Abstract
Purpose
Women with breast cancer frequently use antidepressants; however, questions about the effect of these medications on breast cancer recurrence remain.
Methods
We identified 4216 women ≥18 years with an incident stage I or II breast cancer diagnosed between 1990–2008 in a mixed model healthcare delivery system linked to a cancer registry. Recurrences were ascertained from chart review. Medication exposures were extracted from electronic pharmacy records. We used multivariable Cox proportional hazards models to estimate hazard ratios (HR) and 95% confidence intervals (CI) to assess the association between antidepressant use and breast cancer recurrence and mortality. We also conducted analyses restricted to tamoxifen users.
Results
Antidepressants overall, tricyclic antidepressants, and selective serotonin reuptake inhibitors were not associated with risk of breast cancer recurrence or mortality. Women taking paroxetine only (adjusted HR: 1.66; 95% CI: 1.02, 2.71) and trazadone only (adjusted HR: 1.76; 95% CI: 1.06, 2.92), but not fluoxetine only (adjusted HR: 0.92; 95% CI: 0.55, 1.53), had higher recurrence risks than antidepressant non-users. There was some suggestion of an increased recurrence risk with concurrent paroxetine and tamoxifen use compared to users of tamoxifen only (adjusted HR: 1.49; 95% CI: 0.79, 2.83).
Conclusions
In general, antidepressants did not appear increase risk of breast cancer recurrence; though there were some suggested increases in risk that warrant further investigation in other datasets. Our results combined systematically and quantitatively with results from other studies may be useful for patients and providers making decisions about antidepressant use after breast cancer diagnosis.
Keywords: breast carcinoma, breast carcinoma recurrence, breast carcinoma mortality, antidepressants
INTRODUCTION
Antidepressant use is common among women with breast cancer in the United States, with upwards of one quarter to one third of women using these medications after their cancer diagnosis [1–3]. Thus, understanding the safety of antidepressants is important for the health of the growing number of breast cancer survivors.
Tamoxifen is an important treatment for breast cancer hormone receptor-positive breast cancer [4]. Inhibitors of the enzyme CYP2D6, such as the selective serotonin reuptake inhibitors (SSRIs) paroxetine and fluoxetine, may impair conversion of tamoxifen into its active form, endoxifen [5–8]. The clinical importance of their potential inhibitory effects is unknown and questionable, especially since studies suggest that even genetic variants of CYP2D6 encoding reduced enzymatic activity do not result in worse outcomes [9–13]; however, there is much debate on the effects of these medications in women with breast cancer [14–19] and the Food and Drug Administration (FDA) has issued precautions regarding concomitant use of tamoxifen and paroxetine [20,21].
Epidemiologic research on antidepressant use and breast cancer outcomes varies considerably in exposures and outcomes studied [1,22–31]. Studies of antidepressants that weakly inhibit CYP2D6 (such as citalopram) have generally not been associated with breast cancer recurrence risk [22,23,31]. However, there has been some suggestion of increased risk of breast cancer recurrence [22] and breast cancer mortality [27] among patients who use tamoxifen with the strong CYP2D6 inhibitor paroxetine in some but not all studies [25]. Studies of CYP2D6 inhibitors in general (including medications other than antidepressants) [26], antidepressants with moderate/strong CYP2D6 affinity [30], and SSRIs in as a class [1,28,31] have generally not suggested an association with breast cancer outcomes among tamoxifen users. Of note, studies lacked statistical precision and little information was available on the commonly used antidepressant fluoxetine, which also inhibits CYP2D6. We therefore assessed the association between different classes of antidepressants and individual medications and the risk of breast cancer recurrence.
METHODS
Study overview
This cohort study, Commonly Used Medications and Breast Cancer Outcomes (COMBO), is described in detail elsewhere [32,33]. Briefly, we conducted this study within the western Washington region of Group Health, a mixed model health plan in Washington state and northern Idaho. Study participants had to reside in one of the 13 western Washington counties covered by the western Washington Surveillance, Epidemiology, and End Results program (SEER) registry. We used cancer registry files linked to Group Health enrollment files to identify women aged 18 years and older who were diagnosed with a first primary stage I or II invasive breast cancer between 1990 and 2008, inclusive. Participants had to be enrolled in Group Health’s Integrated Group Practice model for the year before and after their incident breast cancer diagnosis (unless they died during that year). Medical records of potentially eligible participants (N=4426) were reviewed. We excluded participants with no medical record (N=72), bilateral disease (N=6), recurrent or second primary breast cancers that were incorrectly identified as incident first breast cancers (N=79), and no definitive surgery (N=44). We required women be alive and recurrence-free for 120 days after surgery and therefore excluded people who died (N=5) or had metastases (N=4) within 120 days of surgery. The final cohort consisted of 4216 women. Five-year outcomes from a subset of this cohort (N=1306) were included in an earlier report on antidepressants and breast cancer outcomes [1]. The Group Health human subjects review committee approved all study procedures.
The SEER registry provided data on tumor characteristics and certain patient characteristics. When these were not available in SEER, we abstracted them from medical records as part of a detailed chart abstraction [31,32]. Charts were abstracted from one year before diagnosis through patient death, disenrollment from Group Health, or the date of chart abstraction. Data elements included treatment of the incident breast cancer, breast cancer recurrences and second primaries [34]. Data on comorbidity diagnoses (including mental health diagnoses [Supplemental Table 1] and the Charlson comorbidity score [35]), health history and medication use, height, weight, and date and cause of death, came primarily from administrative data sources and the electronic medical record at Group Health. A list of data elements and their sources was previously published by Boudreau and colleagues [32].
