A 59-year-old woman with a history of breast cancer is taking tamoxifen to reduce recurrence risk. She is depressed and reports difficulty sleeping and hot flashes since initiating tamoxifen (a CYP2D6 substrate). Which of the following antidepressants is most appropriate?

Choice A reason: Duloxetine is a serotonin-norepinephrine reuptake inhibitor (SNRI) that can be used for depression and pain. However, it has moderate CYP2D6 inhibition, which may interfere with tamoxifen metabolism and reduce its efficacy. Choice B reason: Venlafaxine is an SNRI with minimal CYP2D6 inhibition. It is effective for depression and also helps alleviate hot flashes, making it the most appropriate choice for this patient. Choice C reason: Bupropion is a norepinephrine-dopamine reuptake inhibitor and a strong CYP2D6 inhibitor. It can significantly reduce the conversion of tamoxifen to its active metabolite, endoxifen, thereby compromising its therapeutic effect. Choice D reason: Fluoxetine is a potent CYP2D6 inhibitor and should be avoided in patients taking tamoxifen due to the risk of reducing its efficacy in preventing breast cancer recurrence.