Abstract
Background
Prior studies evaluating psychotropic medications in relation to breast cancer risk are inconsistent and have not separately evaluated invasive and in situ disease.
Methods
We estimated hazard ratios (HR) and 95% confidence intervals (CI) for the association of psychotropic medication use (any, typical antipsychotics, atypical antipsychotics, lithium) with invasive and in situ breast cancer risk among Women’s Health Initiative participants (N=155,737).
Results
Prevalence of psychotropic medication use was low (n=642; 0.4%). During an average 14.8 (SD 6.5) years of follow-up, 10,067 invasive and 2,285 in situ breast were diagnosed. Any psychotropic medication use was not associated with invasive breast cancer risk compared to non-users (HR 0.82, 95% CI 0.57–1.18). In situ breast cancer risk was higher among “typical” antipsychotic medication users compared with non-users (HR 2.05, 95% CI 0.97–4.30).
Conclusions
Findings do not support an association of psychotropic medication use with invasive breast cancer risk. The possible elevation in in situ breast cancer risk associated with “typical” antipsychotics could not be explained by differences in screening mammography utilization and merits further study.
Impact
Our findings contribute to knowledge of the safety profile of psychotropic medications and may be useful to clinicians and patients considering use of these medications.
Introduction
An estimated 268,600 new female breast cancer (BC) cases are expected in 2019 (1). Psychotropic medications have been associated with modest increases in BC risk in some (2–4), but not other (5–7), epidemiologic investigations. Elevated prolactin levels are a common adverse effect of psychotropic drugs, especially with typical antipsychotics (first-generation drugs). In contrast, atypical antipsychotics (second-generation drugs), except for risperidone, cause smaller prolactin elevations. Higher circulating prolactin levels are associated with higher BC risk, especially for hormone-receptor positive and postmenopausal disease (8). Given prior inconsistent results, we prospectively evaluated associations between psychotropic medication use and postmenopausal BC risk within the Women’s Health Initiative (WHI) cohort, a large prospective population-based cohort with high quality data on medication use and adjudicated BC outcomes.
Methods
WHI enrolled postmenopausal women ages 50–79 years into observational study (OS) or clinical trial (CT) components from 1993–1997 at 40 clinical centers nationwide (N=161,808). Participants provided written informed consent at enrollment, and IRB approval was obtained at each clinical center. For this analysis we excluded participants with a personal BC history (N=5,397) or <1 day follow-up time (N=674), giving a final analytic cohort of 155,737 postmenopausal women.
Participants brought all current prescription and non-prescription medications and supplements to their baseline visit. A research nurse recorded each medication name and dosage. We classified reported antipsychotic medications as “typical” (fluphenazine, chlorpromazine, haloperidol, thiothixene, flupenthixol, and molindone) or “atypical” (risperidone, clozapine, olanzapine, and aripiprazole) based on their structures and mechanisms of action using UpToDate® (Waltham, MA). Participants were categorized as using any psychotropic medications (no, yes) and separately by use of typical (no, yes) or atypical (no, yes) antipsychotics or lithium (no, yes); users of typical antipsychotics who did not also use atypical antipsychotics were classified as “no” for atypical use, and vice versa. BC cases were centrally adjudicated using medical records.
We compared baseline descriptive statistics between users and non-users of psychotropic medications. Hazard ratios (HR) and 95% confidence intervals (CI) examining associations of psychotropic medications with BC were estimated using Cox proportional hazards regression models. Follow-up time began at enrollment; participants were censored at either BC diagnosis, death, loss to follow-up, or March 31, 2018, whichever came first. We decided a priori to adjust for age and WHI study arm (OS vs CT) and arm of hormone therapy clinical trial given known differences in BC risk across these groups; these adjusted HRs changed <2% when additional variables were included (i.e. characteristics summarized in Table 1). Thus, our final model adjusted for age and the WHI study participation variables.
Table 1.