Exposure
Group Health’s pharmacy database provided information on prescription fills at Group Health-owned pharmacies and pharmacy claims throughout the entire study period [36,37]. Each record contained information on the drug dispensed, including national drug code (NDC), quantity, strength, days’ supply, date dispensed, and prescriber. Drug exposures of interest included use of the following after breast cancer diagnosis: 1) any antidepressant, 2) any SSRI, 3) any tricyclic antidepressant (TCA), and 4) any miscellaneous antidepressant. We further classified SSRI use into strong CYP2D6 inhibitors (paroxetine, fluoxetine, and buproprion) and weak/moderate CYP2D6 inhibitors (sertraline, citalopram, fluvoxamine, and escitalopram) [2,30].
For each drug and drug class, we defined episodes of use. We used the days’ supply field to compute the intended duration of each prescription [1,32]. Assuming 80% adherence, we calculated prescriptions’ run-out date by multiplying days’ supply by 1.25 [38]. If a new prescription for the drug or class of interest was dispensed <60 days after the run-out date of the preceding prescription, it was included as part of the same episode of use. Episodes started on the dispensing day of the first prescription and ended on the run-out day of the last prescription [32]. Once someone became a user after breast cancer diagnosis, she remained a user, regardless of when she discontinued use. The rationale for this was that any use – not necessarily current use – could be related to recurrence risk. Concurrent use between antidepressants and endocrine therapy (tamoxifen or aromatase inhibitors) was defined as an overlap of ≥60 days of use [28].
Information on endocrine therapy (tamoxifen and aromatase inhibitors) was obtained from prescription fills. Like all other exposure variables, concurrent antidepressant use was time-varying and unidirectional. Once someone became a concurrent user, she remained a concurrent user, even if she discontinued use of either the antidepressant or tamoxifen. A non-concurrent user could become a concurrent user if the 60 days of overlap was achieved (Supplemental Figure 1).
Outcomes
Recurrence was defined as a ductal carcinoma in situ or invasive cancer of the ipsilateral breast or in any regional or distant sites [32–34]. A cancer was classified as a recurrence only if it occurred more than 120 days after definitive surgery [34]. Date and cause of death were obtained from Washington State death files. Second cancers in the contralateral breast were obtained from the SEER program registry and chart abstraction. They were considered censoring events in the analysis of recurrence.
Statistical analysis
Analysis of breast cancer recurrence
We compared users and non-users of any antidepressant after diagnosis with respect to patient characteristics and features of their cancer using the Chi-square test for categorical variables and the t-test for continuous variables. We used multivariable Cox proportional hazards models to estimate hazard ratios (HR) and their 95% confidence intervals (CI) to assess the association between antidepressant use and breast cancer recurrence risk while accounting for competing risks [39]. Time from diagnosis was the analytic time scale [40] and women entered the analysis when they became at risk for recurrence, which was defined as 120 days after definitive surgery. Women were followed until the earliest of recurrence, second primary breast cancer diagnosis, death, disenrollment from Group Health, or end of study (chart abstraction date). Women were censored when they developed a second primary breast cancer and thus, any recurrence occurring after the second primary was not included as a recurrence outcome. Covariates in all models were selected a priori and included age (18–49, 50–59, 60–69, 70–79, ≥80 years) and year of diagnosis (1990–1994, 1995–1999, 2000–2004, 2005–2008), stage (I, IIA, IIB) [41], estrogen receptor (ER) and progesterone receptor (PR) status (ER+/PR+, ER+/PR−, ER−/PR+, ER−/PR−), primary treatment (mastectomy, breast conserving surgery [BCS] with radiation, BCS without radiation), any chemotherapy treatment, any endocrine therapy, body mass index (BMI) (<18.5, 18.5–24.9, 25.0–29.9, 30.0–34.9, ≥35 kg/m2) in the year before diagnosis, smoking in the year before diagnosis (current, past, never/unknown), menopausal status in the year before diagnosis (peri- or pre-menopausal, post-menopausal), and Charlson comorbidity score (0, 1, ≥2). All variables were included as categorical variables. Endocrine treatment and Charlson comorbidity score were included as time-varying covariates. Persons with unknown ER/PR status and BMI were excluded from the main recurrence and mortality models. We conducted an exploratory analysis with depression as a time-varying covariate.
In analyses of drug class and recurrence risk, we used two approaches to control for confounding by other antidepressants. We conducted one analysis in which we restricted (in a time-varying manner) to non-users of any antidepressant and users of only the antidepressant class of interest. In this analysis, exposure was time-varying in that women could switch from being a non-user to a user of one class, but were censored when they used an antidepressant from another class. In the tables, these are referred to as “restriction” analyses. Separate models were conducted for each antidepressant of interest and women were censored when they used another antidepressant. In the second approach, we included each class of antidepressants as a separate exposure variable in the model so that they were mutually adjusted for one another. In the tables, these are referred to as “adjustment” analyses.
We conducted an analysis limited to tamoxifen users (N=1902) to address the question of whether antidepressants modify tamoxifen’s effectiveness. For the analysis of concurrent tamoxifen use, women entered the analysis once they became at risk of recurrence and had used 60 days of tamoxifen (Supplemental Figure 1). Women with aromatase inhibitor use before tamoxifen use were excluded. Women could be non-users of antidepressants (i.e., tamoxifen only users), non-concurrent users of tamoxifen and antidepressants, or concurrent users of tamoxifen and antidepressants. Concurrent use of antidepressant and tamoxifen was time-varying and occurred once a woman had 60 days of overlap of tamoxifen and antidepressant use. We conducted separate models for concurrent use of tamoxifen and any antidepressant as well as with each antidepressant drug and drug class. Due to small sample size, we adjusted only for diagnosis age, diagnosis year, and stage at diagnosis in these models. Women were censored at the earliest of the start of an aromatase inhibitor, second primary breast cancer, death, disenrollment, and end of study follow-up.
