Interactions Between Tamoxifen and Antidepressants via Cytochrome P450 2D6
Objective: Women taking tamoxifen for the treatment or prevention of recurrence of breast cancer are likely to take antidepressants either for a psychiatric disorder or for hot flashes. Recent evidence suggested that some antidepressants inhibit the metabolism of tamoxifen to its more active metabolites by the cytochrome P450 2D6 (CYP2D6) enzyme, thereby decreasing the anticancer effect. This article reviews the literature on the interactions between newer antidepressants and tamoxifen via CYP2D6 and offers treatment recommendations.
Data Sources: A literature search of clinical and nonclinical studies published prior to September 2008 was conducted on PubMed. We performed 3 different searches combining the terms tamoxifen and SSRIs; tamoxifen and CYP2D6 inhibitors; and antidepressant and breast cancer recurrence. A fourth search with CYP2D6 inhibition and the generic names of individual antidepressants was carried out.
Study selection: Seven clinical research articles were selected. Nonclinical research articles about antidepressants were included if they mentioned in vitro or in vivo inhibition of CYP2D6.
Data Synthesis: There is consistent evidence that paroxetine and fluoxetine have a large effect on the metabolism of tamoxifen and should not be used. Indirect evidence indicates that bupropion may also have a large effect on the metabolism of tamoxifen. Venlafaxine has little or no effect on the metabolism of tamoxifen and may be considered the safest choice of antidepressants. Desvenlafaxine is not metabolized by the P450 system and may consequently be another option. Mirtazapine has not been extensively studied, but existing research suggests minimal effect on CYP2D6. The remaining commonly prescribed antidepressants have mild to moderate degrees of CYP2D6 inhibition.
Conclusions: Clinicians treating patients with breast cancer should review the prescription profiles of their patients to evaluate the need for treatment modification. There are safe options for the treatment of depression and clinicians and patients should bear in mind the health risks of untreated depressive states.
J Clin Psychiatry 2009;70(12):1688–1697
© Copyright 2009 Physicians Postgraduate Press, Inc.
Submitted: November 2, 2008; accepted March 27, 2009(doi:10.4088/JCP.08r04856blu).
Corresponding author: Julie Desmarais, MD, McGill University, Research and Training Building, 1033 Pine Avenue West, Room 107, Montreal, Quebec, Canada H3A 1A1 (firstname.lastname@example.org).
Tamoxifen is a selective estrogen receptor modulator, having estrogenic and antiestrogenic properties on various tissues. In breast tissue, tamoxifen competes with estrogen for estrogen receptors (ERs) to inhibit the stimulatory effect of estrogen on tumor growth. Tamoxifen was approved by the US Food and Drug Administration in 1977 for use as an adjuvant in the treatment of postmenopausal women with ER positive breast cancer or ductal carcinoma in situ. It is also used in the treatment of ER positive metastatic breast cancer in both men and women, as well as for prophylaxis in women at very high risk of developing breast cancer.1 Standard treatment consists of a 5-year course. Over the past 3 decades, tamoxifen has reduced breast cancer deaths by one-third and recurrences by one-half.2 Unfortunately, 35% of women with advanced ER positive cancer do not respond to tamoxifen.3 It has been postulated that genetic variation in enzymes involved in the metabolism of tamoxifen may account for tamoxifen failure in some patients.4
Metabolism of Tamoxifen
Tamoxifen has 3 major active metabolites.4 It is converted to N-desmethyltamoxifen through CYP 3A4 and 3A5, which is then converted to 4-hydroxy-N-desmethyltamoxifen (endoxifen) through cytochrome P450 2D6 (CYP2D6). Tamoxifen is also converted to 4-hydroxytamoxifen through CYP2D6 and, subsequently, to endoxifen through CYP 3A4 and 3A5. The 4-hydroxytamoxifen metabolite is 100-fold more potent as an antiestrogen agent than tamoxifen and N-desmethyltamoxifen. Endoxifen is equivalent to 4-hydroxytamoxifen in terms of potency, but its steady state concentrations are 6 to 10 times higher than the latter. Endoxifen is also 30- to 100-fold more potent than tamoxifen for suppression of cell proliferation.4
