SSRI and Tamoxifen Increase Mortality Risk (CME/CE)

Overlapping use of tamoxifen and the antidepressant paroxetine (Paxil) significantly increases the risk of breast cancer mortality, data from a massive cohort of breast cancer patients showed.

The excess breast-cancer mortality risk ranged as high as 91%, depending on the duration of simultaneous use, researchers reported on-line in BMJ.

Women taking other antidepressants with tamoxifen, including other selective serotonin reuptake inhibitors (SSRIs), did not have an increased risk of breast cancer death.

“We estimate that use of paroxetine for 41% of tamoxifen treatment (the median overlap in our sample) would result in one additional breast cancer death within five years of cessation of tamoxifen for every 19.7 patients so treated; the risk with more extensive overlap would be greater,” David Juurlink, MD, PhD, of Sunnybrook Health Sciences Center in Toronto, and colleagues concluded.

The findings add to an accumulation of evidence suggesting that inhibition of the cytochrome P450 2D6 isozyme (CYP2D6) may adversely affect outcomes in breast cancer patients taking tamoxifen. CYP2D6 is the principle catalyst for converting tamoxifen into endoxifen, a metabolite with 100-fold greater affinity for the estrogen receptor.

Multiple studies have shown that women who have a poor-metabolizer phenotype have lower levels of endoxifen, as do women treated with drugs that inhibit CYP2D6.

“Indeed, in patients who receive tamoxifen in addition to a CYP2D6 inhibitor, endoxifen concentrations vary inversely with the degree of CYP2D6 inhibition,” the authors wrote.

Paroxetine is used to treat depression and vasomotor symptoms in breast cancer patients treated with tamoxifen. Paroxetine is not the only SSRI antidepressant used by breast cancer patients, but it is the only SSRI that irreversibly inhibits CYP2D6.

Whether the metabolic effects of CYP2D6 inhibition translated into adverse breast cancer outcomes had not been determined.

To analyze the issue, Juurlink and colleagues compared prescribing data with clinical records of 24,430 breast cancer patients, ages 66 and older, who initiated tamoxifen therapy from 1993 to 2005. Of those, 7,500 also received an antidepressant.

Ultimately, the investigators narrowed the study population to 2,430 women who took a single SSRI during tamoxifen therapy. The most commonly prescribed SSRI was paroxetine (25.9%), followed by sertraline (22.3%), citalopram (19.2%), venlafaxine (15%), fluoxetine (10.4%), and fluvoxamine (7.2%).

During a mean follow-up of 2.38 years, 1,074 patients died, including 374 breast cancer deaths.

The analysis showed an increased risk of breast cancer death only among women taking paroxetine.

The breast cancer mortality risk increased with the duration of concomitant use of paroxetine and tamoxifen. As the duration of therapeutic overlap increased from 25%, to 50%, to 75% of time on tamoxifen, the excess risk of breast cancer death increased from 24%, to 54%, to 91%.

Investigators repeated the analysis, using death from any cause. Overlapping treatment with tamoxifen and paroxetine led to an increased mortality risk of 13%, 28%, and 46% as the duration of overlap increased from 25% to 75%.

The results suggest clear implications for use of SSRIs in breast cancer patients on tamoxifen, Frank Andersohn, MD, and Stefan Willich, MD, of Charite University in Berlin, wrote in an accompanying editorial.

“The straightforward answer is to avoid prescribing strong CYP2D6-inhibiting SSRIs (such as paroxetine or fluoxetine) for women with breast cancer who are prescribed tamoxifen, and to think about instead drugs with low potential to inhibit CYP2D6 (such as citalopram or venlafaxine),” they wrote.

For women who are already taking a potent inhibitor of CYP2D6, physicians should think about switching to a drug that does not inhibit the enzyme, they added. However, any switch should be accomplished gradually, as abrupt discontinuation of an antidepressant confers risk, as well, they noted.

Co-author Kathleen Pritchard disclosed relationships with sanofi-aventis, AstraZeneca, Roche, Pfizer, Ortho-Biotech, YM Biosciences, Novartis, Abraxis, Amgen, GlaxoSmithKline, Bristol Myers Squibb, and Roche

source : www.medpagetoday.com

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