Analysis of breast cancer mortality
In a secondary analysis, we examined the risk of breast cancer-specific mortality in relation to antidepressant use, using multivariable Cox models with the same exposures of interest as in the main analysis. Once a person started using an antidepressant, she was classified as a user; however, new use after a recurrence diagnosis or second primary was not included, as recurrences and second primaries were likely to be a strong time-varying confounders [42]. We followed women until the earliest of death from another cause, Group Health disenrollment, or end of study follow-up.
Proportional hazards assumptions
We evaluated proportional hazards assumptions by testing the interaction between the medication classes of interest and the logarithm of follow-up time. Separate tests were run for breast cancer recurrence and mortality outcomes. The assumptions held for all exposure-outcome pairs except for miscellaneous antidepressants and breast cancer mortality and any antidepressant and breast cancer mortality. To further assess the non-proportional hazards for, we divided the follow-up time into two periods each containing half the breast cancer deaths (≤4.24 years since diagnosis and >4.24 years). Separate HRs for exposures were estimated for each time period by including an interaction term between time period and the exposure in the multivariate Cox proportional hazards model. For both any antidepressant and miscellaneous antidepressants models, the HRs in the two time periods were not statistically significant and the confidence intervals overlapped. Therefore, we report the overall results for both miscellaneous antidepressants and any antidepressant.
RESULTS
Among the 4216 women who met study eligibility criteria, more than half (N=2302, 54.6%) filled at least one prescription for an antidepressant sometime after their incident breast cancer diagnosis (but before recurrence or second primary). Antidepressant users were more often white, more likely to smoke at baseline, have a mental health diagnosis and filled prescriptions for antidepressants in the year before diagnosis, have lower education levels, more comorbidities, and higher BMI than participants who did not use antidepressants after breast cancer diagnosis (Table 1). Users and non-users were generally similar with respect to risk factors for recurrence, such as stage and other features of initial cancer. However, compared to non-users, antidepressant users were slightly more likely to receive mastectomy over breast conserving surgery with radiation and to receive chemotherapy.
Table 1.
Characteristics of users and non-users of any antidepressants after a diagnosis of breast cancer and before recurrence (Group Health, 1990–2008), N=4,216
| All | Any antidepressant use after diagnosis | ||
|---|---|---|---|
| No | Yes | ||
| (N=4216) n (%)a |
(N=1914) n (%)a |
(N=2302) n (%)a |
|
| Age at diagnosis (years) | |||
| Mean (SD) | 62.2 (13.3) | 62.5 (13.2) | 62.6 (13.4) |
| 18–39 | 139 (3.3) | 65 (3.4) | 74 (3.2) |
| 40–49 | 646 (15.3) | 285 (14.9) | 361 (15.7) |
| 50–59 | 995 (23.6) | 438 (22.9) | 557 (24.2) |
| 60–69 | 1018 (24.1) | 491 (25.7) | 527 (22.9) |
| 70–79 | 940 (22.3) | 436 (22.8) | 504 (21.9) |
| ≥80 | 478 (11.3) | 199 (10.4) | 279 (12.1) |
| Year of diagnosis | |||
| 1990–1994 | 950 (22.5) | 442 (23.1) | 508 (22.1) |
| 1995–1999 | 1191 (28.2) | 520 (27.2) | 671 (29.1) |
| 2000–2004 | 1201 (28.5) | 513 (26.8) | 688 (29.9) |
| 2005–2008 | 874 (20.7) | 439 (22.9) | 435 (18.9) |
| Follow-up time | |||
| Mean (SD) | 7.1 (4.3) | 6.6 (4.3) | 7.4 (4.3) |
| Median | 6.3 | 5.7 | 6.7 |
| Race | |||
| White | 3719 (88.5) | 1640 (86.1) | 2079 (90.5) |
| African American | 136 (3.2) | 73 (3.8) | 63 (2.7) |
| American Indian/Alaska Native | 113 (2.7) | 44 (2.3) | 69 (2.7) |
| Asian/Pacific Islander | 233 (5.5) | 148 (7.8) | 85 (3.7) |
| Other | 1 (0) | 0 (0) | 1 (0) |
| Unknown | 14 | 9 | 5 |
| Ethnicity | |||
| Not Hispanic | 3976 (94.6) | 1798 (94.2) | 2178 (94.8) |
| Hispanic | 229 (5.4) | 110 (5.8) | 119 (5.2) |
| Unknown | 11 | 6 | 5 |
| Menopausal status at diagnosis | |||
| Peri- or Premenopausal | 1145 (27.2) | 522 (27.3) | 623 (27.1) |
| Postmenopausal | 3071 (72.8) | 1392 (72.7) | 1679 (72.9) |
| Education | |||
| High school or less | 418 (23.4) | 188 (22.1) | 230 (24.5) |
| Some college | 634 (35.4) | 281 (33.0) | 353 (37.6) |
| College or post graduate | 737 (41.2) | 382 (44.9) | 355 (37.8) |
| Unknown | 2427 | 1063 | 1364 |
| Cancer characteristics | |||
| AJCC stage at diagnosis | |||