Cytochrome P450 2D6
The CYP2D6 plays an important role in the metabolism of tamoxifen. The gene coding for this cytochrome is polymorphic, with at least 71 reported allelic variants,5 many of which result in the loss of CYP2D6 enzyme function. CYP2D6 polymorphisms that result in poor metabolism are found in 7% to 10% of Caucasians, 2% of African Americans, and 1% of Asians.4
P450 2D6 Phenotype and Tamoxifen Response
In 2005, Goetz et al6 showed that women taking tamoxifen for breast cancer who were homozygous for the CYP2D6*4 allele, a nonfunctioning allele, had shorter relapse-free time and worse disease-free survival compared to women with either 1 or no *4 alleles. Serrano,7 Borges,8 Gjerde,9 and their colleagues found that women with 1 or 2 nonfunctioning CYP2D6 alleles had lower plasma levels of tamoxifen metabolites. Schroth et al10 and Kiyotani et al11 also demonstrated that women treated with tamoxifen who have defective CYP2D6 alleles have significantly more recurrences of breast cancer, shorter relapse-free periods, and worse event-free survival rates in comparison with women with functioning alleles. Data from the Italian Tamoxifen Trial12 furthermore suggest that healthy women with the CYP2D6 *4/*4 genotype are less likely to benefit from tamoxifen as a chemopreventive agent.
On the other hand, Wegman et al13 found no statistically significant difference in the relapse-free survival between women homozygous or heterozygous for CYP2D6*4 and women homozygous for CYP2D6*1, whether they took tamoxifen for 2 or 5 years. In an earlier study,14 they had shown that carriers of the CYP2D6*4 allele demonstrated a decreased risk of recurrence when treated with tamoxifen. Nowell et al15 also found no significant association between CYP2D6 genotype and overall survival in breast cancer patients taking tamoxifen. It is not known, however, if these patients were taking concomitant CYP2D6 inhibitors, and the sample sizes may not have been sufficient to show a statistical difference.
On October 18, 2006, the US Food and Drug Administration Endocrinologic and Metabolic Drugs Advisory Committee recommended that the tamoxifen prescribing information be updated to include information about CYP2D6 genotypes, CYP2D6 genotyping tests, and the potential relationship between 2D6 genotype and clinical outcome. The members of the committee, however, did not reach a consensus as to whether testing should be recommended or considered as an option.16 There is yet no consensus in the literature about the relationship between CYP2D6 genotype and tamoxifen efficacy.
Tamoxifen and Antidepressants
Antidepressants are the most prescribed class of medication in the United States.17 Approximately 8% of civilian noninstitutionalized Americans and approximately one-third of patients visiting medical offices are taking an antidepressant.17 Similarly, it is estimated that 20%–30% of patients taking tamoxifen are also taking antidepressants.18,19 This includes women with breast cancer who are being treated for depression or anxiety as well as those receiving antidepressants for the treatment of vasomotor instability (hot flashes). According to the 2007 US retail market,20 the 9 most commonly prescribed antidepressants were, in decreasing order: sertraline, escitalopram, fluoxetine, paroxetine, venlafaxine, citalopram, trazodone, duloxetine, and bupropion. Overall, approximately 62% of all antidepressants prescribed in the United States are selective serotonin reuptake inhibitors (SSRIs).20
The goal of this article is to review the interaction of the most prescribed antidepressants (SSRIs and newer antidepressants) with tamoxifen via the CYP2D6 enzyme and offer recommendations for the use of antidepressants in women taking tamoxifen. The review is divided into clinical and nonclinical studies. The clinical studies measure the effect of antidepressants on tamoxifen metabolites as well as changes in other substrates of the CYP2D6 enzyme. The nonclinical studies consist of in vitro studies of the inhibition of the CYP2D6 enzyme in human liver microsomes.
To identify clinical research studies, our search strategy began with tamoxifen and SSRIs with clinical trial as a limit, which resulted in 1 original article. Then CYP2D6 was searched with inhibitors and tamoxifen, which retrieved 18 original articles. Four of these articles were retained as they were discussing antidepressants. Tamoxifen and SSRI provided 2 more pertinent original articles, while antidepressant and breast cancer recurrence gave 1 more pertinent article, for a total of 7 clinical research studies.
CYP2D6 inhibition was then searched with fluoxetine, paroxetine, fluvoxamine, citalopram, escitalopram, sertraline, venlafaxine, desvenlafaxine, duloxetine, bupropion, nefazodone, monoamine oxidase inhibitors, and tricyclics. Articles were included if they mentioned in vitro or in vivo inhibition of CYP2D6.
Clinical Studies of Tamoxifen and Antidepressants
Three prospective clinical studies,3,8,21 2 of which are based on the data from the same clinical trial,3,8 have investigated the effect of antidepressants on the levels of endoxifen in women taking tamoxifen, taking into account their metabolizer status as defined by their CYP2D6 genotype (Table 1). All 3 studies found significant decreases in endoxifen levels with paroxetine in extensive metabolizers (EMs). One study investigating the effect of fluoxetine found a similar pattern of decreased endoxifen levels among EM patients.8 The 2 studies examining the effect of venlafaxine found no change in endoxifen levels.3,8 Meanwhile, the effect of sertraline and citalopram was observable but not as pronounced as that of the more strongly inhibiting antidepressants fluoxetine and paroxetine.3,8 Interestingly, the levels of endoxifen of the EM patients taking strongly inhibiting drugs were comparable to those of the poor metabolizers (PM),3,8 and there was no effect of any antidepressants on the levels of endoxifen of nonextensive metabolizing patients in 1 study.21
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Four retrospective clinical studies have investigated the risk of recurrence in relation to the use of antidepressants.22–25 Goetz et al24 retrospectively looked at the outcome of 256 postmenopausal women treated with tamoxifen. Extensive metabolizers with no CYP2D6 inhibitor had the best outcomes, followed by “intermediate metabolizers” (as defined by their CYP2D6 phenotype and thus including genotypical EM patients taking CYP2D6 inhibitors), and phenotypical “poor metabolizers” (which included anyone taking a potent CYP2D6 inhibitor) had the worst outcomes. In a recent study, Lash et al25 suggested that citalopram does not lower the protective effect of tamoxifen on breast cancer recurrence. This study concluded that there was no reduction of tamoxifen effectiveness among regular citalopram users. However, it appears that the CYP2D6 genotype was not taken into consideration. Lehmann et al22 retrospectively studied the effects of CYP 2D6, 2C9, and 3A inhibitors in 28 cases of breast cancer recurrence and 28 controls. The 2D6 inhibitors included fluoxetine, paroxetine, and sertraline. Lehmann et al22 found no impact on the clinical outcome of women exposed to CYP isoform inhibitors and tamoxifen. However, the sample size was not sufficient to detect a significant difference if one truly existed. Chubak et al23 conducted a retrospective cohort study of women with early stage breast cancer to assess the impact of antidepressant use on breast cancer recurrence. A third of these 1,306 women were taking antidepressants (mostly SSRIs [18.6%], especially paroxetine [10.3%]). There was no association found between antidepressant use after breast cancer diagnosis and the risk of recurrence either in general or for specific types of antidepressants. Among ER positive patients taking tamoxifen, the use of fluoxetine and paroxetine was associated with a modest increase in the risk of recurrence, but the number of observations was too small to achieve significance. Again, this study did not have sufficient power to detect small differences in the risk of recurrence.
We can also infer the potential interaction between antidepressants and tamoxifen by reviewing clinical studies26–46 focusing on other medications that are metabolized by the CYP2D6 enzyme (Table 2a and Table 2b). These studies demonstrated that paroxetine, fluoxetine, and bupropion convert approximately half of normal metabolizers to the poor metabolizer phenotype. Little or no effect was observed with venlafaxine, desvenlafaxine, and mirtazapine. Two studies33,39 did not identify an effect of fluvoxamine, but significant increases in CYP2D6 enzyme substrates were reported with sertraline, citalopram, escitalopram, duloxetine, and moclobemide, indicating a mild to moderate degree of enzyme inhibition.
