SSRI use with tamoxifen

The SSRI paroxetine (Paxil®) reduces the effect of tamoxifen in women with breast cancer leading to higher breast cancer mortality according to a new study in the British Medical Journal. Concern about SSRIs interfering with the metabolism of tamoxifen was raised last June at the American Society of Clinical Oncology meeting. Tamoxifen is converted from its prodrug to the active metabolite via the cytochrome P450 pathway, specifically CYP2D6. Paroxetine is an exceptionally strong inhibitor of CYP2D6, the strongest inhibitor of all the SSRIs. In the study, Canadian researchers looked at more than 2400 women from Ontario treated with tamoxifen for breast cancer along with a single SSRI. After adjustment for confounders, absolute increases of 25%, 50%, and 75% in the proportion of time on tamoxifen with overlapping use of paroxetine were associated with 24%, 54%, and 91% increases in the risk of death from breast cancer, respectively (P < 0.05, for each comparison). No such risk was seen with any other antidepressant. The authors conclude that paroxetine use during tamoxifen treatments 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 (BMJ 2010;340:c693). The study is important because up to one-quarter of women diagnosed with breast cancer experience a depressive disorder, and antidepressants are commonly used during tamoxifen treatment for not only depression, but also for treatment of hot flashes and other symptoms. It is evident that paroxetine should never be prescribed to women taking tamoxifen for treatment of breast cancer and that preference should be given to antidepressants that show little or no inhibition of CYP2D6. Among the SSRIs, the strongest inhibitors of CYP2D6 besides paroxetine are fluoxetine (Prozac®), duloxetine (Cymbalta®), and to a lesser extent sertraline (Zoloft®). Among non-SSRI antidepressants, bupropion (Wellbutrin®) also is a strong CYP2D6 inhibitor. Drugs that are not inhibitors of the enzyme include citalopram (Celexa®) and venlafaxine (Effexor®).