Paroxetine (Paxil) Impairs Tamoxifen Benefits in Breast Cancer

What is additionally interesting about these numbers, according to the study’s researcher Dr. David Juurlink (who graciously agreed to speak to me today), is that 7 is the number of women need to treat with Tamoxifen to prevent one breast cancer death. So, Paxil essentially is neutralizing the tamoxifen effect.

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.

(Note – Not all women are inherently able to optimally metabolize tamoxifen to its active metabolites, and research suggests that so called slow metabolizers of tamoxifen may have worse breast cancer outcomes. Genotyping for CYP2D6 variation may prove to be a useful genetic marker for tailoring of cancer treatment in this group.)

Another expected finding of the study was that women taking Venlafaxine (Effexor) had a reduced risk of breast cancer deaths. Venlafaxine is used to treat the hot flashes associated with tamoxifen use, and women who have hot flashes while using tamoxifen may have better survival, probably because the hot flashes are a good sign that the Tamoxifen is being activated to Endoxifen. So this group would be selected to have better survival from the start, and the use of a weak CYP2D6 inhibitor doesn’t appear to impede this survival advantage within the study group.

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.

Enormous credit goes to those who first suspected this interaction between SSRI’s and Tamoxifen, did the excellent research to confirm it, and then went the extra mile to help identify which SSRI’s are safe to use with tamoxifen and which are best to avoid. Treatment of depression in cancer patients can be critical to both their physical as well as emotional recovery, and it’s important that we continue to have options that are effective for depression without interfering with cancer treatment.

What should you do if you are on an SSRI and Tamoxifen?

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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