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Nonclinical Studies of CYP2D6 Inhibition by Antidepressants
In the absence of further studies of the direct effects of antidepressants on levels of endoxifen in women taking tamoxifen or patients taking other medications, we may infer the possible pharmacodynamic effects by reviewing laboratory studies of this interaction carried out in vitro.
In vitro studies31,47–70 of the inhibition of the CYP2D6 enzyme in human liver microsomes have measured the inhibitory constants of various antidepressants (Table 3). The probes used in these studies include psychiatric medications such as imipramine, clomipramine, venlafaxine, desipramine, and clozapine, as well as other medications such as dextromethorphan and metoprolol and other substrates including sparteine, bufuralol, propafenone, and mexiletine. Results are reported as inhibitory constants (Ki), with lower values indicating greater inhibition of the enzyme. Fluoxetine and its metabolites (Ki = 0.15–4.08) and paroxetine (Ki = 0.065–4.85) were the most potent inhibitors, while venlafaxine (Ki = 33–41), mirtazapine (Ki = 41), and desvenlafaxine (Ki > 300) were the least potent. Sertraline (Ki = 0.7–27), fluvoxamine (Ki = 1.3–16.6), and citalopram (Ki = 7–88) were intermediate in potency. Bupropion was not a strong inhibitor (Ki = 21), but its metabolites erythrohydrobupropion (Ki = 1.7) and threohydrobupropion (Ki = 5.4) were more so. Nefazodone is a mild inhibitor of 2D6 (Ki = 18–50). In vitro and in vivo studies have, however, shown that nefazodone is a strong inhibitor of CYP3A4/5,68 although this property is of unknown significance in relation to tamoxifen metabolism.
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Many women with breast cancer are prescribed antidepressants for the treatment of common psychiatric disorders, such as major depression or anxiety, or for symptoms of vasomotor instability (hot flashes). However, most antidepressants, such as many of the SSRIs, have CYP2D6 inhibition properties, which affects the metabolism of tamoxifen to its more potent metabolite, endoxifen. Medications that have CYP2D6 inhibitory action can decrease the plasma concentrations of endoxifen in people who would otherwise respond to tamoxifen, “turning” those with genotypes of extensive metabolizers into poor metabolizers.3,8,21,71 Consequently, CYP2D6 inhibitors may increase their risk of relapse of breast cancer and death.71
We reviewed the evidence from clinical and nonclinical studies regarding the effects of antidepressants on the CYP2D6 enzyme. There is consistent evidence from all sources that paroxetine3,8,21,71 and fluoxetine3,8,71 have a large effect and should not be used in women taking tamoxifen. Indirect evidence regarding bupropion from in vitro studies (Table 3) and research of the effects on other medications (Table 2a and Table 2b) suggest that bupropion is also likely to have a large effect on the metabolism of tamoxifen and should not be used. Clinical3,8 and nonclinical studies (Tables 2a and 2b and 3) report that venlafaxine has little or no effect on the metabolism of tamoxifen and may be considered the safest choice of antidepressants. Clinical studies with desipramine demonstrated that desvenlafaxine at twice the recommended therapeutic dose does not inhibit the activity of CYP2D6 in a clinically meaningful way.72–74 The effect of mirtazapine on tamoxifen has not specifically been studied, but indirect evidence59 suggests that it is likely to have minimal or no effect on the CYP2D6 enzyme. Citalopram appears to have mild8,25 and sertraline has moderate effects3,8,71 on the metabolism of tamoxifen. Although they have not been tested directly with respect to tamoxifen, other research (Table 2a and Table 2b and 3) indicates that escitalopram has mild and fluvoxamine and duloxetine have moderate inhibitory effects on the CYP2D6 enzyme. These antidepressants may be considered as secondary options in which the risk of not treating depression needs to be weighed against the possibility of some reduction in the metabolism of tamoxifen. At this time, it is difficult to assess the possible clinical consequences of this mild to moderate inhibitory effect of these antidepressants, but 1 retrospective study25 in women taking tamoxifen reported no association with breast cancer recurrence with the use of citalopram. Nefazodone is a mild inhibitor of 2D6 in vitro and in vivo68 and a strong inhibitor of 3A4.68 There is insufficient evidence at this time to advise against using inhibitors of 3A4/5. A clinical trial75 looking at levels of tamoxifen in the blood of women with breast cancer and in women at high risk of breast cancer who are receiving tamoxifen together with venlafaxine, citalopram, escitalopram, gabapentin, or sertraline is currently underway and may help us gauge the risks associated with these medications when prescribed concomitantly with tamoxifen.
