J Breast Cancer.  2010 Dec;13(4):325-336. 10.4048/jbc.2010.13.4.325.

Use of Antidepressants in Patients with Breast Cancer Taking Tamoxifen

• Kim SH
• Lee MR
• Lee KC
• Lee JH
• Kwon HC
• Kim DC
• Lee KW
• Cho SH

• KMID: 2286520
• DOI: http://doi.org/10.4048/jbc.2010.13.4.325

Abstract

Tamoxifen, a selective estrogen modulator has been used for more than three decades to treat all stages of estrogen receptor (ER)-positive breast cancer and to prevent the disease. Tamoxifen is a pro-drug that requires metabolic activation to 4-hydroxytamoxifen and 4-hydroxy-N-desmethyltamoxifen (endoxifen) to elicit its pharmacological activity. Endoxifen has identical properties and potency with 4-hydroxytamoxifen, but is present in concentrations up to 10-fold higher than 4-hydroxytamoxifen. The cytochrome P450 2D6 (CYP2D6) enzyme plays a key role in converting tamoxifen into its active metabolites with significantly greater affinity for the ER and greater ability to inhibit cell proliferation. Genetic variants in the CYP2D6 gene may result in CYP2D6 enzymes with reduced or null activity, thereby decreasing the anti-cancer effect. In addition to genetic inactivation of CYP2D6, inhibitors of CYP2D6, including some antidepressants to treat hot flashes or depression in patients with breast cancer, may also alter enzyme activity and negatively affect the outcomes of patients receiving adjuvant tamoxifen. This article reviews and discusses the following issues: tamoxifen metabolism, antiproliferative effects of tamoxifen and its metabolites, CYP2D6 genetic polymorphisms, treatment for hot flashes and depression in breast cancer, and the pharmacological interactions between tamoxifen and antidepressants via CYP2D6. Although routine CYP2D6 testing is not recommended yet, coadministration of potent or intermediate CYP2D6 inhibitors in women taking tamoxifen should be avoided.

Keyword

Antidepressants; Breast neoplasms; Cytochrome P450 2D6; Tamoxifen

MeSH Terms

Antidepressive Agents
Biotransformation
Breast
Breast Neoplasms
Cell Proliferation
Cytochrome P-450 CYP2D6
Depression
Estrogens
Female
Hot Flashes
Humans
Polymorphism, Genetic
Tamoxifen
Antidepressive Agents
Cytochrome P-450 CYP2D6
Estrogens
Tamoxifen

Reference

1. Anderson BO, Yip CH, Smith RA, Shyyan R, Sener SF, Eniu A, et al. Guideline implementation for breast healthcare in low-income and middle-income countries: overview of the Breast Health Global Initiative Global Summit 2007. Cancer. 2008. 113:2221–2243.

2. National Cancer Information Center. Annual Report of National Cancer Registration. 2007. Goyang: National Cancer Center.

3. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005. 365:1687–1717.

4. Smith IE, Dowsett M. Aromatase inhibitors in breast cancer. N Engl J Med. 2003. 348:2431–2442.

5. Mitwally MF, Casper RF. Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate. Fertil Steril. 2001. 75:305–309.

6. Cole MP, Jones CT, Todd ID. A new anti-oestrogenic agent in late breast cancer. An early clinical appraisal of ICI46474. Br J Cancer. 1971. 25:270–275.

7. Controlled trial of tamoxifen as adjuvant agent in management of early breast cancer. Interim analysis at four years by Nolvadex Adjuvant Trial Organisation. Lancet. 1983. 1:257–261.

8. Fisher B, Costantino J, Redmond C, Poisson R, Bowman D, Couture J, et al. A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors. N Engl J Med. 1989. 320:479–484.

9. Osborne CK. Tamoxifen in the treatment of breast cancer. N Engl J Med. 1998. 339:1609–1618.

10. The Korean Breast Cancer Society. Nationwide Korean breast cancer data of 2002. J Korean Breast Cancer Soc. 2004. 7:72–83.

11. Christensen S, Zachariae R, Jensen AB, Vaeth M, Moller S, Ravnsbaek J, et al. Prevalence and risk of depressive symptoms 3-4 months post-surgery in a nationwide cohort study of Danish women treated for early stage breast-cancer. Breast Cancer Res Treat. 2009. 113:339–355.