| I | 2648 (62.8) | 1175 (61.4) | 1473 (64.0) |
| IIA | 1078 (25.6) | 518 (27.1) | 560 (24.3) |
| IIB | 490 (11.6) | 221 (11.5) | 269 (11.7) |
| Lymph node status | |||
| Unknown | 451 | 195 | 256 |
| Negative | 2847 (75.6) | 1304 (75.9) | 1543 (75.4) |
| Positive (1–3 nodes) | 680 (18.1) | 309 (18) | 371 (18.1) |
| Positive (≥4 nodes) | 234 (6.2) | 104 (6.1) | 130 (6.4) |
| Positive (unknown number of nodes) | 4 (0.1) | 2 (0.1) | 2 (0.1) |
| Tumor size | |||
| <2.0 cm | 3110 (73.8) | 1392 (72.8) | 1718 (74.7) |
| ≥2.0 cm | 1104 (26.2) | 521 (27.2) | 583 (25.3) |
| Unknown | 2 | 1 | 1 |
| Tumor histology | |||
| Ductal | 3315 (78.6) | 1506 (78.7) | 1809 (78.6) |
| Lobular | 336 (8) | 147 (7.7) | 189 (8.2) |
| Mixed/other | 565 (13.4) | 261 (13.7) | 304 (13.3) |
| Tumor grade | |||
| Well differentiated | 1041 (26.9) | 471 (26.7) | 570 (27.1) |
| Moderately differentiated | 1600 (41.3) | 714 (40.4) | 886 (42.1) |
| Poorly/undifferentiated | 1233 (31.9) | 582 (33.0) | 651 (30.9) |
| Not determined or stated | 342 | 147 | 195 |
| ER/PR status | |||
| ER & PR unknown | 217 | 93 | 124 |
| ER−/PR− | 667 (16.7) | 313 (17.2) | 354 (16.3) |
| ER+/PR− | 383 (9.6) | 177 (9.7) | 206 (9.5) |
| ER−/PR+ | 61 (1.5) | 24 (1.3) | 37 (1.7) |
| ER+/PR+ | 2888 (72.2) | 1307 (71.8) | 1581 (72.6) |
| Her-2 test (diagnosis in 1998+ only) | |||
| Test done | 2074 (79.7) | 950 (81.0) | 1124 (78.7) |
| Her-2 test result among women with test done | |||
| Positive/Borderline | 353 (17.0) | 152 (16.0) | 201 (17.9) |
| Negative | 1714 (82.6) | 795 (83.7) | 919 (81.8) |
| No result | 7 (0.3) | 3 (0.3) | 4 (0.4) |
| Cancer treatment | |||
| Primary therapy | |||
| Mastectomy with or without radiation | 1521 (36.1) | 635 (33.2) | 886 (38.5) |
| Breast conserving surgery with radiation | 2172 (51.5) | 1039 (54.3) | 1133 (49.2) |
| Breast conserving surgery without radiation | 523 (12.4) | 240 (12.5) | 283 (12.3) |
| Adjuvant treatment (not mutually exclusive) | |||
| Chemotherapy | 1376 (32.6) | 586 (30.6) | 790 (34.3) |
| Tamoxifen | 2057 (48.8) | 884 (46.2) | 1173 (51.0) |
| Aromatase Inhibitor | 849 (20.1) | 353 (18.4) | 496 (21.6) |
| Health history in year prior to diagnosis | |||
| Charlson Index | |||
| 0 | 3229 (76.6) | 1541 (80.5) | 1688 (73.3) |
| 1 | 704 (16.7) | 263 (13.7) | 441 (19.2) |
| ≥2 | 283 (6.7) | 110 (5.7) | 173 (7.5) |
| Body mass index (kg/m2) | |||
| <18.5 | 69 (1.6) | 29 (1.5) | 40 (1.7) |
| 18.5 to <25 kg/m2 | 1453 (34.6) | 698 (36.6) | 755 (33.0) |
| 25 to <30 kg/m2 | 1362 (32.5) | 636 (33.4) | 726 (31.7) |
| 30 to <35 kg/m2 | 766 (18.3) | 330 (17.3) | 436 (19.0) |
| ≥35 kg/m2 | 546 (13.0) | 212 (11.1) | 334 (14.6) |
| Unknown | 20 | 9 | 11 |
| Smoking status | |||
| Current | 253 (6.0) | 83 (4.3) | 170 (7.4) |
| Past | 352 (8.3) | 169 (8.8) | 183 (7.9) |
| Never/Unknown | 3611 (85.6) | 1662 (86.8) | 1949 (84.7) |
| Diagnosis of depression | 402 (9.5) | 39 (2.0) | 363 (15.8) |
| Diagnosis of anxiety | 174 (4.1) | 30 (1.6) | 144 (6.3) |
| Mental health diagnosis | 795 (21.7) | 166 (10.1) | 629 (31.1) |
| Antidepressant use | 935 (22.2) | 53 (2.8) | 882 (38.3) |
| SSRIs | 452 (10.7) | 17 (0.9) | 435 (18.9) |
| TCAs | 422 (10.0) | 28 (1.5) | 394 (17.1) |
| Miscellaneous | 280 (6.6) | 12 (0.6) | 268 (11.6) |
AJCC = American Joint Committee on Cancer; ER = estrogen receptor; PR = progesterone receptor; SD = standard deviation; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant
Column percents may not add to 100% due to rounding
The median duration of use after breast cancer diagnosis for all antidepressants was 23 months (Table 2) and median time to first use was 7.4 months (not shown). SSRIs were the most commonly used class of antidepressants. Of all individual antidepressants, fluoxetine and trazodone were the two most frequently used agents. Overall, use of antidepressants after incident breast cancer diagnosis was not associated with risk of recurrence (adjusted HR: 1.16, 95% CI: 0.94, 1.44) compared to non-users (Table 3). HRs for both SSRIs and TCAs were near 1.0 and were not statistically significant. Miscellaneous antidepressants were associated with a non-significant increased risk, possibly driven by the most commonly used of these medications, trazodone (adjusted HR: 1.76; 95% CI: 1.06, 2.92). We observed an increased recurrence risk among women taking paroxetine only (adjusted HR: 1.66; 95% CI: 1.02, 2.71), but not fluoxetine only (adjusted HR: 0.92; 95% CI: 0.55, 1.53). Risk estimates were elevated for citalopram users, but were based on only three events in the user group.
