tamoxifen into its active forms. A U.S. study presented at the American Society of Clinical Oncology's annual meeting in 2009 found that after two years, 7.5% of women who took only tamoxifen had a recurrence, compared with 16% who took either paroxetine, fluoxetine or sertraline, drugs considered to be the most potent CYP2D6 inhibitors. That difference translates to a 120% increase in the risk of breast cancer recurrence. Patients taking the SSRIs Celexa (citalopram), Lexapro (escitalopram), and Luvox (fluvoxamine) did not have an increased risk of recurrence, due to their lack of competitive metabolism for the CYP2D6 enzyme. A newer study demonstrated a clearer and stronger effect from paroxetine in causing the worst outcomes. Patients treated with both paroxetine and tamoxifen have a 67% increased risk of death from breast cancer, from 24% to 91%, depending on the duration of coadministration. Tamoxifen interacts with certain other antiestrogens. The aromatase inhibitor aminoglutethimide induces the metabolism of tamoxifen. Conversely, the aromatase inhibitor letrozole does not affect the metabolism of tamoxifen. However, tamoxifen induces the metabolism of letrozole and significantly reduces its concentrations. Pharmacology Pharmacodynamics Selective estrogen receptor modulator activity Tamoxifen acts as a selective estrogen receptor modulator (SERM), or as a partial agonist of the estrogen receptors (ERs). It has mixed estrogenic and antiestrogenic activity, with its profile of effects differing by tissue. For instance, tamoxifen has predominantly antiestrogenic effects in the breasts but predominantly estrogenic effects in the uterus and liver. In breast tissue, tamoxifen acts as an ER antagonist so that transcription of estrogen-responsive genes is inhibited. A beneficial side effect of tamoxifen is that it prevents bone loss by acting as an ER agonist (i.e., mimicking the effects of estrogen) in this cell type. Therefore, by inhibiting osteoclasts, it prevents osteoporosis. When tamoxifen was launched as a drug, it was thought that tamoxifen would act as an ER antagonist in all tissues, including bone, and therefore it was feared that it would contribute to osteoporosis. It was therefore very surprising that the opposite effect was observed clinically. Hence tamoxifen's tissue selective action directly led to the formulation of the concept of SERMs. Tamoxifen is a long-acting SERM, with a nuclear retention of the ER–tamoxifen (or metabolite) complex of greater than 48 hours. It has relatively little affinity for the ERs itself and instead acts as a prodrug of active metabolites such as endoxifen (4-hydroxy-N-desmethyltamoxifen) and afimoxifene (4-hydroxytamoxifen; 4-OHT). These