12. So WK, Marsh G, Ling WM, Leung FY, Lo JC, Yeung M, et al. Anxiety, depression and quality of life among Chinese breast cancer patients during adjuvant therapy. Eur J Oncol Nurs. 2010. 14:17–22.

13. Andritsch E, Dietmaier G, Hofmann G, Zloklikovits S, Samonigg H. Global quality of life and its potential predictors in breast cancer patients: an exploratory study. Support Care Cancer. 2007. 15:21–30.

14. Shapiro SL, Lopez AM, Schwartz GE, Bootzin R, Figueredo AJ, Braden CJ, et al. Quality of life and breast cancer: relationship to psychosocial variables. J Clin Psychol. 2001. 57:501–519.

15. Thase ME, Entsuah R, Cantillon M, Kornstein SG. Relative antidepressant efficacy of venlafaxine and SSRIs: sex-age interactions. J Womens Health (Larchmt). 2005. 14:609–616.

16. Payne DK, Hoffman RG, Theodoulou M, Dosik M, Massie MJ. Screening for anxiety and depression in women with breast cancer. Psychiatry and medical oncology gear up for managed care. Psychosomatics. 1999. 40:64–69.

17. Fann JR, Thomas-Rich AM, Katon WJ, Cowley D, Pepping M, McGregor BA, et al. Major depression after breast cancer: a review of epidemiology and treatment. Gen Hosp Psychiatry. 2008. 30:112–126.

18. Drug-interactions with Tamoxifen: a Guide for Breast Cancer Patients and Physician. 2008. In : Consortium on Breast Cancer Pharmacogenomics; Indianapolis: Indiana University School of Medicine.

19. Pezzella G, Moslinger-Gehmayr R, Contu A. Treatment of depression in patients with breast cancer: a comparison between paroxetine and amitriptyline. Breast Cancer Res Treat. 2001. 70:1–10.

20. Roscoe JA, Morrow GR, Hickok JT, Mustian KM, Griggs JJ, Matteson SE, et al. Effect of paroxetine hydrochloride (Paxil) on fatigue and depression in breast cancer patients receiving chemotherapy. Breast Cancer Res Treat. 2005. 89:243–249.

21. Musselman DL, Somerset WI, Guo Y, Manatunga AK, Porter M, Penna S, et al. A double-blind, multicenter, parallel-group study of paroxetine, desipramine, or placebo in breast cancer patients (stages I, II, III, and IV) with major depression. J Clin Psychiatry. 2006. 67:288–296.

22. van Heeringen K, Zivkov M. Pharmacological treatment of depression in cancer patients. A placebo-controlled study of mianserin. Br J Psychiatry. 1996. 169:440–443.

23. Morrow GR, Hickok JT, Roscoe JA, Raubertas RF, Andrews PL, Flynn PJ, et al. Differential effects of paroxetine on fatigue and depression: a randomized, double-blind trial from the University of Rochester Cancer Center Community Clinical Oncology Program. J Clin Oncol. 2003. 21:4635–4641.

24. Carpenter JS, Andrykowski MA, Cordova M, Cunningham L, Studts J, McGrath P, et al. Hot flashes in postmenopausal women treated for breast carcinoma: prevalence, severity, correlates, management, and relation to quality of life. Cancer. 1998. 82:1682–1691.

25. Freedman RR, Norton D, Woodward S, Cornelissen G. Core body temperature and circadian rhythm of hot flashes in menopausal women. J Clin Endocrinol Metab. 1995. 80:2354–2358.

26. Freedman RR, Krell W. Reduced thermoregulatory null zone in postmenopausal women with hot flashes. Am J Obstet Gynecol. 1999. 181:66–70.

27. Goetz MP, Loprinzi CL. A hot flash on tamoxifen metabolism. J Natl Cancer Inst. 2003. 95:1734–1735.

28. Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst. 1998. 90:1371–1388.

29. Notelovitz M, Lenihan JP, McDermott M, Kerber IJ, Nanavati N, Arce J. Initial 17beta-estradiol dose for treating vasomotor symptoms. Obstet Gynecol. 2000. 95:726–731.

30. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA. 2002. 288:321–333.

