SSRIs and Tamoxifen
A population-based cohort study has found that paroxetine use during tamoxifen treatment is associated with an increased risk of death from breast cancer.
The study can be read here.
The following commentary for the Australasian Menopause Society has been written by AMS Board member Professor Martha Hickey MBChB MD FRANZCOG.
Breast cancer affects up to one in every eight Australian women. Up to 25% of breast cancer patients also experience a depressive disorder, and selective serotonin reuptake inhibitors (SSRIs) are commonly used in the treatment of depression. More recently, SSRIs have also been widely used in the management of hot flushes in women who wish to avoid taking estrogen-containing treatments, in particular women with a history of breast cancer (1, 2).
The majority of breast cancers are estrogen-receptor positive. Depending on the stage and grade of tumour, many pre-menopausal and some postmenopausal breast cancer patients with estrogen-receptor positive cancer will be advised to take tamoxifen as an anti-estrogen hormone therapy for five years (or more) following surgery and chemoradiation.
There have been recent concerns about a potential interaction between tamoxifen and certain SSRIs. Tamoxifen is a pro-drug that is metabolised by the hepatic cytochrome P450 enzyme system to its clinically active metabolite, endoxifen. Conversion of tamoxifen to its endoxifen is predominantly by the enzyme CYP2D6. Consequently, drugs that inhibit the CYP2D6 enzyme may potentially interfere with conversion of tamoxifen to its clinically active metabolite.
Paroxetine (Aropax) is an extremely potent inhibitor of CYP2D6. Fluoxetine also inhibits conversion, but is less potent. A recent population based cohort study (3) has shown that women with breast cancer who received paroxetine in combination with tamoxifen were at increased risk of death from breast cancer. This risk was not found with other antidepressants, including fluoxetine (Prozac). However, the sample size of fluoxetine users was only half that of paroxetine users. Overall, 30% of patients studied were taking antidepressants at the same time as tamoxifen. The authors estimate that treatment with paroxetine for 41% of tamoxifen therapy (the median in their study) could result in one additional breast cancer death at five years for every 20 women.
This study has implications for clinical practice. Paroxetine should be avoided in women also taking tamoxifen following breast cancer. This recommendation is based on the clinical observations above and biological plausibility. If women taking tamoxifen require an antidepressant, preference should be given to antidepressants which do not inhibit CYP2D6. Antidepressants that are weaker inhibitors of CYP2D6 include citalopram (Celexa), escitalopram (Lexapro), desvenlafaxine (Pristiq), and sertraline (Zoloft). Venlafaxine (Effexor) seems to have little or no effect on CYP2D6. Other drugs which inhibit CYP2D6 are listed here: http://www.hanstenandhorn.com/hh-article03-09.pdf
- Bordeleau L., Pritchard, K., Goodwin, P., Loprinzi, C. Therapeutic options for the management of hot flashes in breast cancer survivors: an evidence-based review. Clin Ther 2007; 29:230-41.
- Hickey, M., Saunders, C.M., Stuckey, B.G. Management of menopausal symptoms in patients with breast cancer: an evidence-based approach. Lancet Oncol 2005; 6:687-95.
- Kelly, C.M., Juurlink, D.N., Gomes, T., Duong-Hua, M., Pritchard, K.I., Austin, P.C., Paszat, L.F. Selective serotonin reuptake inhibitors and breast cancer mortality in women receiving tamoxifen: a population based cohort study. BMJ 2010; 340:c693.
Last updated 27 April 2010