Table 2.
Antidepressant prescriptions filled after breast cancer diagnosis and before recurrence in 4216 women diagnosed with early stage breast cancer (Group Health, 1990–2008)
| Among users | ||
|---|---|---|
|
| ||
| Number of users (%)a | Median duration of use after diagnosis (months) | |
| Any antidepressant | 2302 (54.6) | 23.1 |
| Selective serotonin reuptake inhibitors | 1498 (35.5) | 18.7 |
| Strong CYP2D6 inhibitors | 1245 (29.5) | 13.8 |
| Paroxetine | 551 (13.1) | 8.5 |
| Fluoxetine | 904 (21.4) | 11.4 |
| Weak/Moderate CYP2D6 inhibitors | 579 (13.7) | 12.0 |
| Sertraline | 301 (7.1) | 10.0 |
| Citalopram | 337 (8.0) | 9.3 |
| Escitalopram | 17 (0.4) | 2.3 |
| Fluvoxamine | 3 (0.1) | 35.0 |
| Tricyclic antidepressants | 1128 (26.8) | 6.7 |
| Amitriptyline | 408 (9.7) | 5.9 |
| Nortriptyline | 537 (12.7) | 3.5 |
| Desipramine | 72 (1.7) | 5.4 |
| Doxepin | 206 (4.9) | 3.8 |
| Imipramine | 135 (3.2) | 6.4 |
| Protriptyline | 1 (0.02) | 1.3 |
| Miscellaneous antidepressants | 1099 (26.1) | 6.8 |
| Buproprion | 261 (6.2) | 6.5 |
| Trazodone | 785 (18.6) | 4.4 |
| Duloxetine | 21 (0.5) | 4.2 |
| Mirtazapine | 96 (2.3) | 6.2 |
| Nefazodone | 11 (0.3) | 6.3 |
| Tranylcypromine | 2 (0.1) | 23.7 |
| Venlafaxine | 127 (3.0) | 11.7 |
Categories of antidepressants are not mutually exclusive
Table 3.
Risk of breast cancer recurrence in relation to the use of antidepressants after a diagnosis of early stage breast cancer (Group Health, 1990–2008), N=4,216
| Person-years | Number of recurrences | Recurrence rate per 1,000 person-years (95% CI) | Unadjusted hazard ratio (95% CI) | Adjusted a hazard ratio (95% CI) | |
|---|---|---|---|---|---|
| Overall | 28063 | 415 | 14.8 (13.4, 16.3) | – | – |
| No antidepressant use | 15662 | 228 | 14.6 (12.8, 16.6) | Reference | Reference |
| Any antidepressant use | 12401 | 187 | 15.1 (13.1, 17.4) | 1.13 (0.93, 1.38) | 1.16 (0.94, 1.44) |
| SSRI use | |||||
| Only – restriction | 2917 | 45 | 15.4 (11.5, 20.7) | 1.05 (0.76, 1.45) | 1.11 (0.79, 1.55) |
| Any – adjustmentb | 7315 | 110 | 15.0 (12.5, 18.1) | 1.11 (0.89, 1.38) | 1.14 (0.88, 1.48) |
| Paroxetine only | 790 | 18 | 22.8 (14.4, 36.2) | 1.55 (0.96, 2.50) | 1.66 (1.02, 2.71) |
| Fluoxetine only | 1235 | 18 | 14.6 (9.2, 23.1) | 0.96 (0.60, 1.56) | 0.92 (0.55, 1.53) |
| Sertraline only | 255 | 3 | 11.8 (3.8, 36.5) | 0.80 (0.26, 2.51) | 0.88 (0.28, 2.76) |
| Citalopram only | 183 | 3 | 16.4 (5.3, 51.0) | 1.09 (0.35, 3.40) | 1.60 (0.52, 4.92) |
| TCA use | |||||
| Only – restriction | 3096 | 45 | 14.5 (10.9, 19.5) | 1.04 (0.76, 1.44) | 0.96 (0.67, 1.38) |
| Any – adjustmentb | 6527 | 93 | 14.2 (11.6, 17.5) | 1.09 (0.87, 1.38) | 1.04 (0.80, 1.35) |
| Amitriptyline only | 1057 | 14 | 13.2 (7.8, 22.4) | 0.94 (0.55, 1.61) | 0.89 (0.50, 1.60) |
| Nortriptyline only | 834 | 13 | 15.6 (9.0, 26.8) | 1.11 (0.63, 1.94) | 0.99 (0.53, 1.85) |
| Miscellaneous antidepressant use | |||||
| Only – restriction | 1279 | 23 | 18.0 (12.0, 27.1) | 1.27 (0.83, 1.95) | 1.41 (0.89, 2.23) |
| Any – adjustmentb | 5125 | 75 | 14.6 (11.7, 18.4) | 1.12 (0.87, 1.44) | 1.12 (0.83, 1.51) |
| Bupropion only | 180 | 0 | 0 | – | – |
| Trazodone only | 899 | 19 | 21.1 (13.5, 33.1) | 1.55 (0.97, 2.48) | 1.76 (1.06, 2.92) |
SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant; CI = confidence interval
All estimates are from separate models accounting for competing risks. Adjusted for age at diagnosis (18–49, 50–59, 60–69, 70–79, 80+ years), year of diagnosis (1990–1994, 1995–1999, 2000–2004, 2005–2008), American Joint Commission on Cancer stage (I, IIA, IIB), estrogen receptor (ER) and progesterone receptor (PR) status (ER+/PR+, ER+/PR−, ER−/PR+, ER−/PR−), primary treatment (mastectomy, breast conserving surgery with radiation, breast conserving surgery without radiation), chemotherapy treatment (yes, no), endocrine therapy (yes, no), body mass index (<18.5, 18.5–24.9, 25.0–29.9, 30.0–34.9, 35+ kg/m2), smoking at diagnosis (current, past, never/unknown), menopausal status at diagnosis (peri- or pre-menopausal, post-menopausal), and Charlson score (0, 1, 2+). Total number of participants in adjusted model was 3979 due to exclusion of women with unknown ER/PR status or BMI.