31. Nelson HD, Vesco KK, Haney E, Fu R, Nedrow A, Miller J, et al. Nonhormonal therapies for menopausal hot flashes: systematic review and meta-analysis. JAMA. 2006. 295:2057–2071.

32. Sumner BE, Grant KE, Rosie R, Hegele-Hartung C, Fritzemeier KH, Fink G. Effects of tamoxifen on serotonin transporter and 5-hydroxytryptamine(2A) receptor binding sites and mRNA levels in the brain of ovariectomized rats with or without acute estradiol replacement. Brain Res Mol Brain Res. 1999. 73:119–128.

33. Stearns V, Ullmer L, Lopez JF, Smith Y, Isaacs C, Hayes D. Hot flushes. Lancet. 2002. 360:1851–1861.

34. Stearns V, Beebe KL, Iyengar M, Dube E. Paroxetine controlled release in the treatment of menopausal hot flashes: a randomized controlled trial. JAMA. 2003. 289:2827–2834.

35. Loprinzi CL, Kugler JW, Sloan JA, Mailliard JA, LaVasseur BI, Barton DL, et al. Venlafaxine in management of hot flashes in survivors of breast cancer: a randomised controlled trial. Lancet. 2000. 356:2059–2063.

36. Loprinzi CL, Diekmann B, Novotny PJ, Stearns V, Sloan JA. Newer antidepressants and gabapentin for hot flashes: a discussion of trial duration. Menopause. 2009. 16:883–887.

37. Stearns V. Clinical update: new treatments for hot flushes. Lancet. 2007. 369:2062–2064.

38. Loprinzi CL, Sloan JA, Perez EA, Quella SK, Stella PJ, Mailliard JA, et al. Phase III evaluation of fluoxetine for treatment of hot flashes. J Clin Oncol. 2002. 20:1578–1583.

39. Kimmick GG, Lovato J, McQuellon R, Robinson E, Muss HB. Randomized, double-blind, placebo-controlled, crossover study of sertraline (Zoloft) for the treatment of hot flashes in women with early stage breast cancer taking tamoxifen. Breast J. 2006. 12:114–122.

40. Stearns V, Slack R, Greep N, Henry-Tilman R, Osborne M, Bunnell C, et al. Paroxetine is an effective treatment for hot flashes: results from a prospective randomized clinical trial. J Clin Oncol. 2005. 23:6919–6930.

41. Biglia N, Torta R, Roagna R, Maggiorotto F, Cacciari F, Ponzone R, et al. Evaluation of low-dose venlafaxine hydrochloride for the therapy of hot flushes in breast cancer survivors. Maturitas. 2005. 52:78–85.

42. Loibl S, Schwedler K, von Minckwitz G, Strohmeier R, Mehta KM, Kaufmann M. Venlafaxine is superior to clonidine as treatment of hot flashes in breast cancer patients--a double-blind, randomized study. Ann Oncol. 2007. 18:689–693.

43. Knabbe C, Kopp A, Hilgers W, Lang D, Muller V, Zugmaier G, et al. Regulation and role of TGF beta production in breast cancer. Ann N Y Acad Sci. 1996. 784:263–276.

44. Zugmaier G, Ennis BW, Deschauer B, Katz D, Knabbe C, Wilding G, et al. Transforming growth factors type beta 1 and beta 2 are equipotent growth inhibitors of human breast cancer cell lines. J Cell Physiol. 1989. 141:353–361.

45. Yildiz A, Guleryuz S, Ankerst DP, Ongur D, Renshaw PF. Protein kinase C inhibition in the treatment of mania: a double-blind, placebo-controlled trial of tamoxifen. Arch Gen Psychiatry. 2008. 65:255–263.

46. Bratherton DG, Brown CH, Buchanan R, Hall V, Kingsley Pillers EM, Wheeler TK, et al. A comparison of two doses of tamoxifen (Nolvadex) in postmenopausal women with advanced breast cancer: 10 mg bd versus 20 mg bd. Br J Cancer. 1984. 50:199–205.

47. Decensi A, Gandini S, Guerrieri-Gonzaga A, Johansson H, Manetti L, Bonanni B, et al. Effect of blood tamoxifen concentrations on surrogate biomarkers in a trial of dose reduction in healthy women. J Clin Oncol. 1999. 17:2633–2638.

