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Interactions Between Antidepressants and Tamoxifen

Women receiving tamoxifen for the treatment or prevention of breast cancer should be aware of possible drug-drug interactions with specific antidepressant medications (e.g., SSRI). These antidepressants are used widely to treat depression and anxiety disorders. In addition, multiple studies have shown that these 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 for the treatment of breast cancer. It reduces relapse rates of breast cancer and increases overall survival. Tamoxifen is also used to reduce the risk of breast cancer in women at high risk for the disease. Tamoxifen’s effects in the breast depend on its ability to antagonize estrogen. Tamoxifen’s anti-estrogen affinity is thought to depend on the activity of its primary metabolite, endoxifen. Tamoxifen is metabolized to endoxifen through 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 (Jin et al, 2005). Many commonly used antidepressants are CYP2D6 inhibitors, thus clinicians and patients must consider possible interactions when using these treatments in women taking tamoxifen.

In several studies (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. Based on current research, the psychotropic medications which are the strongest CYP2D6 inhibitors include paroxetine, fluoxetine, buproprion, duloxetine, while sertraline, escitalopram, and doxepin are moderate inhibitors, and venlafaxine is a weak inhibitor.

In 2006, an FDA advisory committee debated if the label for tamoxifen should include information about increased risks based on CYP2D6 metabolism. The subcommittee recommended that the label should be updated to reflect an increased risk of treatment failure when tamoxifen is co-administered with potent CYP2D6 inhibitors.

CPY2D6 Inhibitors

Strong Inhibitors (Should be avoided if possible):

Moderate Inhibitors:

  • Sertraline
  • Citalopram/Escitalopram
  • Doxepin

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

If antidepressants are indicated in the treatment of a woman currently taking tamoxifen, the following treatment recommendations have been made:

  1. If possible, avoid antidepressants, including fluoxetine and paroxetine, that are strong inhibitors of the CPY2D6 enzyme (see the list of inhibitors above)
  2. If the antidepressant is being used solely for the management of hot flushes, other agents, such as gabapentin, may be used instead
  3. If it is not possible to avoid these antidepressants, another option for postmenopausal women only would be to switch from tamoxifen to an aromatase inhibitor, if medically appropriate

Erica Pasciullo, BA
Hadine Joffe, MD, MSc

Read More:

Drug-Drug Interactions, specifically with CPY2D6 enzyme: University of Indiana Division of Clinical Pharmacology

Memo to the Media in the Journal of the National Cancer Institute


Preskorn, SH. Clinically relevant pharmacology of selective serotonin reuptake inhibitors. An overview with emphasis on pharmacokinetics and effects on oxidative drug metabolism. Clin Pharmacokinet. 1997;32 Suppl 1:1-21.

Goetz MP, Knox SK, Suman VJ, Rae JM, Safgren SL, Ames MM, Visscher DW, Reynolds C, Couch FJ, Lingle WL, Weinshilboum RM, Fritcher EG, Nibbe AM, Desta Z, Nguyen A, Flockhart DA, Perez EA, Ingle JN.. The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen. Breast Cancer Res Treat. 2007 Jan;101(1):113-21. Epub 2006 Nov 18.

Rapkin, AJ. Vasomotor symptoms in menopause: physiologic condition and central nervous system approaches to treatment. Am J Obstet Gynecol. 2007 Feb;196(2):97-106.

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.

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5 Responses to Interactions Between Antidepressants and Tamoxifen

  1. aki October 28, 2009 at 12:31 pm #

    This article is very very important.I think the oncologist should know, it is not enough the psychiatrist knows about the interactions. It should be mentioned on the label of this group of antidepressants.


  2. Ruth Steinman, MD November 6, 2009 at 9:20 am #

    I have a 38 year old patient with a history of post-partum depression who one month into Tamoxifen treatment developed a severe agitated depression with suicidal ideation. She describes a history of mood changes with BCP use in her twenties. She is high risk for recurrence of breast cancer and her cancer is highly estrogen sensitive, so a decision not to treat with Tamoxifen is a difficult one for her.

    I had a recent patient who developed a similar agitated depression during pregnancy.

    I am wondering if there is a name for this-women who have a CNS extremely vulnerable to hormonal changes who develop an extreme level of agitation.

  3. MGH Center for Women's Mental Health November 13, 2009 at 12:36 pm #

    This is a very interesting observation. While there is no specific name to describe what you have observed, there do seem to be certain women who are more vulnerable to mood changes during hormonal transitions. For example, we sometimes see women with histories of postpartum depression who develop recurrent symptoms during the menopausal transition.

    There is not too much research on this topic. Bloch and colleagues observed that in women with histories of postpartum depression, a similar episode of depression could be elicited by abruptly withdrawal of estrogen.

    Bloch M, Schmidt PJ, Danaceau M, Murphy J, Nieman L, Rubinow DR. Effects of gonadal steroids in women with a history of postpartum depression. Am J Psychiatry. 2000 Jun;157(6):924-30.

  4. Edna Spohn December 17, 2009 at 7:06 pm #

    This article is excellent advice. I am taking Tamoxifen and had just been prescribed Lexapro —- the generic version.
    I did not pick it up at the pharmacy, but brought these articles out to show him that I didn’t think I should be taking that medicine.
    Now is there some risk of taking venlafaxine which is a weak inhibitor which I had been prescribed,but it interfers with my night time sleeping?
    I initially spotted this information in the Fall issue of the CURE magazine

  5. gayle barnett December 22, 2012 at 12:16 am #

    @Edna Spohn,
    I am currently taking fluoxetine, a strong inhibitor, and a doctor has just perscribed tamoxifen. It is my understanding that these two drugs should not be taken together. What was your solution?

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