Unexposed groups for these analyses, i.e., non-users of specific antidepressants, are not shown in this table.
In the analysis restricted to tamoxifen users, concurrent use of most antidepressants was not associated with recurrence risk (Table 4). There was some suggestion of a decreased risk associated with concurrent weak CYP2D6-inhibitor use (adjusted HR: 0.51; 95% CI: 0.16, 1.62) and increased risk with concurrent paroxetine use (adjusted HR: 1.49; 95% CI: 0.79, 2.83). However, these estimates were based on only 6 and 16 events in the concurrent user groups, respectively. There were even fewer events among non-concurrent antidepressant users. For fluoxetine, recurrence risk was elevated with non-concurrent (adjusted HR: 2.21, CI: 1.04, 4.66) tamoxifen use, but not concurrent use.
Table 4.
Risk of breast cancer recurrence in relation to antidepressant use after a diagnosis of hormone receptor positive breast cancer among 1902 tamoxifen users (Group Health, 1990–2008)a
| Person-years | Number of recurrences | Recurrence rate per 1,000 person-years (95% CI) | Adjusted hazard ratio (95% CI)c | |
|---|---|---|---|---|
| Any antidepressant | ||||
| Non-user (tamoxifen only) | 7406 | 125 | 16.9 (14.1, 20.1) | Reference |
| Non-concurrent w/tamoxifen | 799 | 12 | 15.0 (7.8, 26.2) | 1.48 (0.75, 2.91) |
| Concurrent w/tamoxifenb | 3464 | 54 | 15.6 (11.7, 20.3) | 0.90 (0.64, 1.37) |
|
| ||||
| SSRIs | ||||
| Non-user (tamoxifen only) | 9240 | 150 | 16.2 (13.7, 19.1) | Reference |
| Non-concurrent w/tamoxifen | 651 | 12 | 18.4 (9.5, 32.2) | 1.82 (0.92, 3.61) |
| Concurrent w/tamoxifenb | 1778 | 29 | 16.3 (10.9, 23.4) | 1.10 (0.68, 1.79) |
| SSRI, Strong CYP2D6 inhibitord | ||||
| Non-user | 9654 | 155 | 16.1 (13.6, 18.8) | Reference |
| Non-concurrent w/tamoxifen | 585 | 11 | 18.8 (9.4, 33.7) | 1.84 (0.91, 3.73) |
| Concurrent w/tamoxifenb | 1430 | 25 | 17.5 (11.3, 25.8) | 1.15 (0.69–1.92) |
| SSRI, Weak/Moderate CYP2D6 inhibitorf | ||||
| Non-user (tamoxifen only) | 10881 | 184 | 16.9 (14.6, 19.5) | Reference |
| Non-concurrent w/tamoxifen | 241 | 1 | 4.2 (0.1, 23.1) | 0.43 (0.06, 3.15) |
| Concurrent w/tamoxifenb | 547 | 6 | 11.0 (4.0, 23.9) | 0.51 (0.16, 1.62) |
| Paroxetine | ||||
| Non-user (tamoxifen only) | 10659 | 172 | 16.1 (13.8, 18.7) | Reference |
| Non-concurrent w/tamoxifen | 340 | 3 | 8.8 (1.8, 25.8) | 0.95 (0.30, 3.05) |
| Concurrent w/tamoxifenb | 670 | 16 | 23.9 (13.6, 38.8) | 1.49 (0.79, 2.83) |
| Fluoxetine | ||||
| Non-user (tamoxifen only) | 10367 | 170 | 16.4 (14.0, 19.1) | Reference |
| Non-concurrent w/tamoxifen | 459 | 11 | 24.0 (12.0–42.9) | 2.21 (1.04, 4.66) |
| Concurrent w/tamoxifenb | 843 | 10 | 11.9 (5.7, 21.8) | 0.73 (0.34, 1.59) |
|
| ||||
| TCAs | ||||
| Non-user (tamoxifen only) | 9451 | 153 | 16.2 (13.7, 19.0) | Reference |
| Non-concurrent w/tamoxifen | 546 | 11 | 20.2 (10.1, 36.1) | 1.26 (0.58, 2.74) |
| Concurrent w/tamoxifenb | 1672 | 27 | 16.2 (10.6, 23.5) | 0.79 (0.48, 1.31) |
|
| ||||
| Miscellaneous antidepressant | ||||
| Non-user (tamoxifen only) | 10229 | 170 | 16.6 (14.2, 19.3) | Reference |
| Non-concurrent w/tamoxifen | 412 | 10 | 24.3 (11.6, 44.7) | 1.99 (0.90, 4.40) |
| Concurrent w/tamoxifenb | 1028 | 11 | 10.7 (5.3, 19.1) | 0.74 (0.36, 1.52) |
SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant; CI = confidence interval; w/ = with
Restricted to 1902 women using tamoxifen for ≥60 days and no prior aromatase inhibitor use
Concurrent use ≥60 days
