by Dr. Leo Galland
Women with breast cancer are often treated with the drug tamoxifen, which blocks the effects of estrogen on breast cancer cells. Tamoxifen, however, only becomes effective after it is converted to an active metabolite in the liver.
This conversion is performed by an enzyme called CYP2D6. Several popular antidepressant drugs such as Prozac (fluoxetine) and Paxil (paroxetine) block CYP2D6 and interfere with the effectiveness of tamoxifen, potentially leading to an increase in the risk of death from breast cancer.
A recent review from McGill University in Montreal, Canada, expressed concern about the antidepressants Prozac (fluoxetine) and Paxil (paroxetine), because they strongly inhibit CYP2D6 and are often given to women for depression, anxiety or hot flashes. Writing in the Journal of Clinical Psychiatry, the researchers note: “There is consistent evidence that paroxetine and fluoxetine have a large effect on the metabolism of tamoxifen and should not be used.” (Desmarais et al.)
A recent study from Sunnybrook University in Toronto, Canada, and published in the British Medical Journal (BMJ) concluded that “Paroxetine use during tamoxifen treatment is associated with an increased risk of death from breast cancer, supporting the hypothesis that paroxetine can reduce or abolish the benefit of tamoxifen in women with breast cancer.” (Kelly et al.)
This research provides a strong warning that the antidepressants Prozac (fluoxetine) and Paxil (paroxetine) should not be taken while undergoing treatment with tamoxifen.
References and Abstracts:
J Clin Psychiatry. 2009 Dec;70(12):1688-1697. Interactions between tamoxifen and antidepressants via cytochrome P450 2D6.
Desmarais JE, Looper KJ.McGill University, Research and Training Building, 1033 Pine Avenue West, Room 107, Montreal, Quebec, Canada H3A 1A1. firstname.lastname@example.org.
OBJECTIVE: Women taking tamoxifen for the treatment or prevention of recurrence of breast cancer are likely to take antidepressants either for a psychiatric disorder or for hot flashes. Recent evidence suggested that some antidepressants inhibit the metabolism of tamoxifen to its more active metabolites by the cytochrome P450 2D6 (CYP2D6) enzyme, thereby decreasing the anticancer effect. This article reviews the literature on the interactions between newer antidepressants and tamoxifen via CYP2D6 and offers treatment recommendations.
DATA SOURCES: A literature search of clinical and nonclinical studies published prior to September 2008 was conducted on PubMed. We performed 3 different searches combining the terms tamoxifen and SSRIs; tamoxifen and CYP2D6 inhibitors; and antidepressant and breast cancer recurrence. A fourth search with CYP2D6 inhibition and the generic names of individual antidepressants was carried out.
STUDY SELECTION: Seven clinical research articles were selected. Nonclinical research articles about antidepressants were included if they mentioned in vitro or in vivo inhibition of CYP2D6.
DATA SYNTHESIS: There is consistent evidence that paroxetine and fluoxetine have a large effect on the metabolism of tamoxifen and should not be used. Indirect evidence indicates that bupropion may also have a large effect on the metabolism of tamoxifen. Venlafaxine has little or no effect on the metabolism of tamoxifen and may be considered the safest choice of antidepressants. Desvenlafaxine is not metabolized by the P450 system and may consequently be another option. Mirtazapine has not been extensively studied, but existing research suggests minimal effect on CYP2D6. The remaining commonly prescribed antidepressants have mild to moderate degrees of CYP2D6 inhibition.
CONCLUSIONS: Clinicians treating patients with breast cancer should review the prescription profiles of their patients to evaluate the need for treatment modification. There are safe options for the treatment of depression and clinicians and patients should bear in mind the health risks of untreated depressive states.
BMJ. 2010 Feb 8;340:c693. doi: 10.1136/bmj.c693. Selective serotonin reuptake inhibitors and breast cancer mortality in women receiving tamoxifen: a population based cohort study.
Kelly CM, Juurlink DN, Gomes T, Duong-Hua M, Pritchard KI, Austin PC, Paszat LF. Department of Medicine, Sunnybrook Health Sciences Centre, Toronto, Canada.
OBJECTIVE: To characterise whether some selective serotonin reuptake inhibitor (SSRI) antidepressants reduce tamoxifen’s effectiveness by inhibiting its bioactivation by cytochrome P450 2D6 (CYP2D6).
DESIGN: Population based cohort study.
PARTICIPANTS: Women living in Ontario aged 66 years or older treated with tamoxifen for breast cancer between 1993 and 2005 who had overlapping treatment with a single SSRI.
MAIN OUTCOME MEASURES: Risk of death from breast cancer after completion of tamoxifen treatment, as a function of the proportion of time on tamoxifen during which each SSRI had been co-prescribed.
RESULTS: Of 2430 women treated with tamoxifen and a single SSRI, 374 (15.4%) died of breast cancer during follow-up (mean follow-up 2.38 years, SD 2.59). After adjustment for age, duration of tamoxifen treatment, and other potential confounders, absolute increases of 25%, 50%, and 75% in the proportion of time on tamoxifen with overlapping use of paroxetine (an irreversible inhibitor of CYP2D6) were associated with 24%, 54%, and 91% increases in the risk of death from breast cancer, respectively (P<0.05 for each comparison). By contrast, no such risk was seen with other antidepressants. We estimate that use of paroxetine for 41% of tamoxifen treatment (the median overlap in our sample) would result in one additional breast cancer death within five years of cessation of tamoxifen for every 19.7 (95% confidence interval 12.5 to 46.3) patients so treated; the risk with more extensive overlap would be greater.
CONCLUSION: Paroxetine use during tamoxifen treatment is associated with an increased risk of death from breast cancer, supporting the hypothesis that paroxetine can reduce or abolish the benefit of tamoxifen in women with breast cancer.