tricyclic antidepressants were prescribed in 18.3% of women. Women with poor adherence to tamoxifen and those who died from unknown causes were excluded from the analysis. Subjects were followed from the index date until death from breast cancer or the end of the study period, whichever occurred first.
Of the 2,430 women treated with tamoxifen and a single SSRI, 374 (15.4%) died of breast cancer during follow-up; mean follow-up time was 2.38 years. After adjusting for age, duration of tamoxifen treatment, and other potential confounders, researchers found an increased risk of death from breast cancer in women taking paroxetine, a potent inhibitor of CYP2D6). In contrast, no increased risk of breast cancer mortality was associated with exposure to the other antidepressants during tamoxifen treatment.
The study showed that the only antidepressant which increased the risk for breast cancer death was paroxetine. Fluoxetine, a strong inhibitor of CYP2D6, did not affect risk; however, the authors speculate that this finding may be due to the small number of women taking fluoxetine in this study. The authors conclude by recommending that clinicians avoid using any drugs which are strong inhibitors of CYP2D6. This recommendation is supported also by the finding of Goetz and colleagues who demonstrated that women lacking the CYP2D6 enzyme function (poor metabolizers) had an almost 2-fold increased risk of recurrent breast cancer, compared with women who had full CYP2D6 function (good metabolizers).
While some articles have advocated the avoidance of all SSRI antidepressants, 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 section of co-administered to avoid significant interactions.
1. If possible, avoid antidepressants, including fluoxetine and paroxetine,that are strong inhibitors of the CPY2D6 enzyme (see list below).
2. If the antidepressant is being used solely for the management of hot flushes, other agents, such as gabapentin (Neurontin), may be used instead.
3. If it is not possible to avoid these antidepressants, 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):
• Paroxetine (Paxil)
• Fluoxetine (Prozac)
• Bupropion (Wellbutrin)
• Duloxetine (Cymbalta)
• Sertraline (Zoloft)
• Citalopram/Escitalopram (Celexa/Lexapro)
• Doxepin (Sinequan)
Weak Inhibitors (Use not restricted by treatment with tamoxifen):
• Venlafaxine (Effexor)
• Desvenlafaxine (Pristiq)
Ruta Nonacs, MD, PhD
Hadine Joffe, MD, MSc
Goetz MP, Rae JM, Suman VJ, et al. Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. J Clin Oncol 23:9312-9318, 2005
Jin Y, Desta Z, Stearns V, Ward B, Ho H, Lee KH, Skaar T, Storniolo AM, Li L, Araba A, Blanchard R, Nguyen A, Ullmer L, Hayden J, Lemler S, Weinshilboum RM, Rae JM, Hayes DF, Flockhart DA. CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst. 2005 Jan 5;97(1):30-9.
Kelly CM, Juurlink DN, Gomes T, Duong-Hua M, Pritchard KI, Austin PC, Paszat LF.