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Tamoxifen-SSRIs interaction: Clinical manifestations of inhibition and lack of inhibition of CYP2D6

Francisco Appiani, MD

Universidad de Buenos Aires, Facultad de Medicina, Buenos Aires, Argentina

Brendan T. Carroll, MD

Ohio University, College of Osteopathic Medicine, Athens, OH, USA, Veterans Affairs Medical Center, Chillicothe, OH, USA

Camilo Muñoz,, MD

Hospital Lucio Molas Santa Rosa, Neurocognitive Rehabilitation Section, Santa Rosa, La Pampa, Argentina

Juan Trecco, MD

Asociación Civil para el Estudio, y Desarrollo de las Neurociencias, (ACEDEN), Trenque Lauquen, Buenos Aires, Argentina

KEYWORDS: tamoxifen, breast cancer, metabolism



Tamoxifen is an estrogen receptor modulator that is used for the treatment of hormone receptor positive breast cancer. As a prodrug, treatment efficacy may be mediated by 2 active metabolites: 4-hydroxytamoxifen (4-OH-TAM) and 4-hydroxy-N-desmethyltamoxifen (endoxifen). These metabolites have at least 100-fold higher potency than the parent drug, and in vitro studies have demonstrated that cytochrome P450 2D6 (CYP2D6) is responsible for tamoxifen metabolism.1,2

There are reports that patients who are CYP2D6 poor metabolizers have a higher risk of relapse and lower incidence of hot flashes with tamoxifen treatment. This is in part because of lower levels of endoxifen.2

Depressive symptoms are a frequent complication of breast cancer and many patients are treated with selective serotonin reuptake inhibitors (SSRIs). Moreover, SSRIs also are used to treat hot flashes, a common side effect of tamoxifen.3

The SSRIs paroxetine and fluoxetine are considered strong CYP2D6 inhibitors. The inhibition of CYP2D6 may decrease tamoxifen metabolites and may adversely affect the efficacy of breast cancer treatment.3


We describe the case of Ms. W, age 47, who was diagnosed with estrogen receptor positive intraductal carcinoma in situ. She was treated with surgery and tamoxifen, 20 mg/d. After a month of treatment, Ms. W complained of hot flashes and mood symptoms. She was diagnosed with a major depressive episode and started on paroxetine, 20 mg/d. With this pharmacological regimen she stabilized within a month, and her hot flashes disappeared.

Because of potential consequences of tamoxifen-paroxetine interaction, it was decided to replace paroxetine with citalopram, 20 mg/d. With this drug Ms. W remained euthymic, but she started to experience hot flashes again. It was decided to continue with the same treatment, because she said her hot flashes were tolerable.

This case could be an example of clinical manifestations of inhibition of the CYP450 system during tamoxifen-paroxetine interaction. Paroxetine is a CYP2D6 inhibitor that decreases tamoxifen active metabolites. It is interesting to note that Ms. W had better treatment tolerance when she was treated with paroxetine. The same occurs with genetically determined poor metabolizers (CYP2D6 *4/*4 genotype). Therefore, it is possible to speculate that the absence of hot flashes during tamoxifen treatment could be related to low levels of active metabolites because of paroxetine’s CYP2D6 in-hibition. On the other hand, citalopram may have released metabolism inhibition and lead to the reemergence of tamoxifen side effects. This clinical situation can be seen as a possible increase in tamoxifen effect and could be associated with a better outcome.

DISCLOSURES: The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.


  1. Jin Y, Desta Z, Stearns V, et al. CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst. 2005;97:30–39.
  2. Jordan VC. New insights into the metabolism of tamoxifen and its role in the treatment and prevention of breast cancer. Steroids. 2007;72:829–842.
  3. Henry NL, Stearns V, Flockhart DA, et al. Drug interactions and pharmacogenomics in the treatment of breast cancer and depression. Am J Psychiatry. 2008;165:1251–1255.

CORRESPONDENCE: Brendan T. Carroll, MD, Ohio University College of Osteopathic Medicine, Athens, OH, USA, Veterans Affairs Medical Center, 116A, 17273 State Route 104, Chillicothe, OH 45601, USA, E-MAIL: