LEARNING OBJECTIVES
After reading this article you will be able to:
describe the management of depression in women with breast cancer
explain the impact of tamoxifen and the aromatase inhibitors on menopausal symptoms and secondary depression and anxiety symptoms
describe the interactions between SSRIs and tamoxifen.
The relationship between breast cancer and selective serotonin reuptake inhibitors (SSRIs) is complex. Breast cancer accounts for one-quarter of all cancers in women worldwide, with rapid increases in incidence reported in Europe and North America over the past 40 years (Sung Reference Sung, Ferlay and Siegel2021). Given that almost 50% of women have clinically significant depression or anxiety in the year after their diagnosis (Burgess Reference Burgess, Cornelius and Love2005), and as many of these may require treatment with SSRIs, the challenges faced by the population who require co-prescription of SSRIs with their breast cancer treatment are worthy of consideration. Studies have reached differing conclusions regarding the association between breast cancer and depression, with particular discrepancies in findings relating to incidence, mortality rates and medication interactions in breast cancer and depression.
Breast cancer
Incidence and aetiology
Breast cancer is the most commonly diagnosed cancer in the world. In 2020, 2.3 million cases were diagnosed, accounting for 11.7% of all new cancer diagnoses (Sung Reference Sung, Ferlay and Siegel2021). Hereditary mutations account for up to 10% of breast cancers, with half of these being mutations in the breast cancer genes BRCA1 or BRCA2, collectively referred to as BRCA mutations (Kuchenbaecker Reference Kuchenbaecker, Hopper and Barnes2017). However, breast cancer is a heterogeneous condition. In addition to the grading of the degree of spread, breast cancers are classified by the immunohistochemistry testing of oestrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 (HER2) and Ki-67 protein status. This classification enables the planning of treatment and prognostication, and tumour status provides evidence-based recommendations for adjuvant therapy (Gennari Reference Gennari, André and Barrios2021; Loibl Reference Loibl, André and Bachelot2024). Metastatic breast cancer is defined as cancer that has spread from the breast and local lymph nodes to other organs. Over 20% of women with breast cancer will develop distant metastases, leading to an estimated 400 000 to 500 000 deaths per year worldwide (Ly Reference Ly, Nguyen and Vinh-Hung2010). In the USA, 3.5% of women diagnosed with breast cancer already have metastatic disease at the time of initial diagnosis (Ly Reference Ly, Nguyen and Vinh-Hung2010).
Treatments for breast cancer include surgery, radiotherapy, systemic adjuvant or neoadjuvant chemotherapy, systemic endocrine therapy (Fig. 1) and immunotherapy. Endocrine therapy is the area in which there is the most overlap with mental health difficulties, so that will be the main focus of this article.
A comparison of endocrine treatments for breast cancer.
Endocrine treatments for breast cancer
Patients who are oestrogen receptor or progesterone receptor positive should receive adjuvant endocrine (hormone) therapy for 5–10 years. In addition, endocrine treatment is the treatment modality of choice for metastatic breast cancer (Davies Reference Davies, Pan and Godwin2013).
Tamoxifen
Tamoxifen is a selective oestrogen receptor modulator and is indicated as adjuvant therapy for breast cancer in pre- or postmenopausal women (and also men with breast cancer) who have completed initial treatment with surgery or radiotherapy (Early Breast Cancer Trialists’ Collaborative Group 2015, 2025; Gradishar Reference Gradishar and Salerno2016). It is used in the treatment of females with ductal carcinoma in situ (non-invasive breast cancer) after surgery and radiation, to reduce the risk of developing invasive breast cancer in the future. In hormone-sensitive cancers, tamoxifen reduces the annual breast cancer mortality rate by one-third, and the 5-year recurrence rate by half (Davies Reference Davies, Godwin and Gray2011). There is evidence that continuing treatment for 10 years can confer additional protection against recurrence and mortality (Davies Reference Davies, Pan and Godwin2013). The Gale Model (also known as the Breast Cancer Risk Assessment Tool (BCRAT): bcrisktool.cancer.gov) can calculate breast cancer risk reduction in certain patients at high risk, and in those at high risk, tamoxifen is an important component of treatment.
Tamoxifen selectively binds to oestrogen receptors, producing both oestrogenic and anti-oestrogen effects in various tissues. In breast tissue, it antagonistically competes with oestrogen for binding sites and causes anti-oestrogenic and anti-tumour effects. It slows cell cycling through downstream intracellular processes, classifying it as cytostatic. In bone, it stimulates oestrogen receptors instead of blocking them, exerting an oestrogen-agonist effect, and may prevent osteoporosis in postmenopausal women (Kristensen Reference Kristensen, Ejlertsen and Dalgaard1994; Ganz Reference Ganz and Land2008; Lee Reference Lee, Cheng and Chao2008).
Aromatase inhibitors
Aromatase inhibitors are superior for treatment of breast cancer in postmenopausal women, and have been associated with a significant reduction in recurrences and superior drug-free survival at 10 years (Cuzick Reference Cuzick, Sestak and Baum2010; Ruhstaller Reference Ruhstaller, Giobbie-Hurder and Colleoni2019). Exemestane is a steroidal, and letrozole and anastrozole are non-steroidal aromatase inhibitors. Aromatase inhibitors block oestrogen production by blocking the enzyme aromatase, which converts androgens into oestrogen, and by doing so, it reduces oestrogen levels in postmenopausal women. Unlike tamoxifen, which modulates oestrogen receptors, aromatase inhibitors have a direct inhibitory effect on oestrogen synthesis. Aromatase inhibitors are associated with significant side-effects, such as joint pain and mood changes, and carry an increased risk of developing osteoporosis (Early Breast Cancer Trialists’ Collaborative Group 2015).
Breast cancer and depression
Depression and other mental illnesses are common in cancer, and the recognition of the impact of mental disorders on people with cancer has led to the development of psycho-oncology services internationally. The prevalence of mood disorders in people undergoing treatment for breast cancer ranges from 40 to 55% for depression and from 40 to 46.8% for anxiety (Vahdaninia Reference Vahdaninia, Omidvari and Montazeri2010; Zhang Reference Zhang, Li and Zhang2025). Several key predisposing factors have been identified as being associated with these disorders among people with breast cancer, including a history of depression or anxiety, younger age at diagnosis, a lack of social support, severe physical symptoms (from the disease or the treatment), some medications, fear of death and disease recurrence. In addition, the psychological considerations include changes in body image, femininity and role, sexual characteristics and attractiveness (Vahdaninia Reference Vahdaninia, Omidvari and Montazeri2010). Some patients report that pre-existing symptoms of depression and anxiety deteriorate during chemotherapy (Burgess Reference Burgess, Cornelius and Love2005).
Breast cancer and its treatments can have a negative impact on a person’s quality of life. For many, it is associated with fears, such as fear of disease progression, of the development of the disease in their daughters, fear for the future, employment-related problems and difficulties relating to body image and sexuality – communication challenges with medical teams and with family members, particularly children, are also pervasive (Krigel Reference Krigel, Myers and Befort2014). One study that examined quality of life in people diagnosed with metastatic breast cancer showed that they gave greater importance to treatments that prolonged disease-free survival than treatments that prolonged absolute survival (Hurvitz Reference Hurvitz, Lalla and Crosby2013). Although many breast cancer survivors rate their quality of life as being positive, Ferrell et al’s seminal paper in this area indicates that patients report concerns regarding adjustment and psychosocial problems more frequently than physical difficulties, and these findings have been replicated in more recent studies across a range of settings (Ferrell Reference Ferrell, Grant and Funk1996).
It has been reported in the literature that people with metastatic disease report poorer quality of life, higher levels of pain and fatigue, and greater difficulty with physical, social and emotional functioning compared with those with non-metastatic disease (Vila Reference Vila, Barco Berron and Gil-Gil2020). Williamson and colleagues reported that the assessment tools used in studies of less advanced disease may not be sufficiently sensitive to adequately evaluate the disease-specific concerns of people with metastatic breast cancer (Williamson Reference Williamson, Love and Clague DeHart2018).
Guideline-based treatment of depression in cancer
The American Society of Clinical Oncology (ASCO) guideline for the management of depression in people with cancer was updated in 2023, on the basis of a systematic review of evidence (meta-analyses, systematic reviews and randomised controlled trials) (Andersen Reference Andersen, Lacchetti and Ashing2023). The guideline is applicable to people diagnosed with all forms of cancer, including breast cancer. It presents a stepped-care model, with psychoeducation as the basic intervention, and incorporating cognitive–behavioural therapy, behavioural activation, mindfulness-based cognitive therapy and exercise therapy for milder depressive episodes. For more severe episodes, these interventions are supplemented with interpersonal therapy. The guideline encompasses the use of pharmacotherapy for those who do not access or respond to psychological therapy or who have previously responded well to pharmacotherapy. It emphasises the importance of regular assessment of mental health following an initial cancer diagnosis, and acknowledges the impact of anhedonia and difficulties in motivation on the individual’s ability to engage with treatment. Similarly, the European Society for Medical Oncology (ESMO) clinical practice guidelines (Grassi Reference Grassi, Caruso and Riba2023) recognise the increased incidence of depression and anxiety in people with cancer and emphasise psychological therapies, noting that pharmacotherapy may be indicated alone or together with psychotherapy. The ESMO guidelines highlight the potential interactions between tamoxifen in particular and SSRIs.
Both sets of guidelines consider the risk factors for suicide in people with cancer, including older age at diagnosis, lower level of education, non-partnered relationship status, living in rural or sparsely populated areas, psychological comorbidity, hopelessness, advanced stages of cancer and low cancer-related performance status. They highlight the need for access to crisis response, ideally as a brief, practical strategy for reducing short-term suicide risk, supported by local protocols for acute risk.
Many studies of mental health in cancer have examined the potential benefits of group-based psychotherapeutic interventions on quality of life, reporting reductions in mental distress and improvements in adjustment and coping (Rosendahl et al., Reference Rosendahl, Gawlytta and Ressel2023). However, the majority of these studies, including the Cochrane review in this area (Jassim et al (2015), cited in Andersen Reference Andersen, Lacchetti and Ashing2023), have excluded women with metastatic breast cancer.
Menopause secondary to cancer treatment
Women undergoing treatment for breast cancer can experience a treatment-induced menopause through a number of mechanisms. For some women, such as those with BRCA mutations, it may be advised that they consider oophorectomy. Many chemotherapies cause damage to ovarian follicles, leading to ovarian failure – this is more common in women aged over 40 years. Finally, hormonal therapies, as described above, have a significant impact on oestrogen availability. All of these treatment-related menopauses are sudden in onset and characterised by severe symptoms, which may include depression and anxiety as well as vasomotor symptoms, fatigue, bone loss, vaginal dryness and cognitive problems. However, the management of menopause-related symptoms in women with hormone-sensitive breast cancer is challenging as hormone-replacement treatment is, of course, not an option in this population, and systemic hormone replacement therapy is contraindicated.
There is some evidence that SSRIs can be of use in managing vasomotor symptoms and mood in menopause. Nelson et al (Reference Nelson, Vesco and Haney2006) reported that, although not as effective as oestrogen, SSRIs and serotonin–noradrenaline reuptake inhibitors (SNRIs) have evidence of efficacy and may be suitable treatment options for more severely symptomatic women who are unable to take oestrogen. One study described a 60% reduction in vasomotor symptoms after 4 weeks of treatment with venlafaxine 75 mg once daily (Loprinzi et al (2000), cited in Nelson Reference Nelson, Vesco and Haney2006). In the UK, the British Menopause Society recommends the use of SSRIs and SNRIs for the management of vasomotor symptoms of menopause as well as for the management of mood and anxiety disorders (British Menopause Society 2020). However, the current National Institute for Health and Care Excellence (NICE) guidelines no longer recommend SSRIs for the routine management of vasomotor symptoms of menopause (NICE 2015).
Tamoxifen and SSRIs
The literature suggests that 20–30% of patients taking tamoxifen are co-prescribed antidepressants either for psychiatric reasons or off-label for the vasomotor symptoms of menopause. Therefore, the question of the relationship between tamoxifen and SSRIs is one that arises frequently in the clinical management of people who have comorbid depression and breast cancer.
The interaction with some SSRIs is due to tamoxifen being metabolised in the liver by cytochrome P450 enzymes, particularly CYP2D6. CYP2D6 converts tamoxifen into its most potent metabolite, endoxifen, and reduced CYP2D6 activity (Box 1) leads to lower endoxifen levels and may reduce tamoxifen’s effectiveness. Therefore, there is a theoretical risk that SSRIs that are potent inhibitors of CYP2D6 may reduce the bioavailability of the active metabolites of tamoxifen (Table 1). Specifically, paroxetine, which is a potent CYP2D6 inhibitor, has a direct impact on slowing the metabolism of tamoxifen to its major active metabolite, which has been speculated to have the potential to decrease the efficacy of tamoxifen.
Cytochrome P450 2D6 (CYP2D6) metaboliser phenotypes and activation of tamoxifen
Even without selective serotonin reuptake inhibitors, individuals with poor CYP2D6 metabolism may not fully activate tamoxifen. Approximately 100 allelic variants of CYP2D6 have been identified, and these present as four phenotypes:
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• poor metabolisers, who have two non-functional CYP2D6 alleles and so no CYP2D6 activity;
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• intermediate metabolisers, who have one functional and one deficient allele, which results in reduced CYP2D6 activity;
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• extensive metabolisers, who have two functional alleles and therefore have normal CYP2D6 activity;
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• ultra-rapid metabolisers, who have multiple functional alleles, which result in excess CYP2D6 activity.
Overview of selective serotonin reuptake inhibitors and other commonly used antidepressants and their cytochrome P450 (CYP2D6 and CYP3A4) inhibition status, potential interactions, dosing range and other key characteristics
The evidence base
The evidence base on the adverse effects of SSRIs on tamoxifen is contradictory. Several case–control studies and one retrospective cohort study found no increase in breast cancer recurrence in people taking SSRIs and tamoxifen. In contrast, another retrospective cohort study did report an increased risk of recurrence in patients taking paroxetine with tamoxifen (Kelly Reference Kelly, Juurlink and Gomes2010), and a case–control study suggested an increased risk of recurrence with co-prescription of tamoxifen and CYP2D6 inhibitors (Aubert Reference Aubert, Stanek and Yao2009).
However, larger-scale studies do not confirm any increased risks in people taking SSRIs with tamoxifen, compared with those taking tamoxifen alone (Donneyong Reference Donneyong, Bykov and Bosco-Levy2016). Donneyong et al (Reference Donneyong, Bykov and Bosco-Levy2016) examined this in a population from five US-based databases over an 18-year period. They found that 14 532 women were prescribed tamoxifen and SSRIs, and compared the outcomes of those taking potent CYP2D6-inhibiting SSRIs (paroxetine and fluoxetine) with those taking other SSRIs. They did not find an increased risk of death in the group taking potent CYP2D6-inhibiting SSRIs. Haque et al (Reference Haque, Shi and Schottinger2016) reported on the long-term follow-up of 16 887 people with breast cancer and examined the relationship between tamoxifen and antidepressant drugs. They found no convincing evidence of any increased risk of subsequent breast cancer in those prescribed SSRIs and tamoxifen concomitantly.
An additional consideration is the effect of SSRIs and tamoxifen on QT-interval prolongation, which has been reported when some SSRIs were given to patients taking tamoxifen (Taylor Reference Taylor, Barnes and Young2021). This is, of course, a concern for people who are prescribed other psychotropic medications, especially atypical antipsychotics.
Guidelines on co-prescription
Bradbury et al (Reference Bradbury, Hutton and Beltran-Bless2022) give an overview of various evidence-based guidelines on the concurrent use of tamoxifen and antidepressants in their systematic review of the relationship between co-prescription and adverse outcomes, in a population of over 100 000 patients. They found no convincing evidence of adverse outcomes, and in the end concluded that the pharmacological interactions, although theoretically plausible, do not appear to be associated with harm. They therefore conclude that guidelines advising avoidance of, or caution, with co-prescription may inadvertently cause harm, especially where the advice has resulted in switching from tamoxifen to alternative agents, or changing from an antidepressant that has been effective for an individual patient to another that may not be as efficacious (Bradbury Reference Bradbury, Hutton and Beltran-Bless2022).
The ESMO guidelines state: ‘SSRIs have few significant drug–drug interactions, with the notable exception of tamoxifen metabolism, which is least affected by escitalopram, sertraline and venlafaxine. The only [antidepressant] to demonstrate a negative clinical outcome is paroxetine, which should be avoided in patients taking tamoxifen’ (Grassi Reference Grassi, Caruso and Riba2023).
SSRIs and carcinogenesis
Some research has examined the question of whether SSRIs are associated with the incidence of breast cancer in the first place. Oestrogen and progesterone play a key role in many breast cancers, and about 70% of breast cancers are oestrogen receptor positive (ER-positive). The factors that influence risk include genetics (e.g. BRCA mutations), hormonal exposure and lifestyle. Epidemiological studies in the area deliver, in the main, conflicting data, with some suggesting a slight increase in breast cancer risk, especially with long-term SSRI use, and others finding no significant correlation. However, it is worth considering that people with severe mental illness have increased rates of cancer-related mortality compared with the general population. The rates of breast cancer are, according to some studies, higher among people with schizophrenia but, according to others, no different from those in the general population. The gap between incidence and mortality may be explained by the disparity in access to care, as people with severe mental illness tend to receive less or delayed care (Kisely Reference Kisely, Alotiby and Protani2023).
In addition to the matter of CYP2D6 inhibition, other theoretical biological mechanisms underlying interactions between tamoxifen and SSRIs are the effects on oestrogen metabolism, where some SSRIs may affect enzymes involved in oestrogen metabolism, potentially increasing oestrogen levels. This is of relevance in people prescribed tamoxifen for conditions other than cancer. Paroxetine is a weak selective oestrogen receptor modulator (SERM). Some studies suggest it may itself promote oestrogen-dependent breast cancer. However, findings remain inconclusive. There is also a theoretical risk that some SSRIs are associated with elevated prolactin, linked to breast cancer risk (Tworoger Reference Tworoger, Eliassen and Zhang2013). Obesity and alcohol use have also been associated with SSRI use and the development of breast cancer independently, but these are likely to be confounders and are established risk factors for breast cancer independent of the co-prescription of SSRIs in this population (Niu Reference Niu, Li and Yan2024). And finally, there is limited evidence suggesting that SSRIs could influence oxidative stress, which may contribute to carcinogenesis, although SSRIs are more likely to reduce stress markers (including interleukin 6 (IL-6), tumour necrosis factor alpha (TNF-α) and 8-hydroxy-2-deoxyguanosine (8-OHdG)) in people with major depression who show a treatment response their use (Lindqvist Reference Lindqvist, Dhabhar and James2017).
Interactions between aromatase inhibitors and SSRIs
Another important research question on this topic has been whether SSRIs reduce the effectiveness of aromatase inhibitors: in other words, do they increase the risk of recurrence? Unlike tamoxifen (which requires CYP2D6 for activation), aromatase inhibitors do not rely on CYP2D6 for metabolism. Aromatase inhibitors are primarily metabolised by CYP3A4 in the liver, and most SSRIs do not strongly inhibit CYP3A4, making it theoretically less likely that they will have a significant impact on the effectiveness of aromatase inhibitors.
However, concerns have been voiced about the potential for interaction between SSRIs and aromatase inhibitors. For example, potent CYP3A4 inhibitors (e.g. fluvoxamine) may increase serum levels of aromatase inhibitors, but this is not typically a major clinical concern. Most SSRIs (citalopram, escitalopram, sertraline, paroxetine, fluoxetine) do not significantly affect the metabolism of aromatase inhibitors. As a result, the preferred SSRIs in women with breast cancer who are prescribed aromatase inhibitors are citalopram, escitalopram and sertraline, as these have the weakest or minimal CYP3A4 inhibition and are accordingly unlikely to have any impact on the effectiveness of aromatase inhibitors.
Aromatase inhibitors are not documented to interact with SSRIs and cause any adverse effects. However anastrozole is predominantly oxidised by CYP3A4 and less commonly by CYP3A5, CYP2C8, CYP1A2 and CYP2C9 in the liver (Turkistani Reference Turkistani and Marsh2012). A study by Ozyurt et al., Reference Ozyurt, Ozden and Gemici2022) reported increased serum anastrozole levels in women who were taking escitalopram, while no significant alteration was noted in serum oestradiol levels. This suggests a need for some caution in the co-prescription of anastrozole with escitalopram and that there may be a potential role for therapeutic drug monitoring to individualise and optimise adjuvant endocrine therapy among breast cancer patients. Although escitalopram co-prescription might contribute to a compensatory increase in plasma anastrozole levels in patients with obesity, this finding may illustrate individual genetic variability in anastrozole metabolism, which may underlie any potential drug–drug interaction (Ozyurt et al., Reference Ozyurt, Ozden and Gemici2022). Valachis et al (Reference Valachis, Garmo and Weinman2016) examined the relationship between adherence to endocrine therapy ( tamoxifen or aromatase inhibitors) and SSRI use. They examined a registry-based cohort of 18 432 women with ER-positive breast cancer who received endocrine therapy and did not find any relationship between cancer survival and SSRI use, even when specifically examining those individuals who were prescribed strong CYP26D-inhibiting SSRIs.
Additional considerations with SSRIs
Given that there is a well-documented association between tamoxifen and low mood, it is not surprising that the literature has considered the drug’s potential as a treatment agent for mania. One systematic review that examined the effect of tamoxifen on mood disorders reported that the drug was associated with ‘antimanic properties’ (Carmassi Reference Carmassi, Cordone and Dell’Oste2021). Theoretically, given that tamoxifen has an inhibitory effect on protein kinase C (PKC), it has been speculated that it might have a role in the management of bipolar disorder, specifically in the management of acute mania. Tamoxifen exhibits anti-PKC activity at higher doses, likely due to its inhibiting effect on PKC, with the potential contribution of oestrogenic effects (Bagdadi et al (2021), cited in Joseph Reference Joseph, Vishwanath and Praharaj2024). The Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines recommend tamoxifen as a third-line treatment for acute mania (Yatham et al (2018), cited in Joseph Reference Joseph, Vishwanath and Praharaj2024). Unfortunately, its efficacy is limited by the variability in bioavailability due to individual variability in CYP2D6 expression (as outlined in Box 1). As a result, research is currently being conducted into the potential use of endoxifen, which has more potent anti-PKC activity and does not have the same impact on CYP2D6 (Joseph Reference Joseph, Vishwanath and Praharaj2024).
Conclusion
The relationship between breast cancer and depression is complex and is likely mediated through very clear biological mechanisms as well as via the more commonly described psychosocial mechanisms. Although depressive episodes need to be managed in much the same way as in the rest of the population, it is important that clinicians consider the role of endocrine treatments, and the menopause they can induce, in women with breast cancer presenting with mood and anxiety symptoms. Careful prescribing is required, bearing in mind the increased risk of mood and anxiety disorders in this population and the relationship between symptoms and treatment.
MCQs
Select the single best option for each question stem
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1 The number of breast cancer diagnoses made in 2020 was:
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a 600 000
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b 1.2 million
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c 1.8 million
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d 2.3 million
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e 5 million.
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2 The following medication is a steroidal aromatase inhibitor:
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a tamoxifen
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b exemestane
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c anastrozole
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d letrozole
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e sertraline.
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3 Tamoxifen may be associated with the following symptoms:
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a vasomotor symptoms of menopause
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b anxiety symptoms
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c depressive symptoms
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d b and c
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e all of the above.
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4 Among women who are prescribed tamoxifen, the proportion co-prescribed SSRIs is:
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a 1–2%
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b 4–6%
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c 8–10%
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d 15–18%
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e 20–30%.
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5 The following medication is a potent inhibitor of CYP2D6:
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a sertraline
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b alprazolam
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c escitalopram
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d amitriptyline
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e paroxetine.
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MCQ answers
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1 d
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2 b
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3 e
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4 e
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5 e
Data availability
Data availability is not applicable to this article as no new data were created or analysed in this study.
Funding
This research received no specific grant from any funding agency, commercial or not-for-profit sectors.
Declaration of interest
None.
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