All estimates are from separate models accounting for competing risks. Censoring events were start of aromatase inhibitors, second primary breast cancer, death, Group Health disenrollment, and end of study follow-up. Adjusted for age at diagnosis (18–49, 50–59, 60–69, 70–79, 80+ years), year of diagnosis (1990–1994, 1995–1999, 2000–2004, 2005–2008), and American Joint Commission on Cancer stage
Paroxetine and fluoxetine
Sertraline, citalopram, fluvoxamine, and escitalopram
Antidepressant use was not associated with breast cancer mortality (adjusted HR: 95% CI: 1.09; 95% CI: 0.83, 1.43) (Table 5). Confidence intervals for classes of antidepressants and individual drugs were wide. Post-hoc adjustment for depression did not change results meaningfully and are therefore not presented.
Table 5.
Risk of breast-cancer specific death in relation to the use of antidepressants after a diagnosis and before recurrence (Group Health 1990–2008), N=4,216
| Person-years | Number of deaths due to breast cancer | Breast cancer mortality rate per 1,000 person-years (95% CI) | Unadjusted hazard ratio (95% CI) | Adjusteda hazard ratio (95% CI) | |
|---|---|---|---|---|---|
| Overall | 29900 | 264 | 8.8 (7.8, 10.0) | – | – |
| No use | 16724 | 145 | 8.7 (7.4, 10.2) | Reference | Reference |
| Any antidepressant use | 13176 | 119 | 9.0 (7.5, 10.8) | 1.03 (0.81, 1.32) | 1.09 (0.83, 1.43) |
| SSRI use | |||||
| Only – restriction | 3024 | 18 | 6.0 (3.7, 9.4) | 0.85 (0.52, 1.40) | 0.89 (0.52, 1.50) |
| Any – adjustment | 7714 | 70 | 9.1 (7.2, 11.5) | 1.03 (0.78, 1.36) | 1.14 (0.83, 1.56) |
| Paroxetine only | 834 | 4 | 4.8 (1.8, 12.8) | 0.76 (0.28, 2.08) | 0.99 (0.35, 2.83) |
| Fluoxetine only | 1268 | 7 | 5.5 (2.6, 11.6) | 0.82 (0.38, 1.77) | 0.71 (0.30, 1.67) |
| Sertraline only | 258 | 3 | 11.7 (3.8, 36.1) | 1.98 (0.63, 6.26) | 2.42 (0.83, 7.02) |
| Citalopram only | 189 | 2 | 10.6 (2.6, 42.3) | 1.69 (0.42, 6.89) | 2.52 (0.57, 11.20) |
| TCA use | |||||
| Only – restriction | 3269 | 20 | 6.1 (3.9, 9.5) | 0.92 (0.57, 1.49) | 0.82 (0.48, 1.42) |
| Any - adjustment | 7035 | 65 | 9.2 (7.2, 11.8) | 1.06 (0.80, 1.41) | 1.04 (0.77, 1.43) |
| Amitriptyline only | 1101 | 5 | 4.5 (1.9, 10.9) | 0.75 (0.30, 1.83) | 0.71 (0.28, 1.81) |
| Nortriptyline only | 889 | 6 | 6.7 (3.0, 15.0) | 1.05 (0.46, 2.40) | 0.81 (0.31, 2.08) |
| Miscellaneous antidepressant use | |||||
| Only – restriction | 1312 | 10 | 7.6 (4.1, 14.2) | 1.22 (0.64, 2.34) | 1.55 (0.79, 3.04) |
| Any – adjustment | 5407 | 43 | 8.0 (5.9, 10.7) | 0.88 (0.63, 1.22) | 0.92 (0.61, 1.38) |
| Bupropion only | 180 | 1 | 5.6 (0.8, 39.5) | 0.94 (0.13, 6.71) | 1.70 (0.22, 13.10) |
| Trazodone only | 929 | 6 | 6.5 (2.9, 14.4) | 1.07 (0.47, 2.43) | 1.25 (0.51, 3.00) |
SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant; CI = confidence interval
All estimates are from separate models. Adjusted for age at diagnosis (18–49, 50–59, 60–69, 70–79, 80+ years), year of diagnosis (1990–1994, 1995–1999, 2000–2004, 2005–2008), American Joint Commission on Cancer stage (I, IIA, IIB), estrogen receptor (ER) and progesterone receptor (PR) status (ER+/PR+, ER+/PR−, ER−/PR+, ER−/PR−), primary treatment (mastectomy, breast conserving surgery with radiation, breast conserving surgery without radiation), chemotherapy treatment (yes, no), endocrine therapy (yes, no), body mass index (<18.5, 18.5–24.9, 25.0–29.9, 30.0–34.9, 35+ kg/m2), smoking at diagnosis (current, past, never/unknown), menopausal status at diagnosis (peri- or pre-menopausal, post-menopausal), and Charlson score (0, 1, 2+). Total number of participants in adjusted model was 3924 due to exclusion of women with unknown ER/PR status or BMI.
