An important Canadian study has shown that the use of paroxetine (Paxil) in breast cancer patients taking tamoxifen is associated with an increased risk of death from breast cancer. These findings, which were published this week in the British Medical Journal, add to a growing body of evidence that certain (but not all) SSRI antidepressants neutralize tamoxifen’s beneficial effects in treating breast cancer by interfering with it’s metabolism.
First, a few things about the study –
- The study was done using a combination of pharmacy records, cancer registry records, hospital databases and death certificates in seniors, the age group for whom this data were readily available.
- The study included women taking both tamoxifen and an SSRI between 1993 and 2005.
- The median age was 74 years old (range 70-79 years)
- We know nothing about the stage of breast cancer in these patients
- By the end of the 2.8 year follow up, 44% of the participants had died from any cause (not surprising given the age of the study cohort), including 15% in whom breast cancer was listed as one of the causes of death.
- No comparisons were done among women taking tamoxifen only. The researchers compared women taking different SSRI’s to one another, and within each SSRI group, compared different duration of uses as a way to measure the effect of the potential interaction.
What the researchers found
Use of Paxil was associated with an increase in deaths from both breast cancer and other causes during the follow-up period. (See PowerPoint graph ). The increase in risk was higher with longer overlapping use of Paxil with tamoxifen, and ranged from 25% to 91% increase as time on the two drugs together increased, meaning that the risk was almost double with longest use in the study. All of these results were statistically significant. (For those who know statistics, that’s a relative risk of 1.24 to 1.91 and the 95% confidence intervals did not include 1).
In more meaningful layman’s terms, there will be 1 additional breast cancer death for every 20 women taking Paxil and Tamoxifen together 41% of the time (the average in the study). If Paxil is taken the entire time tamoxifen is used, there will be 1 additional death for every 7 women treated with both drugs.
The Results are Biologically Plausible
In order to be effective, tamoxifen must be converted in the body to its active metabolites, the most potent of which is 4-hydroxy-N-desmethyltamoxifen or endoxifen. The conversion of tamoxifen to endoxifen is catalyzed by an enzyme called CYP2D6. SSRI antidepressants interfere with CPY2D6 to varying degrees, with Paxil being the most potent of the SSRI’s in this regard . (So potent that they actually call it “suicide inhibition”.) Thus, use of Paxil makes tamoxifen less effective, attenuating the survival advantage imparted by tamoxifen use.
What was unexpected in the study results was that fluoxetine (Prozac), another known potent inhibitor of CYP2D6, was not associated with an increase death risk compared to the other less potent CYP2D6 inhibitors. The researchers warn, however, that this may be due to the relatively small numbers of women on this drug in their population. “We want to be careful that this study is not used to bless the use of fluoxetine in tamoxifen users”, says Dr Juurlink.
A few more notes on study design
Given the robustness of the data sets they had, which appear to include both cancer registry and hospital records, it’s a shame that the researchers did not have information on breast cancer stage, an important potential confounding factor. It’s a limitation of the study that they acknowledge in the paper.
I also found it odd that the researchers chose only to compare the SSRI’s to one another, without having a control group of tamoxifen users not taking an SSRI. Juurelink explained that this was a deliberate choice, to avoid potential unknown variables that would affect mortality and be associated with the need to use antidepressants.
Importance of Drug-Drug Interactions
We were first clued in to the potential interactions between SSRI’s and tamoxifen in 2005, when a landmark paper was published in JNCI on the pharmacologic interactions of these two classes of drugs. Since them, several other pharmacologic studies have confirmed the interactions and clarified which SSRI’s are problematic and which are not, and concomitant use of the more potent PYP2D6 inhibitors has decreased. In 2009, a paper presented at the American Society of Clinical Oncology reported that women who used a potent or moderate CYP2D6- inhibiting SSRI (paroxetine, fluoxetine or serttraline) in conjunction with tamoxifen had a two-fold increase in breast cancer recurrence compared to use of weakly-inhibiting SSRI’s (citalopran, escitalopram and fluvoxamine). This BMJ study is the first to report an increase in breast cancer mortality resulting from these interactions.
First of all, DO NOT suddenly stop your SSRI, since severe withdrawal symptoms can occur. DO talk to your doctor about which SSRI medication you are taking. If it is paroxetine or fluoxetine, it is recommended that you try to change to an SSRI that is a less potent or non-inhibitor of tamoxifen metabolism.
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Kelly, C., Juurlink, D., Gomes, T., Duong-Hua, M., Pritchard, K., Austin, P., & Paszat, L. (2010). Selective serotonin reuptake inhibitors and breast cancer mortality in women receiving tamoxifen: a population based cohort study BMJ, 340 (feb08 1) DOI: 10.1136/bmj.c693
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The potential of drug interactions scares me to death. Having MS, I take a mind-boggling daily regimen of meds to treat an equally mind-boggling number of symptoms. I take more pills every day then my hypertensive, s/p TWO cabg's, overweight and totally sedentary 77 year old father.
Because I also just had a shoulder replacement (it is SUCH a joy to be me lol) I have an entire cadre of healthcare providers prescribing meds for me. I am careful to make sure each of them knows what I am taking. But what if they miss one?! I'm a nurse, but I don't know every drug interaction. It is exhausting researching each drug in order to keep myself safe.
And then there are the presently unknown interactions, such as the one in this study. I know life is always a gamble, but I would like to even my odds.
Like you, I am struck by the fact that the cancer stage isn't referenced. The stage certainly is significant to the data. There is a crucial difference between these drugs causing a higher mortality rate with Stage I ca as opposed to women with Stage IV.
Finally, this makes me feel so sad. Like women with breast cancer need something else to worry about.
Thanks so much for this post.
This is my first time to post this but don't forget to vote for TBTAM for best Weblog. There are just a few days left and she is in third place but can catch up if everyone votes.
Is the 7 women needed to treat to prevent a breast cancer death limited to women who've been diagnosed with an invasive cancer?
I had heard the number was closer to 100 and now I"m wondering if the 1 to 100 number only applies to women taking tamoxifen who've had DCIS/LCIS or are taking it as a preventative, as opposed to women who've actually been diagnosed with an invasive cancer.
Rose-
I believe it is limited to breast cancer patients, the numbers would be very different if one looked at just high risk women.
Thanks for your thoughtful comment.
Peggy
Rose-I believe it is limited to breast cancer patients, the numbers would be very different if one looked at just high risk women. Thanks for your thoughtful comment. Peggy
Rose-I believe it is limited to breast cancer patients, the numbers would be very different if one looked at just high risk women. Thanks for your thoughtful comment. Peggy
Rose-I believe it is limited to breast cancer patients, the numbers would be very different if one looked at just high risk women. Thanks for your thoughtful comment. Peggy
[…] advantage of citalopram is that, unlike some SSRIs (Paxil and Prozac), it does not appear to impair the efficacy of tamoxifen. These other drugs […]