Descriptive characteristics of participants at baseline, N=155,737
| Psychotropic Drug Use | |||
|---|---|---|---|
| Characteristic | Users (N=642) | Non-Users (N=155,095) | P value |
| Age, years; Mean (SD) | 62.14 (7.20) | 63.19 (7.22) | 0.0003 |
| White; N (%) | 526 (82.2) | 128,048 (82.8) | 0.45 |
| Married; N (%) | 292 (45.7) | 96,463 (62.5) | <0.0001 |
| College degree; N (%) | 286 (45.0) | 60,614 (39.4) | 0.01 |
| Body mass index, kg/m2; Mean (SD) | 29.02 (6.19) | 27.98 (5.94) | <0.0001 |
| Obese; N (%) | 228 (36.1) | 46,417 (30.2) | 0.0003 |
| Current Smoker; N (%) | 105 (16.6) | 10,679 (7.0) | <0.0001 |
| ≥1 Alcoholic drink/week; N (%) | 158 (24.8) | 57,509 (37.4) | <0.0001 |
| Healthy Eating Index score; Mean (SD)1 | 63.66 (10.13) | 65.05 (10.43) | 0.0007 |
| First degree relative with breast cancer; N (%) | 103 (16.0) | 26,753 (17.2) | 0.42 |
| Ever had a mammogram; N (%) | 622 (97.2) | 148,694 (96.4) | 0.27 |
| History of benign breast disease; N (%) | 141 (23.1) | 31,370 (21.4) | 0.30 |
| Nulliparous; N (%) | 116 (18.3) | 18,104 (11.7) | <0.0001 |
| Age at menopause; Mean (SD) | 47.26 (6.98) | 48.09 (6.45) | 0.002 |
| Current postmenopausal hormone therapy use; N (%) | 263 (41.0) | 63,934 (41.3) | 0.76 |
| Observational study participant; N (%) | 416 (64.8) | 87,508 (56.4) | <0.0001 |
| Typical antipsychotic use; N (%)2 | 272 (42.4) | n/a | -- |
| Atypical antipsychotic use; N (%)2 | 59 (9.2) | n/a | -- |
| Lithium use; N (%)2 | 326 (50.8) | n/a | -- |
n/a: not applicable
Healthy Eating Index score calculated based on U.S. Department of Agriculture guidelines, where a higher score indicates a diet that more closely adheres to the guidelines
Some participants used more than one type of psychotropic medication, therefore the sum of typical, atypical, and lithium users is greater than the total number of users of any medication
We performed sensitivity analyses among the subgroup of women with regular mammograms during the first 10 years of follow-up, as determined by study protocol for CT participants or self-report of ≥6 mammograms during the 10 year period for OS participants (N=133,754). We repeated analyses restricting to estrogen-receptor positive (ER+) BCs. We also incorporated medication use at the year 3 follow-up visit, and repeated analyses as described above, starting follow-up time at year 3, and also estimating HRs for the consistency of psychotropic medication use between baseline and year 3 (never used, initiated use, stopped use, consistent use).
Results
Prevalence of psychotropic medication use was low (n=642; 0.4%), with most users taking either a typical antipsychotic (n=272; 42.4%) or lithium (n=326; 50.8%) (Table 1). During an average 14.8 (SD 6.5) years of follow-up, 10,097 invasive and 2,285 in situ BCs were diagnosed (Table 2). The average age at BC diagnosis was 72.0 years (range 50–99). No association between any psychotropic medication use and invasive BC was observed (HR 0.82, 95% CI 0.57–1.18); likewise, there was no association of typical or atypical antipsychotics or lithium with invasive BC risk. Psychotropic medication use was positively associated with increased in situ BC risk (HR 1.66, 95% CI 0.98–2.81), which likely was driven by typical antipsychotic use (HR 2.05, 95% CI 0.97–4.30); results were similar when restricted to participants with regular mammograms (HR 1.87, 95% CI 0.84–4.16). Results were similar when restricting to ER+ cancers and when modeling psychotropic medication use at year 3. No associations were observed between consistency of psychotropic medication use at baseline and year 3 and invasive or in situ BC risk (data not shown).
Table 2.