Not all of the commonly prescribed antidepressants have been studied with respect to their possible effect on the metabolism of tamoxifen, and the clinical implications of mild and moderate degrees of inhibition of CYP2D6 enzyme have not been well established. Given that antidepressants are among the most commonly prescribed medications, and women with breast cancer have high rates of depression and are likely to be prescribed antidepressants, clarifying these issues should become research priorities in breast cancer. Clinicians treating patients with breast cancer should review the prescription profiles of their patients to identify those who may need to modify their treatment based on a careful risk assessment (Table 4). Psychotherapy may be considered as an alternative or adjunct to antidepressant medications if clinically indicated.
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Other selective estrogen receptor modulators, such as raloxifene, may be considered as alternatives to tamoxifen. Raloxifene is metabolized by glucuronide conjugation and not by the P450 enzymes.76,77 Raloxifene has been approved in the United States for breast cancer prevention in postmenopausal women at increased risk of invasive breast cancer and in postmenopausal women with osteoporosis.78 Hence, interactions between raloxifene and commonly used antidepressants may be less problematic. Moreover, third-generation aromatase inhibitors can be substituted to selective estrogen receptor modulators in postmenopausal women with breast cancer. Anastrozole and letrozole are approved for the first-line treatment of hormone-sensitive advanced breast cancer in postmenopausal women. Anastrozole, letrozole, and exemestane are all indicated for the second-line treatment of advanced breast cancer in postmenopausal women.79 The main target of aromatase inhibitors is CYP19. The aromatase inhibitors are not metabolized by CYP2D6 and do not appear to inhibit it,80 thus limiting the potential for drug interactions with current antidepressants.
This review indicates the need to consider the possible pharmacokinetic interactions between antidepressants and tamoxifen. However, clinicians and patients may be reassured that there are safe options for the treatment of depression and should bear in mind the health risks of untreated depressive states.
Drug names: amitriptyline (Limbitrol and others), anastrozole (Arimidex), bupropion (Aplenzin, Wellbutrin, and others), citalopram (Celexa and others), clomipramine (Anafranil and others), clozapine (FazaClo, Clozaril, and others), desipramine (Norpramin and others), desvenlafaxine (Pristiq), dextromethorphan (Bromfed, Prometh, and others), duloxetine (Cymbalta), escitalopram (Lexapro), exemestane (Aromasin), fluoxetine (Prozac, Sarafem, and others), fluvoxamine (Luvox and others), gabapentin (Neurontin and others), imipramine (Tofranil, Surmontil, and others), letrozole (Femara and others), metoprolol (Lopressor, Toprol, and others), mirtazapine (Remeron and others), paroxetine (Paxil, Pexeva, and others), phenelzine (Nardil), propafenone (Rythmol and others), raloxifene (Evista), sertraline (Zoloft and others), tranylcypromine (Parnate and others), venlafaxine (Effexor and others).
Author affiliations: Department of Psychiatry, McGill University (Drs Desmarais and Looper); and Sir Mortimer B. Davis Jewish General Hospital (Dr Looper), Montréal, Québec, Canada.
Financial disclosure: Drs Desmarais and Looper have no personal affiliations or financial relationships with any commercial interest to disclose relative to the article.
Funding/support: None reported.
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