By Sharon Kirkey, Canwest News ServiceFebruary 8, 2010Paxil, an antidepressant commonly prescribed to women with breast cancer, can reduce or even abolish the effects of the breast-cancer drug tamoxifen, increasing a woman's risk of death, Canadian researchers are warning.

Published this week in the British Medical Journal, the study exposes an "extremely common" and potentially life-threatening drug interaction that is "widely underappreciated," yet entirely avoidable, the researchers say.

"For women taking these two drugs together, I think there are better options for the treatment of depression," Dr. David Juurlink, a senior scientist at the Institute for Clinical Evaluative Sciences in Toronto and one of the study's authors said in a statement.

Breast cancer is the most commonly diagnosed cancer in women worldwide; an estimated 1.5 million new cases will be diagnosed globally this year, including about 22,700 in Canada.

Tamoxifen has been used for the treatment of breast cancer for more than three decades. For women with early stage estrogen receptor-positive breast cancer, the drug reduces the risk of recurrence by about half, and the risk of cancer death by about one-third, according to the study.

"If there was a hall of fame for cancer drugs, tamoxifen would be there," Juurlink said in an interview. "It is a spectacularly effective drug for breast cancer."

But tamoxifen depends on an enzyme in the liver to activate it. It doesn't do anything on its own; rather, it has to be converted to its active metabolite, called endoxifen, to work.

The idea that drugs might interfere with this critical process by switching the enzyme off dates back roughly 20 years, "but there's been very little research on what the real-world consequences of that drug interaction would be," Juurlink said.

Antidepressants are especially important because they're taken not just for a week or two, but for months and often years.

Up to 25 per cent of breast cancer patients develop depression. Many of them are prescribed selective serotonin reuptake inhibitors, or SSRIs, a class that includes paroxetine — Paxil and its generics. Along with other SSRIs, paroxetine is also sometimes prescribed for tamoxifen-related hot flashes.

The Toronto researchers looked at 2,430 women in Ontario, aged 66 and older, who were treated with tamoxifen as well as a single SSRI between 1993 and 2005. Among the 2,430 women in the study, 374, or 15 per cent, died of breast cancer during followup.

For each antidepressant, the researchers asked, does combining this drug with tamoxifen influence the risk of dying from breast cancer?

They found that the use of paroxetine, but not other SSRIs, in combination with tamoxifen was associated with an increased risk of dying from breast cancer.

The women in the study were taking an antidepressant, on average, for nearly half of the time (41 per cent) they were also on tamoxifen. The standard time on tamoxifen therapy is five years.

The team estimates that taking paroxetine for 41 per cent of tamoxifen therapy would result in one additional breast cancer death within five years for every 20 women so treated.

The more time taking both drugs together, the greater the risk.

Roughly one additional breast cancer death would be expected for every seven women who took paroxetine the entire time they were taking tamoxifen.

"Most of the time when we think of the consequences of combining two drugs, the risks or harms are fairly immediate — the problem happens within a few days or a few weeks, Juurlink said.

"This is an interaction with consequences that occur far into the future."

In their study, paroxetine was the most commonly prescribed SSRI antidepressant.

"Think about the math here," Juurlink said. "There are a million and a half new breast cancer cases each year, many of whom will take tamoxifen. If 25 per cent of them develop depression, and even half of those receive an SSRI, and paroxetine is the most common agent — we're literally talking about thousands of women each year who could be missing out on the benefits of a tremendously beneficial drug for breast cancer."

He warned women not to stop taking paroxetine suddenly. Withdrawal symptoms can be severe if the drug is stopped abruptly.

But "if women taking tamoxifen need to be on an antidepressant, there are better choices than paroxetine," Juurlink said. Drugs such as venlafaxine (brand name includes Effexor) or citalopram (Celexa) don't appear to interfere with tamoxifen "to anywhere near the same degree."

Rosalind Bell, president of Breast Cancer Action in Ottawa, said that, for some women, a diagnosis of breast cancer is a "psychological hit to the extent that the medication intervention seems to help quite a bit."

"It's frequent; it's not the majority," she said. But the study "should be made as widely available as possible. Good heavens, it's certainly avoidable."