Revisiting the drug interaction between tamoxifen and SSRI antidepressants

Few topics in therapeutics are more vexing than drug interactions. They number in the thousands, involve confusing terminology, and are rarely supported by evidence stronger than case reports and volunteer studies.1 It’s not surprising, therefore, that experts disagree on which interactions are serious and which ones are not.2 And yet their importance is undeniable because they can cause serious morbidity or even death, despite epitomizing, in theory at least, avoidable drug related harm.

Over the past decade, few drug interactions have been as controversial as those involving tamoxifen and selective serotonin reuptake inhibitor (SSRI) antidepressants,3 explored yet again by Donneyong and colleagues in a linked study (doi:10.1136/bmj.i5014).4 On its surface, the issue seems straightforward: as a prodrug, tamoxifen requires conversion to active metabolites, the most important of which is endoxifen. This process is influenced by cytochrome-P450 isoenzyme 2D6 (CYP2D6), an enzyme characterized by marked variability from person to person. Some SSRIs but not others inhibit CYP2D6, conceivably attenuating or even abolishing the benefits …