Unexposed groups for these analyses, i.e., non-users of specific antidepressants, are not shown in this table.
DISCUSSION
Our study provides some reassurance that many commonly used antidepressant medications are not associated with an increased risk of breast cancer recurrence. Results from this large, population-based retrospective cohort study are generally consistent with other studies that have generally not observed an increased risk of breast cancer recurrence with antidepressant use [6].
We hypothesized that paroxetine and fluoxetine would increase recurrence risk among tamoxifen users because these antidepressants inhibit the conversion of tamoxifen to its active form [5–7]. There was a suggestion of increased risk with concurrent paroxetine use among tamoxifen users. This finding is consistent with point estimates in one study (odds ratio for recurrence: 2.4, 95% CI: 0.6–9.5) [22], but not another (HR for disease free survival: 0.84; 95% CI: 0.34–2.05) [25]. Of note, all three studies (including ours) had wide confidence intervals.
Among tamoxifen users, we also observed that fluoxetine was associated with an increased risk of recurrence when taken separately from tamoxifen (i.e., non-concurrently) but not at the same time (i.e., concurrently). This is surprising and inconsistent with the biological hypothesis, which would suggest that fluoxetine, a strong CYP2D6 inhibitor, would affect breast cancer recurrence risk by reducing tamoxifen’s effectiveness if the two medications were used concurrently. In general, our findings for non-concurrent antidepressant use among tamoxifen users should be cautiously interpreted due to small sample size.
We saw an increased risk of recurrence with trazodone use. Trazodone may be a weak/moderate CYP2D6 inhibitor [30,43], but to our knowledge, other studies have not looked specifically at the risk of recurrence in relation to trazodone use. Given trazadone is commonly used for insomnia [44], it is unclear whether our findings are due to chance or confounding by indication. The suggested increased risk of recurrence with citalopram should also be interpreted cautiously as it was based on only three events and is not consistent with findings from larger studies [22,23,31]. Similarly, the small number of deaths due to breast cancer in each drug exposure category limits our ability to draw conclusions.
Our study had relatively long follow-up and high-quality longitudinal, prospectively collected data on exposures, outcomes, and confounders with gold-standard chart-review for many of these variables. Variables were not subject to recall bias. A limitation was that we had very small number of events when examining individual drugs, particularly for analyses of non-concurrent use among patients taking tamoxifen. This has been a common issue in other studies of specific antidepressant use and breast cancer recurrence [22,23,25,26,31] and motivates the need for pooled meta-analyses on specific drugs. We anticipated this problem, but believed that these analyses were still important to conduct. Women will benefit from having information about the risk profiles of individual antidepressants to make decisions about which may be safer to use after breast cancer diagnosis. Last, COMBO uses data from a single health plan and includes an educated, primarily white population, and individuals with access to both medical care and prescription drug benefits. This may limit generalizability to some populations if the biological effect of antidepressants differs by patient characteristics.
Having access to the most important predictors of cancer recurrence (i.e., disease characteristics) helped reduce confounding, but residual confounding may have been present. For example, there may be lifestyle risk factors for recurrence that are also associated with antidepressant use. Confounding by indication is also a possibility in this study; even though all medications studied are used for depression, some have other indications (e.g., anxiety, pain, sleep). We did not have information on the reasons for antidepressant use and therefore could not adjust for it. It is also possible that antidepressants were used for symptoms of an undiagnosed recurrence. Under such circumstances, they could appear to increase the risk of recurrence due to reverse causality (i.e., protopathic bias). To protect against confounding by indication in the breast cancer mortality analysis (i.e., a woman started using antidepressants because she had a recurrence), we counted only exposure initiated before recurrence [42].
Conclusions
Our results provide important information on antidepressant use after breast cancer diagnosis including information on individual drugs, which – when combined systematically and quantitatively with results from other studies – may be useful for patients and providers making decisions about whether to use these medications.
Supplementary Material
Acknowledgments
The authors would like to thank Dr. Heidi Wirtz for helpful discussions and input on preliminary analyses.
FUNDING
This study was funded by the National Cancer Institute at the National Institutes of Health, Award Number 1R01CA1205621 to Denise M. Boudreau. Part of the data collection was supported by a grant from the National Cancer Institute: U01CA63731, PI: Buist. The collection of cancer incidence data used in this study was supported by the Cancer Surveillance System of the Fred Hutchinson Cancer Research Center, which is funded by Contract No. N01-CN-67009 and N01-PC-35142 from the Surveillance, Epidemiology and End Results (SEER) Program of the National Cancer Institute with additional support from the Fred Hutchinson Cancer Research Center and the State of Washington. Funders did not participate in the design, data collection, manuscript drafting, or decision to submit the manuscript for publication.
Footnotes
CONFLICTS OF INTERST
Ms. Yu has received funding from unrelated research grants awarded to Group Health Research Institute from Amgen and Bayer. Dr. Boudreau has received funding from unrelated research grants awarded to Group Health Research Institute from Amgen, Sanofi Aventis, and Johnson & Johnson.
ETHICAL APPROVAL
For this type of study formal consent is not required.
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