Sweats and Hot Flashes
Many of the SSRIs can inhibit the cytochrome P450 enzymes involved in the metabolism of tamoxifen, which is commonly used in the treatment of breast cancer. When SSRIs are being used, drug-drug interactions should be noted. Tamoxifen, used in the management of breast cancer, is metabolized by the cytochrome P450 enzyme system, specifically CYP2D6. Wild-type CYP2D6 metabolizes tamoxifen to an active metabolite, 4-hydroxy-N-desmethyl-tamoxifen, also known as endoxifen. A prospective trial evaluating the effects of the coadministration of tamoxifen and paroxetine, a CYP2D6 inhibitor, on tamoxifen metabolism, found that paroxetine coadministration resulted in decreased concentrations of endoxifen. The magnitude of decrease was greater in women with the wild-type CYP2D6 genotype than in those with a variant genotype (P = .03).[Level of evidence: II]
In a prospective observational study of 80 women initiating adjuvant tamoxifen therapy for newly diagnosed breast cancer, variant CYP2D6 genotypes and concomitant use of SSRI CYP2D6 inhibitors resulted in reduced endoxifen levels. Variant CYP2D6 genotypes do not produce functional CYP2D6 enzymes.[Level of evidence: II] Since this study was published, several researchers have been evaluating the clinical implications of this finding.;[48,49,50][Level of evidence: II] One study followed more than 1,300 women for a median of 6.3 years and concluded that women who were poor metabolizers or heterozygous extensive/intermediate metabolizers (hence, less CYP2D6 activity) had higher rates of recurrence, worse event-free survival, and worse disease-free survival than did women who were extensive metabolizers. Similarly, a retrospective cohort study of more than 2,400 women in Ontario who were being treated with tamoxifen and had overlapping treatment with an SSRI has been completed. Authors concluded that women who concomitantly used paroxetine and tamoxifen had an increased risk of death that was proportionate to the amount of time they used these agents together.[Level of evidence: II] Clinical implications of these changes and of other CYP2D6 genotypes  have not yet been elucidated, but the pharmacokinetic interaction between tamoxifen and the newer antidepressants used to treat hot flashes merits further study. Likewise, the risk of soy phytoestrogen use on breast cancer recurrence and/or progression has not yet been clarified. Soy phytoestrogens are weak estrogens found in plant foods. In vitro models suggest that these compounds have a biphasic effect on mammary cell proliferation that is dependent on intracellular concentrations of phytoestrogen and estradiol.