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Breast Cancer Drug Tamoxifen Increases Anxiety Behaviors in Female Nonhuman Primates

April 8, 2005

Researchers caution side effects are strong enough to hinder compliance with medication

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Lisa Newbern, 404-727-7709,

ATLANTA — Tamoxifen, the most widely prescribed drug for treating and preventing breast cancer in women, increases anxiety behaviors in female rhesus macaques, according to a study conducted at the Yerkes National Primate Research Center of Emory University by Yerkes, Emory and Atlanta-based Center for Behavioral Neuroscience (CBN) researchers. The researchers caution the extent of the side effects could hinder compliance in women using the popular medication. The study is reported in the online edition of Psychoneuroendocrinology in the journal’s April edition.

While studies have shown tamoxifen significantly improves survival rates for women with breast cancer by blocking the effects of estrogen, clinical evidence suggests the drug increases rates of anxiety and the incidence of hot flashes, both of which may result from reduced action of estrogen. To determine if tamoxifen had these behavioral effects in both the presence and absence of estrogen, Mark Wilson, PhD, chief of the Division of Psychobiology at Yerkes, and his colleagues compared the behavior of four groups of adult female rhesus macaques that were not producing estrogen. The groups were divided into a placebo group; a group that received estradiol, a natural estrogen; a tamoxifen group; and a tamoxifen-plus-estradiol group.

After a three-week period, the researchers observed rates of anxiety-like behaviors were significantly higher in the tamoxifen and tamoxifen-plus-estradiol groups compared with females receiving estradiol only.

“Tamoxifen not only appears to antagonize estrogen’s anxiety-reducing effect, but also to increase anxiety-like behavior by itself, in the absence of estrogen,” said Wilson. “While tamoxifen is an extremely effective anti-cancer medication, women may stop taking it because of its negative effects on behavior and emotion.”

In other tests, Wilson and his colleagues measured serotonin activity, a marker for depression, in the animals’ brains to determine if depression increased with tamoxifen. As expected, the researchers found estradiol increased serotonin activity in the monkeys, causing them not to be depressed. In both the tamoxifen and the tamoxifen-plus-estradiol groups, however, serotonin activity was unaffected compared to placebo treated controls. “We expected tamoxifen would reduce serotonin activity because of its attenuating effects on estradiol,” said Wilson. “Our findings, however, suggest tamoxifen must be producing its negative behavioral effects through its action on a different neurotransmitter involved in mood.”

Wilson and his colleagues’ latest finding about tamoxifen adds to a growing body of evidence about the drug’s negative behavioral effects. In a previous study, Wilson and his colleagues found tamoxifen inhibits sexual behavior in female rhesus macaques.

Currently, Wilson, in conjunction with a team of researchers from the Emory University School of Medicine Department of Psychiatry and Behavioral Sciences and the Winship Cancer Institute, is examining the interaction between tamoxifen and a commonly prescribed class of anti-depression medications – selective serotonin reuptake inhibitors (SSRIs). The 12-month study is following two groups of rhesus macaques, a tamoxifen-only group and a tamoxifen-plus-SSRI group, to determine whether SSRIs diminish anxiety behaviors. The study will determine whether the SSRIs reduce the anxiety-like behavior in tamoxifen-treated monkeys and, if so, if they do so by changing the metabolism of tamoxifen thereby reducing its biological activity. Although this would relieve symptoms of anxiety, it also could reduce the efficacy of tamoxifen to fight breast cancer. Such findings will be critical information for clinicians.

The tamoxifen study was funded by a grant from the National Institute on Child Health and Development. The current study involving SSRIs is funded by the Woodruff Health Sciences Research Fund, which is designed to stimulate interdisciplinary research collaborations within the Emory community.

The Robert W. Woodruff Health Sciences Center of Emory University is an academic health science and service center focused on missions of teaching, research, health care and public service. Its components include the Emory University School of Medicine, Nell Hodgson Woodruff School of Nursing, and Rollins School of Public Health; Yerkes National Primate Research Center; Winship Cancer Institute of Emory University; and Emory Healthcare, the largest, most comprehensive health system in Georgia. Emory Healthcare includes: The Emory Clinic, Emory-Children's Center, Emory University Hospital, Emory University Hospital Midtown, Wesley Woods Center, and Emory University Orthopaedics & Spine Hospital. The Woodruff Health Sciences Center has a $2.5 billion budget, 17,600 employees, 2,500 full-time and 1,500 affiliated faculty, 4,700 students and trainees, and a $5.7 billion economic impact on metro Atlanta.

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