August 2009

Folate and Depression
L-methylfolate (Deplin) shows theoretical promise as an augmenting strategy for treatment-resistant depression, but so far there is little clinical evidence of its efficacy.

Breast Cancer, Tamoxifen, and 2D6 Inhibitors
Antidepressants and other drugs that inhibit the cytochrome P450 2D6 isoenzyme may cause low levels of tamoxifen in women with breast cancer.

In Brief
Lithium in Drinking Water May Decrease Suicide Risk; No Association Found Between Fish Consumption and Dementia

Treating Depression in Parkinson's Disease
Two studies provide preliminary but encouraging data about nortriptyline and omega-3 fatty acids as potential treatments for depression in patients with Parkinson's disease.

Breast Cancer, Tamoxifen, and 2D6 Inhibitors

August 2009

Each year, approximately 180,000 women in the United States are diagnosed with invasive breast cancer.1 Even though breast cancer incidence and deaths have been declining recently, breast cancer claimed about 40,000 lives in 2008 in the United States.2 Roughly 75% of women with newly diagnosed breast cancers will have tumors that express estrogen and/or progesterone receptors on cell surfaces.3 For premenopausal women, the standard of care for estrogen receptor-positive invasive breast cancer is tamoxifen (Soltamox and others), which is anti-estrogenic in the breast and estrogenic on some other organs. An estimated 60,000 postmenopausal women diagnosed each year with noninvasive breast cancer may also be offered tamoxifen to reduce the risk of a new primary breast cancer.4

Tamoxifen itself is a relatively weak selective estrogen receptor modulator. However, it is transformed via the hepatic cytochrome P450 (CYP) system to several active metabolites that are approximately 100 times more potent as anti-androgens than the parent compound.4

Women who are genetically poor metabolizers of CYP2D6 are more likely to experience a recurrent breast cancer on tamoxifen therapy, presumably because they achieve lower levels of the active tamoxifen anti-estrogen metabolites. The same appears true when women take 2D6-inhibiting drugs. Henry and others cite evidence that women taking antidepressants that are potent inhibitors of CYP2D6, such as paroxetine (Paxil and others) and fluoxetine (Prozac and others), have low levels of tamoxifen's active metabolites.4 Women taking antidepressants that are weak 2D6 inhibitors, such as sertraline (Zoloft and others) and citalopram (Celexa and others), have intermediate levels of the active metabolites. Venlafaxine (Effexor and others), which does not inhibit 2D6, had little effect on concentrations of the active metabolite endoxifen. The authors speculate that other selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) that are weak inhibitors of 2D6, such as fluvoxamine (Luvox and others) and escitalopram (Lexapro), may have little effect on endoxifen concentrations.

Breast cancer is a common and deadly disease. A majority of women who suffer from it have tumors that express steroid hormone receptors, and many of them are likely to take tamoxifen. Physicians should be cautious about prescribing drugs that are potent inhibitors of CYP2D6—including some antidepressants—to such patients.

We thank Dr Chittaranjan Andrade, whose article on this topic in his newsletter, Synergy Times, inspired this piece.

1American Cancer Society: Breast cancer facts and figures, 2007-2008.

2Briest S, Stearns V: Tamoxifen metabolism and its effect on endocrine treatment of breast cancer. Clin Adv Hematol Oncol 2009;7:185-192.

3Anderson WF, Chatterjee N, Ershler WB, Brawley OW. Estrogen receptor breast cancer phenotypes in the Surveillance, Epidemiology, and End Results database. Breast Cancer Res Treat. 2002;76:27-36.

4Henry NL, Stearns V, Flockhart DA, Hayes DF, Riba M: Drug interactions and pharmacogenomics in the treatment of breast cancer and depression. Am J Psychiatry 2008;165:1251-1255.