48. Clarke R, Liu MC, Bouker KB, Gu Z, Lee RY, Zhu Y, et al. Antiestrogen resistance in breast cancer and the role of estrogen receptor signaling. Oncogene. 2003. 22:7316–7339.

49. Jordan VC, Collins MM, Rowsby L, Prestwich G. A monohydroxylated metabolite of tamoxifen with potent antioestrogenic activity. J Endocrinol. 1977. 75:305–316.

50. Jordan VC. Metabolites of tamoxifen in animals and man: identification, pharmacology, and significance. Breast Cancer Res Treat. 1982. 2:123–138.

51. Borgna JL, Rochefort H. Hydroxylated metabolites of tamoxifen are formed in vivo and bound to estrogen receptor in target tissues. J Biol Chem. 1981. 256:859–868.

52. Robertson DW, Katzenellenbogen JA, Long DJ, Rorke EA, Katzenellenbogen BS. Tamoxifen antiestrogens. A comparison of the activity, pharmacokinetics, and metabolic activation of the cis and trans isomers of tamoxifen. J Steroid Biochem. 1982. 16:1–13.

53. Jin Y, Desta Z, Stearns V, Ward B, Ho H, Lee KH, et al. CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst. 2005. 97:30–39.

54. Johnson MD, Zuo H, Lee KH, Trebley JP, Rae JM, Weatherman RV, et al. Pharmacological characterization of 4-hydroxy-N-desmethyl tamoxifen, a novel active metabolite of tamoxifen. Breast Cancer Res Treat. 2004. 85:151–159.

55. Lim YC, Desta Z, Flockhart DA, Skaar TC. Endoxifen (4-hydroxy-N-desmethyl-tamoxifen) has anti-estrogenic effects in breast cancer cells with potency similar to 4-hydroxy-tamoxifen. Cancer Chemother Pharmacol. 2005. 55:471–478.

56. Lim YC, Li L, Desta Z, Zhao Q, Rae JM, Flockhart DA, et al. Endoxifen, a secondary metabolite of tamoxifen, and 4-OH-tamoxifen induce similar changes in global gene expression patterns in MCF-7 breast cancer cells. J Pharmacol Exp Ther. 2006. 318:503–512.

57. Buck MB, Coller JK, Murdter TE, Eichelbaum M, Knabbe C. TGFbeta2 and TbetaRII are valid molecular biomarkers for the antiproliferative effects of tamoxifen and tamoxifen metabolites in breast cancer cells. Breast Cancer Res Treat. 2008. 107:15–24.

58. Hiratsuka M, Agatsuma Y, Omori F, Narahara K, Inoue T, Kishikawa Y, et al. High throughput detection of drug-metabolizing enzyme polymorphisms by allele-specific fluorogenic 5' nuclease chain reaction assay. Biol Pharm Bull. 2000. 23:1131–1135.

59. Hiratsuka M, Takekuma Y, Endo N, Narahara K, Hamdy SI, Kishikawa Y, et al. Allele and genotype frequencies of CYP2B6 and CYP3A5 in the Japanese population. Eur J Clin Pharmacol. 2002. 58:417–421.

60. Nasu K, Kubota T, Ishizaki T. Genetic analysis of CYP2C9 polymorphism in a Japanese population. Pharmacogenetics. 1997. 7:405–409.

61. Coughtrie MW, Gilissen RA, Shek B, Strange RC, Fryer AA, Jones PW, et al. Phenol sulphotransferase SULT1A1 polymorphism: molecular diagnosis and allele frequencies in Caucasian and African populations. Biochem J. 1999. 337:45–49.

62. Hollander M, Wolfe D. Nonparametric Statistical Methods. 1973. New York: John Wiley & Sons.

63. Goetz MP, Rae JM, Suman VJ, Safgren SL, Ames MM, Visscher DW, et al. Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. J Clin Oncol. 2005. 23:9312–9318.

64. Goetz MP, Knox SK, Suman VJ, Rae JM, Safgren SL, Ames MM, et al. The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen. Breast Cancer Res Treat. 2007. 101:113–121.

65. Schroth W, Antoniadou L, Fritz P, Schwab M, Muerdter T, Zanger UM, et al. Breast cancer treatment outcome with adjuvant tamoxifen relative to patient CYP2D6 and CYP2C19 genotypes. J Clin Oncol. 2007. 25:5187–5193.

