Effect of selective serotonin reuptake inhibitors use on endocrine therapy adherence and breast cancer mortality: a population-based study

In patients with estrogen receptor (ER)-positive breast cancer, adjuvant endocrine therapy, such as tamoxifen and aromatase inhibitors (AIs), reduces the risk of breast cancer recurrence and death [1, 2]. However, a considerable proportion of patients discontinue their oral endocrine treatment [3] despite the risk of jeopardizing their chances of survival from breast cancer [4, 5]. There are many reasons why people do not adhere to medical treatments [6] and a significant one of these is depression [7], which is fairly prevalent in patients with breast cancer [8]. There is some evidence that the concomitant use of antidepressant and endocrine therapy in breast cancer is associated with a poorer clinical outcome but the reasons for this have not been fully explored [9, 10]. Two distinct, but not mutually exclusive, explanations are possible for this, namely an adherence effect and a drug interaction effect [4, 9].

Depression reduces the adherence to oral endocrine therapy [11]. The association between depression, antidepressant therapy, and adherence to endocrine therapy is complex, and several aspects need further investigation. First, the role of antidepressant therapy before initiation of endocrine therapy on adherence is unclear. Barron et al. reported an association between antidepressant use before breast cancer diagnosis and non-persistence to tamoxifen therapy [12], but He et al. could not reveal a similar association in a larger dataset [13]. Second, whether continuing antidepressant therapy after breast cancer diagnosis affects adherence to endocrine therapy has not been studied. In addition, the effect of time to antidepressants initiation in respect to breast cancer diagnosis on adherence has not been studied either.

A second explanation of the negative effect of the concomitant use of antidepressants and oral endocrine therapy is the potential risk for reduced activity of endocrine therapy due to drug interaction. The biologic rationale for this is that tamoxifen is a pro-drug that is catalyzed to its active substance endoxifen predominantly by cytochrome P450 isoenzyme 2D6 (CYP2D6) [14]; a cytochrome that can be inhibited by the selective serotonin reuptake inhibitors (SSRIs) antidepressants. If this interaction has a clinically relevant effect, the consequences for clinical management are substantial: Tamoxifen has key role as adjuvant endocrine therapy in a large proportion of women with early breast cancer [1]; a considerable proportion of breast cancer patients suffer from significant depressive symptoms [8]; the current recommendation is to use SSRIs as first-line treatment against depression [15, 16].

Several studies have tried to investigate the clinical effect of this potential interaction but have been hampered by a limited number of events [17, 18], the use of a too low cut-off for acceptable adherence rate [17], and the lack of analyses on the effect of the length of time with concomitant use of tamoxifen and SSRI [4, 19]. Two studies could overcome these limitations, but their results are contradictory. Kelly et al. showed an association between a specific SSRI medication, paroxetine, and increased risk of death from breast cancer [10]. However, Haque et al. could not find an increased risk for breast cancer recurrence in patients who concurrently used tamoxifen and SSRI, including paroxetine [20]. As a result, whether a clinically significant interaction between SSRI and tamoxifen as it is supported by preclinical data exists is still controversial.

We investigated whether the concomitant use of SSRI and tamoxifen influences the risk of death due to breast cancer. Since any such impact could be due to either drug interaction or pattern of adherence, our secondary purpose was to investigate the association between SSRI use, in both the prediagnostic and the postdiagnostic period of breast cancer, and adherence to oral endocrine therapy.

We identified 18,432 women with ER-positive breast cancer without distant metastasis treated with adjuvant endocrine therapy during the study period (Jan 1, 2004–July 31, 2011). In total, 445 women died due to breast cancer by the end of follow-up.

The nested case–control study included 445 cases (deaths due to breast cancer) and 11125 controls (Fig. 1).The adherence cohort included 9104 women who were diagnosed with non-metastatic ER-positive breast cancer from July 2007 to July 31, 2011.

The study design with the different patient cohorts are outlined in Fig. 2.

In our population-based study, we found no association between concomitant use of SSRI and tamoxifen and breast cancer-specific survival. The lack of association was consistent even when the analysis was restricted to patients that used strong CYP2D6-inhibiting SSRIs or patients with long-term co-administration of tamoxifen with SSRI. However, poor adherence on endocrine therapy was clearly associated with worse prognosis. Regarding the role of SSRI on adherence to endocrine therapy, we found a negative effect of both pre- and postdiagnostic SSRI use on adherence with the exception of patients with SSRI use for a longer period of time during study follow-up in whom the adherence was comparable to those who have not been treated with SSRI.

