Original article
Systematic review of the epidemiologic and trial evidence of an association between antidepressant medication and breast cancer

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Abstract

Biologic studies have suggested that antidepressant use may increase breast cancer risk. We conducted a systematic review of trials and controlled epidemiologic studies to assess this association. Pooled data from 31 primary efficacy drug company trials of fluoxetine suggested no increased risk but the short duration of these trials may have been insufficient to detect an association. In one prospective cohort study antidepressant use was associated with breast cancer, but this study was conducted among women attending for breast screening, and only limited data on antidepressant use were available. In a second large prospective drugs screening study no association was found between either amitriptyline or imipramine and breast cancer. In a large well-conducted retrospective cohort study there was no association between antidepressant use and breast cancer. A second retrospective cohort study was flawed, with exposure in those who developed breast cancer being measured over a shorter time period than in those who remained disease free. Two of four case–control studies found no association between antidepressant use and breast cancer after control for a number of potential confounding factors. We conclude that epidemiologic evidence does not support an association between antidepressant use and breast cancer.

Introduction

Breast cancer is the commonest malignancy in women worldwide, accounting for nearly one-fifth of all female cancers [1]. Antidepressant drug use is also common, and is increasing 2, 3. Biological studies, conducted in the 1990s, suggested that both tricyclic and serotonin reuptake inhibitor (SSRI) antidepressants may increase breast cancer risk or promote tumor growth [4]. These findings created alarm in the medical and popular press 5, 6. Animal studies performed by scientists working for a pharmaceutical company that produces fluoxetine, an SSRI, found no evidence of increased risk with this drug [7].

Biological plausibility for an association comes from animal and laboratory studies that show that both tricyclic and SSRI antidepressants are chemically similar to an antioestrogen binding site that stimulates breast cancer growth in animals [4], inhibits lymphocyte proliferation [4], and stimulates secretion of prolactin from the pituitary gland 8, 9. However, the therapeutic and side-effect profiles of antidepressants indicate that they influence a number of different biological pathways, and some researchers have suggested that they may even have antitumor potential because they inhibit cellular proliferation [10].

Findings from animal studies may not be relevant to humans, but media reports from these, without good evidence to refute the findings, may lead to inappropriate changes in prescribing behavior for women with depression. On the other hand, given the widespread and increasing use of antidepressants, if there were an association between antidepressant use and breast cancer this would have important public health implications. Therefore, it is essential that evidence of an association between antidepressants and breast cancer is sought in studies of women. Two recently published studies—a community-based case–control study [11] and a prospective cohort study [12]—found conflicting results concerning the association between antidepressant use and breast cancer, the former reporting no association and the latter a positive association. Neither study undertook a systematic review of the available evidence to examine the direction of association in all other studies that have been conducted. In this article we summariae all available evidence from trials and epidemiological studies.

Section snippets

Data sources

We searched Medline (1966–June 2002), Embase (1980–June 2002), PsycLit (1981–June 2002), Science Citation's Index (1975–June 2002), and the Cochrane Database of Systematic Reviews and Controlled Trials Register (2001 issue 1) using Medical Subject Headings (MeSH) and free text terms where appropriate. We combined the terms “antidepressive agents,” “serotonin (re)uptake inhibitors,” “tricyclic, monoamine oxidase inhibitors,” and the generic names of all antidepressant drugs included in chapter

Results

In this section we have included descriptions of the methodologic strengths and weaknesses of each study. The likely impact of these on study results are discussed more fully in the discussion section of the article.

The results of the literature search are presented in Figure 1. Details from primary efficacy trials from one drug company, two prospective and two retrospective cohort studies, and four case control studies were analyzed (Table 1). Figure 2 shows the effect sizes from each study.

Discussion

The suspected association, based on animal studies, between antidepressant use and breast cancer cannot be confirmed with current epidemiologic evidence. Most studies found no association between antidepressant use and breast cancer risk.

A positive association was found in one prospective cohort study [12]. Exposure misclassification in this study is unlikely to be linked to breast cancer occurrence (i.e., it is nondifferential), and therefore, would most likely bias the estimate towards the

Acknowledgments

We thank Gary D Friedman, Division of Research, Kaiser Permanent Medical Care Programme, Northern California, who provided additional data from the Kaiser Permanent drugs screening cohort, and Eli-Lily Pharmaceuticals for provision of their trial data and permission to use this in our review. Richard Martin and Klim McPherson, Department of Social Medicine, University of Bristol, provided useful comments on earlier drafts of the article. There were no conflicts of interest in this article. D.A.

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