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Antidepressants and tamoxifen

JUN 2010

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Drug interactions may increase risk of cancer recurrence or death.

Tamoxifen is a standard adjuvant treatment for women with estrogen receptor-positive breast cancer — the most common type, fueled by the hormone estrogen. Typically, women take tamoxifen for five years after undergoing initial cancer treatment (surgery, radiation, or chemotherapy). The drug is also used as a preventive agent for women at high risk of developing breast cancer, based on family history or genetic profile.

Since it received FDA approval in 1977, tamoxifen has reduced breast cancer recurrences by one-half and breast cancer deaths by one-third in women with early-stage estrogen receptor-positive breast cancer. Unfortunately, the drug does not benefit every woman who takes it.

One reason is genetic. The liver uses the cytochrome P450 enzymes to metabolize many drugs. One of them, CYP2D6, is the principal enzyme that converts tamoxifen into endoxifen, a form that is active in the body. Variations in the gene that synthesizes CYP2D6 can limit women's ability to convert tamoxifen into its active form; about 7% of women have no CYP2D6 activity.

But drug interactions also contribute — an important consideration for mental health clinicians, as approximately 20% to 30% of the women who take tamoxifen also use antidepressants to alleviate depression, anxiety, or hot flashes. Some antidepressants are such strong inhibitors of CYP2D6 that women who take these drugs may not benefit from tamoxifen. Two papers suggest that three antidepressants — paroxetine (Paxil), fluoxetine (Prozac), and bupropion (Wellbutrin) — are most likely to inhibit CYP2D6 and interfere with tamoxifen treatment.

In one paper, researchers at McGill University reviewed seven clinical studies of women taking both tamoxifen and antidepressants. They also examined laboratory studies to assess the inhibitory effects of various antidepressants on the CYP2D6 enzyme in cell cultures. They found consistent evidence that two selective serotonin reuptake inhibitors (SSRIs) — paroxetine and fluoxetine — were strong inhibitors of CYP2D6. Indirect evidence from the laboratory studies suggested that bupropion, an antidepressant that affects the neurotransmitters norepinephrine and dopamine, also severely inhibits CYP2D6. Other drugs had less of an impact on this enzyme (see table).

Choosing among antidepressants

Antidepressants vary in their ability to inhibit CYP2D6 (the enzyme that converts tamoxifen into its active form, endoxifen).

Drug

Effect on CYP2D6

Advice

venlafaxine (Effexor)

Minimal

Safest choice if taken with tamoxifen.

desvenlafaxine (Pristiq), mirtazapine (Remeron)

Direct studies with tamoxifen are lacking, but effect on endoxifen levels should be minimal.

citalopram (Celexa), escitalopram (Lexapro), nefazodone (Serzone)

Mild

Secondary choices if above are not options.

Only citalopram and sertraline have been studied directly with tamoxifen, so risk of reducing levels of endoxifen should be weighed against benefits of antidepressants.

duloxetine (Cymbalta), sertraline (Zoloft), fluvoxamine (Luvox)

Moderate

paroxetine (Paxil), fluoxetine (Prozac), bupropion (Wellbutrin)

Strong

Best to avoid if taking tamoxifen.

Source: Desmarais JE, et al. Journal of Clinical Psychiatry (Dec. 2009): Vol. 70, No. 12, pp. 1688-97.

More recently, researchers at Sunnybrook Health Sciences Centre in Toronto published the first study designed to examine whether CYP2D6 inhibition affected clinical outcomes of women taking both tamoxifen and SSRIs. The researchers analyzed health care records for 2,430 women age 66 and older who began tamoxifen treatment between 1993 and 2005 and were also taking a single SSRI. (They excluded those who switched to another SSRI during tamoxifen treatment, or who took another type of antidepressant.)

When the study ended in 2007, 374 of the women had died of breast cancer. When the researchers broke the deaths down by SSRI use and compared hazard ratios, they estimated that, within five years after ending tamoxifen treatment, one additional breast cancer death would occur for every 20 women who used paroxetine for 41% of the time they were also taking tamoxifen (the median duration of combined use in the study). Risk of death increased with duration of the paroxetine-tamoxifen overlap.

Although the McGill researchers found that fluoxetine had a strong effect on CYP2D6, the Toronto researchers found no evidence that this drug increased risk of death, although they cautioned that the number of women taking this SSRI may have been too small to provide sufficient statistical power. They also examined outcomes for women taking four other SSRIs, and found no evidence that any of these drugs affected mortality, although (once again) small sample sizes were a problem.

Both of these studies had limitations. The McGill study involved clinical trials designed mainly to look at genetic profiles and tamoxifen metabolism, for example. And the Toronto researchers were unable to obtain information about breast cancer stage in participants — obviously an important predictor of survival.

Nevertheless, these studies add to a growing body of evidence that certain antidepressants can hinder the anticancer effects of tamoxifen. Although the evidence is not yet perfect, clinicians treating women taking tamoxifen are wise to avoid prescribing the antidepressants that are most likely to inhibit CYP2D6.

Women who are unable to take or switch to an antidepressant that is less likely to interfere with tamoxifen could ask their oncologists about other anti-estrogen drugs. Raloxifene (Evista), for example, is metabolized differently from tamoxifen and does not rely on any of the cytochrome P450 enzymes. Other alternatives are drugs such as anastrozole (Arimidex) and letrozole (Femara), which are metabolized through the CYP19 enzyme rather than CYP2D6.

Additional research is under way to examine the impact of particular antidepressants on tamoxifen metabolism, and may provide additional guidance once published.

Desmarais JE, et al. "Interactions Between Tamoxifen and Antidepressants via Cytochrome P450 2D6," Journal of Clinical Psychiatry (Dec. 2009): Vol. 70, No. 12, pp. 1688–97.

Kelly CM, et al. "Selective Serotonin Reuptake Inhibitors and Breast Cancer Mortality in Women Receiving Tamoxifen: A Population-Based Cohort Study," BMJ (Feb. 2010): Vol. 340, electronic publication.

For more references, please see www.health.harvard.edu/mentalextra.