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Depression's effect on immune system may worsen cancer, study suggests

- By Stephanie Pappas

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David Spiegel

Women with breast cancer and depression are at higher risk of cancer recurrence and early death than breast cancer patients without depression, recent research shows. Now, Stanford University School of Medicine scientists have found evidence that the reason could be the psychiatric disorder’s effects on immune cells.

The new study found that the more symptoms of depression exhibited by women with metastatic breast cancer, the less intense their immune responses were to seven common bacteria, fungi and yeasts. The researchers also found that patients with more cortisol, an immune-suppressing hormone released at high levels during chronic stress and depression, did not respond to as many of the immune-irritating substances than did women with lower cortisol levels.

“This tells us stress and depression may impair a cancer patient’s body’s ability to fight off infection and potentially to deal with the progression of the disease,” said David Spiegel, MD, the Jack, Lulu and Sam Willson professor and associate chair of psychiatry and behavioral sciences. Spiegel is the senior author of the study, now available online in advance of its print publication in the journal Brain, Behavior and Immunity.

Between 15 and 25 percent of cancer patients experience major depression, marked by feelings of hopelessness, helplessness, worthlessness, fatigue and loss of interest in daily life. Depression may make cancer patients’ prognosis worse: Studies have shown that higher levels of depression correlate with faster tumor growth, and Spiegel and others have found evidence that women with some types of cancer live longer if they participate in support groups designed to reduce emotional problems. Multiple studies have shown that people with depression have higher levels of the hormone cortisol, which acts on the immune system. And earlier studies done by Spiegel and former postdoctoral researcher Sandra Sephton, PhD, found that abnormal patterns of cortisol levels throughout the day predicted early mortality years later in women with metastatic breast cancer. Those studies prompted Spiegel and other researchers to wonder if elevated cortisol caused by depression disrupts the immune system and leaves patients vulnerable to both their tumors and outside infection.

To investigate the link between depression and disease process, Spiegel and his colleagues focused on depressive symptoms, cortisol and cell-mediated immunity in 72 women with metastatic breast cancer. Cell-mediated immunity is the deployment of pathogen-killing immune cells to wounds or infected areas.

First, the women completed questionnaires detailing any depression symptoms, and collected samples of their saliva using cotton swabs four times a day for three days. The researchers analyzed those samples for cortisol levels. They then asked the women to take a test in which harmless fragments of infectious agents like the tetanus bacterium and candida yeast were injected just under the skin of their forearms. Only common agents, or antigens, were used, so most women would have been previously exposed and their immune systems primed to react to the latest invasion with a flood of immune cells. Two days later, researchers measured the sites of the injection for swelling, a sign that the immune cells had responded to the antigens and were present.

The results showed that women with lower total cortisol levels responded to almost twice as many antigens as their high-cortisol counterparts. And though they didn’t see a significant correlation between depression scores and cortisol levels, the researchers found that those with low depression scores had an average diameter of about 5 millimeters of swelling at their injection sites. For those with high depression scores, the average diameter was closer to 3 millimeters.

The results leave a lot of questions, but they do suggest that both cortisol and depression suppress cellular immune response. Some of the suppressed cells are known cancer-fighters, Spiegel said. Though the depression and high cortisol link wasn’t strong in this study, Spiegel noted that there was a relationship between high morning levels of cortisol and depression, suggesting that the hormone was dysregulated in depressed patients.

“What the investigators at Stanford have done is begin to identify the mechanisms for the relationship between depression and a worse outcome in cancer,” said Emory University School of Medicine psychiatrist Andrew Miller, MD, who also directs a psychiatric oncology program in Atlanta and was not involved in the Stanford study. However, he cautioned, there is still controversy in the field over whether cortisol acts directly to suppress immune cells or whether other mechanisms, such as inflammation, play a role.

More research will need to be done to tease out the role of cortisol in cancer prognosis. But the findings underscore the importance of treating not only the physical, but the psychological needs of cancer patients, said Spiegel, who is also a member of Stanford's Cancer Center.

The research was funded by the National Institute of Mental Health, the National Cancer Institute, the National Institute on Aging, the John D. and Catherine T. MacArthur Foundation, and the Fetzer Institute. Firdaus Dhabhar, PhD, associate professor of psychiatry and behavioral sciences and member of the Stanford Institute for Immunology, Transplantation and Infection, shared first authorship with psychologist Sandra Sephton, PhD, of the University of Louisville in Kentucky. Stanford medical student Alex Keuroghlian was a co-author.

Stephanie Pappas is a science-writing intern for the Office of Communication & Public Affairs.

Stanford Medicine integrates research, medical education and health care at its three institutions - Stanford School of Medicine, Stanford Health Care, and Stanford Children's Health. For more information, please visit the Office of Communications website at

2021 ISSUE 2

Unlocking the secrets of the brain

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