66. Schroth W, Goetz MP, Hamann U, Fasching PA, Schmidt M, Winter S, et al. Association between CYP2D6 polymorphisms and outcomes among women with early stage breast cancer treated with tamoxifen. JAMA. 2009. 302:1429–1436.

67. Nowell SA, Ahn J, Rae JM, Scheys JO, Trovato A, Sweeney C, et al. Association of genetic variation in tamoxifen-metabolizing enzymes with overall survival and recurrence of disease in breast cancer patients. Breast Cancer Res Treat. 2005. 91:249–258.

68. Wegman P, Vainikka L, Stal O, Nordenskjold B, Skoog L, Rutqvist LE, et al. Genotype of metabolic enzymes and the benefit of tamoxifen in postmenopausal breast cancer patients. Breast Cancer Res. 2005. 7:R284–R290.

69. Wegman P, Elingarami S, Carstensen J, Stal O, Nordenskjold B, Wingren S. Genetic variants of CYP3A5, CYP2D6, SULT1A1, UGT2B15 and tamoxifen response in postmenopausal patients with breast cancer. Breast Cancer Res. 2007. 9:R7.

70. CYP2D6 pharmacogenomics of tamoxifen treatment. Technol Eval Cent Asses Program Exec Summ. 2008. 23:1–4.

71. Goetz MP, Kamal A, Ames MM. Tamoxifen pharmacogenomics: the role of CYP2D6 as a predictor of drug response. Clin Pharmacol Ther. 2008. 83:160–166.

72. Stearns V, Johnson MD, Rae JM, Morocho A, Novielli A, Bhargava P, et al. Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. J Natl Cancer Inst. 2003. 95:1758–1764.

73. Borges S, Desta Z, Li L, Skaar TC, Ward BA, Nguyen A, et al. Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism: implication for optimization of breast cancer treatment. Clin Pharmacol Ther. 2006. 80:61–74.

74. Ahern TP, Pedersen L, Cronin-Fenton DP, Sorensen HT, Lash TL. No increase in breast cancer recurrence with concurrent use of tamoxifen and some CYP2D6-inhibiting medications. Cancer Epidemiol Biomarkers Prev. 2009. 18:2562–2564.

75. Kotlyar M, Brauer LH, Tracy TS, Hatsukami DK, Harris J, Bronars CA, et al. Inhibition of CYP2D6 activity by bupropion. J Clin Psychopharmacol. 2005. 25:226–229.

76. Reese MJ, Wurm RM, Muir KT, Generaux GT, St John-Williams L, McConn DJ. An in vitro mechanistic study to elucidate the desipramine/bupropion clinical drug-drug interaction. Drug Metab Dispos. 2008. 36:1198–1201.

77. Hernandez RK, Sorensen HT, Jacobsen J, Pedersen L, Lash TL. Tamoxifen treatment in Danish breast cancer patients and 5-year risk of arterial atherosclerotic events: a null association. Cancer Epidemiol Biomarkers Prev. 2008. 17:2509–2511.

78. Patroneva A, Connolly SM, Fatato P, Pedersen R, Jiang Q, Paul J, et al. An assessment of drug-drug interactions: the effect of desvenlafaxine and duloxetine on the pharmacokinetics of the CYP2D6 probe desipramine in healthy subjects. Drug Metab Dispos. 2008. 36:2484–2491.

79. Nichols AI, Fatato P, Shenouda M, Paul J, Isler JA, Pedersen RD, et al. The effects of desvenlafaxine and paroxetine on the pharmacokinetics of the cytochrome P450 2D6 substrate desipramine in healthy adults. J Clin Pharmacol. 2009. 49:219–228.

80. Preskorn SH, Nichols AI, Paul J, Patroneva AL, Helzner EC, Guico-Pabia CJ. Effect of desvenlafaxine on the cytochrome P450 2D6 enzyme system. J Psychiatr Pract. 2008. 14:368–378.

81. Tamoxifen in Women With Breast Cancer and in Women at High-Risk of Breast Cancer Who Are Receiving Venlafaxine, Citalopram, Escitalopram, Gabapentin, or Sertraline. U.S National Institutes of Health. Accessed August 15th, 2010. http://www.clinicaltrials.gov/ct2/show/NCt00667121?term=endoxifen+levels+AND+antidepressnats&rank=1.