Early pharmacological studies revealed a decreased endoxifen plasma concentration in patients who were poor CYP2D6 metabolizers or those who received concomitant CYP2D6 inhibitors, such as SSRIs [9, 25, 26]. This observation raised the hypothesis that the concomitant administration of tamoxifen and SSRIs could have a detrimental effect on tamoxifen efficacy. However, the results from two well-designed, large studies aimed to investigate this hypothesis are contradictory [10, 20]. Kelly et al. found that concomitant use of tamoxifen and paroxetine increased the risk for death due to breast cancer. However, the study did not include data on breast cancer stage which could influence the results by including more patients with late-stage disease in the paroxetine group. On the other hand, Haque et al. could not find any association between SSRI use during tamoxifen and breast cancer recurrence, but no data on breast cancer survival were presented.

Our results that poor adherence to endocrine therapy was associated with worse prognosis are consistent with prior studies [4, 5, 27] and further support the need to develop interventions to improve adherence to endocrine adjuvant therapy.

SSRI users had a worse adherence rate than non-SSRI users. This observation was consistent irrespective of the time of SSRI initiation (before or after breast cancer diagnosis) indicating an association between SSRI use with non-adherence to endocrine therapy. Considering the fact that nearly 80 % of patients with SSRI prescription in Sweden is due to depression [28], we hypothesize that there is an association between depression and non-adherence to endocrine therapy. Our results and hypothesis are in accordance with a recent meta-analysis that showed that patients with depressive symptoms had lower adherence to endocrine therapy [11]. However, an association between medical conditions other than depression in which SSRIs are indicated, i.e., panic or anxiety disorders, and non-adherence to endocrine therapy is also possible and further research is needed. Based on the current evidence about the role of depression on endocrine therapy adherence, it has been hypothesized that effective management of depressive symptoms in patients with cancer aids in promoting long-term adherence to endocrine therapy. Although there is some indirect evidence on the positive effect of psychotherapy consultations as part of management against depression on treatment adherence [29], no data exist on the potential effect of pharmacotherapy for depression on adherence. Interestingly, we found an improvement in adherence in patients who received SSRI for a longer period of time during study follow-up (SSRI use more than 50 % of time, namely more than 1 year). This suggests that if the patients with breast cancer and depression receive SSRI treatment as indicated (1–2 years after stabilization of symptoms for the first episode; 5 years to lifetime for subsequent episode [30‐32]), the adherence to endocrine therapy will be improved. This is the first study that suggests a positive effect of antidepressive pharmacotherapy on adherence to cancer therapy.

Our study has some limitations. First, prescription refill does not guarantee that the patient has actually consumed the prescribed medication; as a result, there is a risk for underestimation of non-adherence. However, this underestimation is likely to be similar in SSRI users and non-users. Second, we gathered data on comorbidities from inpatient registry and there is a considerably risk that some common comorbidities might be missed. However, the adjustment of our analyses with the CCI measure, which is a measure of more severe comorbid conditions, did not influence the results, indicating that comorbidities do not seem to affect the results. Third, we had no data on the CYP2D6 genotype in our cohort. However, a recent meta-analysis concluded that there is no evidence that different CYP2D6 polymorphisms affect breast cancer prognosis in breast cancer patients treated with tamoxifen [33]. Another potential limitation of our study is the lack of data on the indication of SSRI use in our cohort. Some SSRIs may have been used for the treatment of hot flashes related to endocrine therapy. However, the most evidence-based and commonly used antidepressant for this indication is venlafaxine, which is the only recommended antidepressant against hot flashes by the national swedish breast cancer guidelines [23], and therefore, we excluded this drug from our analyses to minimize the risk of bias. Moreover, venlafaxine is a non-significant inhibitor of CYP2D6 [34]. Furthermore, our study concentrated on SSRIs and did not take into account other antidepressants. The proportion of women receiving antidepressants other than SSRIs is considered low in our cohort because of the recommendation to use SSRI as first-line therapy against depression in Sweden [15]. Finally, our analyses did not take into account the concomitant use of other strong CYP2D6 inhibitors. However, the clinical indication for the use of other strong CYP2D6 inhibitors (bupropion, quinidine) is limited and as result the number of patients treated with these medications is expected to be low. In addition, differences in use of other strong CYP2D6 inhibitors by SSRI usage are not expected in our cohort.

In conclusion, we could not find a negative effect of SSRI use during tamoxifen treatment with respect to risk of breast cancer death even in subgroups of patients that the biological rationale behind the hypothesis was supposed to be stronger (use of strong CYP2D6-inhibitors or use of SSRIs for a long period concomitant with tamoxifen). We suggest that, in breast cancer patients who are successfully treated with SSRIs and are planning to start with tamoxifen, there is no need to change SSRI therapy. However, physicians should discuss other treatment options instead of strong CYP2D6-inhibiting SSRIs with their patients with breast cancer on tamoxifen that need to start with antidepressive therapy, given the biological rationale and the results from one previous well-designed epidemiological study [20]. Finally, depressive symptoms should be captured early in breast cancer patients and adequate pharmacotherapy should be initiated with support to facilitate adherence to both antidepressants and tamoxifen.