The results of this study provide clinical epidemiologic support for the hypothesis that citalopram, taken concurrently with tamoxifen, does not reduce tamoxifen’s protective effect against breast cancer recurrence in early stage patients whose tumor cells express the estrogen receptor. This support is in agreement with recent recommendations that tamoxifen-treated breast cancer patients with indications for antidepressant medications may be safely prescribed citalopram or another SSRI with low potency to inhibit CYP2D6
], and fills a void in the evidence base identified by the US National Comprehensive Cancer Network’s treatment guidelines [21
Most SSRI prescriptions in our study were for citalopram or its s-stereoisomer, which is a modest inhibitor of CYP2D6
compared with some other SSRI medications [11
]. Use of other SSRI medications (fluoxetine, paroxetine, or sertraline) while taking tamoxifen, some of which are more potent inhibitors of CYP2D6
], was also unassociated with recurrence risk in our results. The frequencies of prescriptions for these other SSRIs were, however, too low to say with confidence that they do not reduce the effectiveness of tamoxifen.
This study extends our earlier results [13
] by including 366 ER+/TAM+ cases and their 366 matched controls, resulting in 37 cases and 35 controls who ever used citalopram while taking tamoxifen. The earlier study included only 184 ER+/TAM+ cases and their 184 matched controls, resulting in only 17 cases and 21 controls who ever used citalopram while taking tamoxifen. Fifty-six percent of ER+/TAM+ cases and controls in this study were included in the earlier study, and 46% of citalopram-exposed cases were included in the earlier study. The present study’s null result is, therefore, much more precisely measured than the null result of the earlier study. In addition, the large sample size and comprehensive prescription registry allowed investigation of, and control for, exposure to a wide range of prescription medications.
Despite the study’s size and methodologic strength as a population-based case-control study, the results should be interpreted with the following limitations in mind. First, we do not know the reasons why SSRIs were prescribed to the study participants. SSRIs may have been prescribed to treat either depression or hot flashes [23
], but SSRI prescriptions for hot flashes are very rare in Danish breast cancer patients. Second, we do not know whether participants carried CYP2D6
variant alleles that reduce the enzyme’s activity. Genetic variation in CYP2D6
function, however, is not related to switching SSRI antidepressants or discontinuation of SSRI antidepressants [24
], and does not affect response to, or tolerance of, citalopram in particular [25
]. If CYP2D6
genotype is unrelated to receipt or adherence to citalopram prescription, then the absence of genotyping data could not bias the results. Furthermore, clinicians caring for breast cancer patients who present with indications for SSRI antidepressants will seldom know the patient’s CYP2D6
genotype, so this study’s result applies directly to the typical clinical setting.
Third, we have not confirmed that patients actually took either tamoxifen or a prescribed SSRI. In Denmark, tamoxifen is dispensed by breast cancer physicians to breast cancer patients at follow-up visits. SSRI medications recorded in the prescription registry are paid for and retrieved by patients, and then partly reimbursed by the national health care system. Both of these systems should assure good adherence to the registered medications. Fourth, most women taking SSRI prescription medications did not take them for the full duration of their tamoxifen therapy. This pattern reflects the clinical practice in this population during the study period. It would be very difficult to find a population in which a substantial proportion of tamoxifen-treated breast cancer patients took SSRI medications for the full five years of their tamoxifen therapy. Indeed, no such study has been reported. Finally, breast cancer patients with estrogen-receptor positive tumors were assigned treatment protocols calling for one, two, or five years of tamoxifen therapy, whereas current guidelines recommend five years of tamoxifen therapy [21
]. Many of the women assigned to tamoxifen protocols shorter than five years took tamoxifen for much longer (unpublished validation data), and we recorded the full duration of their use in the analysis of intermittent and regular use. In addition, recurrence risks between tamoxifen-treated and placebo-treated women differ as early as one year after initiation of tamoxifen treatment [8
], so inhibition of tamoxifen effectiveness by concurrent SSRI prescriptions should have been apparent among all women included in our study.
While these results may seem at odds with the strong biologic rationale and in vivo
evidence supporting the hypothesis that any CYP2D6
inhibition would reduce tamoxifen’s effectiveness, this information may not be as compelling as it first seems [26
]. SSRI medications could reduce the plasma concentration of tamoxifen’s secondary metabolites without reducing its anti-tumorigenicity [27
]. Tamoxifen doses as low as 1 mg/day affect biomarkers of cardiovascular, bone, and tumor endpoints to about the same degree as the usual dose of 20 mg/day [28
], so the three-fold reduction in the concentration of tamoxifen’s secondary metabolites associated with receipt of the SSRI paroxetine [22
] may have little consequence. Our results, combined with this emerging alternative view of the limited potential for CYP2D6
inhibition to interact with tamoxifen, suggest that breast cancer patients with indications for an SSRI may be prescribed citalopram while taking tamoxifen with little effect, if any, on their risk of breast cancer recurrence.