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.
Behavioral interventions as a primary or adjunctive modality may also play a role in hot flash management. Core body temperature has been shown to increase before a hot flash; therefore, interventions to keep body temperature down could improve hot flash management. Some methods of controlling body temperature include the use of loose-fitting cotton clothing as well as the use of fans and open windows to keep air moving. Based on the theory that serotonin may be involved as a central hot flash trigger, behavioral interventions such as stress management may modulate serotonin, causing a decrease in hot flashes. Relaxation training and slow, deep breathing [55,56] have been found to decrease hot flash intensity by as much as 40% to 50% in controlled pilot trials. More research with well-designed control arms is needed to further clarify the main effect of such behavioral treatments as well as the additive and synergistic effects with other treatments. One pilot study also found that self-hypnosis, utilizing cooling suggestions, reduced hot flash scores an average of 68%.[Level of evidence: I] Self-hypnosis is being studied further in larger controlled trials as well as in combination with low-dose antidepressants.