Multivariable adjusted associations between psychotropic medication use at baseline and incident breast cancer, N=155,7371
| Full Study Population N=155,737 |
Regular Mammogram Users N=133,754 |
|||||||
|---|---|---|---|---|---|---|---|---|
| Cases | Person-Years | Adjusted HR (95% CI) | P value | Cases | Person-Years | Adjusted HR (95% CI) | P value | |
| Invasive breast cancer | ||||||||
| Any psychotropic drug use | ||||||||
| No | 10,067 | 2,292,928 | 1 (ref) | -- | 9,274 | 2,022,856 | 1 (ref) | -- |
| Yes | 30 | 8,358 | 0.82 (0.57–1.18) | 0.29 | 29 | 7,116 | 0.89 (0.62–1.28) | 0.53 |
| Typical antipsychotic use | ||||||||
| No | 10,087 | 2,297,891 | 1 (ref) | -- | 9,294 | 2,027,051 | 1 (ref) | -- |
| Yes | 10 | 3,395 | 0.67 (0.36–1.25) | 0.21 | 9 | 2,922 | 0.66 (0.35–1.28) | 0.22 |
| Atypical antipsychotic use | ||||||||
| No | 10,093 | 2,300,660 | 1 (ref) | -- | 9,299 | 2,029,485 | 1 (ref) | -- |
| Yes | 4 | 626 | 1.45 (0.54–3.87) | 0.46 | 4 | 487 | 1.78 (0.67–4.75) | 0.25 |
| Lithium use | ||||||||
| No | 10,079 | 2,296,770 | 1 (ref) | -- | 9,285 | 2,026,046 | 1 (ref) | -- |
| Yes | 18 | 4,516 | 0.92 (0.58–1.46) | 0.72 | 18 | 3,926 | 1.01 (0.64–1.61) | 0.96 |
| In situ breast cancer2 | ||||||||
| Any psychotropic drug use | ||||||||
| No | 2,271 | 2,291,956 | 1 (ref) | -- | 2,153 | 2,021,940 | 1 (ref) | -- |
| Yes | 14 | 8,340 | 1.66 (0.98–2.81) | 0.06 | 13 | 7,098 | 1.67 (0.97–2.88) | 0.07 |
| Typical antipsychotic use | ||||||||
| No | 2,278 | 2,296,919 | 1 (ref) | -- | 2160 | 2,026,135 | 1 (ref) | -- |
| Yes | 7 | 3,376 | 2.05 (0.97–4.30) | 0.06 | 6 | 2,903 | 1.87 (0.84–4.16) | 0.13 |
| Lithium use | ||||||||
| No | 2,278 | 2,295,780 | 1 (ref) | -- | 2159 | 2,025,112 | 1 (ref) | -- |
| Yes | 7 | 4516 | 1.53 (0.73–3.22) | 0.26 | 7 | 3926 | 1.64 (0.78–3.44) | 0.19 |
All models adjusted for age, OS vs CT participation, HT trial arm
Estimates for atypical antipsychotic medication use are not estimable because no users were diagnosed with in situ breast cancer
Discussion
Our results do not support an association between psychotropic medication use and subsequent invasive BC risk. We did observe a suggestive two-fold increase in in situ BC risk associated with typical antipsychotic use, which persisted among the subgroup of women with regular mammograms. The consistency of these results suggests that screening differences between users and non-users may not fully account for the elevated risk. However, our findings were limited by a small number of psychotropic medication users, including only 7 typical antipsychotic users later diagnosed with in situ BC, and thus should be interpreted cautiously. We are unaware of a potential biologic mechanism that would result in psychotropic medications increasing only in situ BC risk. Additional limitations include the potential for underreporting of psychotropic medications if women selectively chose not to bring such medications to their clinical visit, as well as the inability to distinguish between diagnostic and screening mammograms for OS participants. Prior studies have either included only invasive cases (2) or have not stratified analyses by invasiveness (3–7), thus additional evaluations, perhaps with pooled data across multiple studies, are needed. Overall, our findings contribute to knowledge of the safety profile of psychotropic medications and may be useful to clinicians and patients considering use of these medications.
Acknowledgments
The authors would like to thank the following:
Program Office: (National Heart, Lung, and Blood Institute, Bethesda, Maryland) Jacques Rossouw, Shari Ludlam, Joan McGowan, Leslie Ford, and Nancy Geller Clinical Coordinating Center: (Fred Hutchinson Cancer Research Center, Seattle, WA) Garnet Anderson, Ross Prentice, Andrea LaCroix, and Charles Kooperberg Investigators and Academic Centers: (Brigham and Women’s Hospital, Harvard Medical School, Boston, MA) JoAnn E. Manson; (MedStar Health Research Institute/Howard University, Washington, DC) Barbara V. Howard; (Stanford Prevention Research Center, Stanford, CA) Marcia L. Stefanick; (The Ohio State University, Columbus, OH) Rebecca Jackson; (University of Arizona, Tucson/Phoenix, AZ) Cynthia A. Thomson; (University at Buffalo, Buffalo, NY) Jean Wactawski-Wende; (University of Florida, Gainesville/Jacksonville, FL) Marian Limacher; (University of Iowa, Iowa City/Davenport, IA) Jennifer Robinson; (University of Pittsburgh, Pittsburgh, PA) Lewis Kuller; (Wake Forest University School of Medicine, Winston-Salem, NC) Sally Shumaker; (University of Nevada, Reno, NV) Robert Brunner; (University of Minnesota, Minneapolis, MN) Karen L. Margolis
Funding
The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts, HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C
Abbreviations:
- BC
breast cancer
- CI
confidence interval
- CT
clinical trial
- ER
estrogen receptor
- HR
hazard ratio
- OS
observational study
- WHI
Women’s Health Initiative
Footnotes
Conflict of Interest: The authors have no potential conflicts of interest to disclose
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