Screening for Depression in Patients With Breast Cancer

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RELEASE DATE

October 1, 2022

EXPIRATION DATE

October 30, 2024

FACULTY

Donna M. Lisi, PharmD, BCPS, BCPP, BCGP, BCACP, BCMTMS
Clinical Pharmacist
Somerset, New Jersey

FACULTY DISCLOSURE STATEMENTS

Dr. Lisi has no actual or potential conflicts of interest in relation to this activity.

Postgraduate Healthcare Education, LLC does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors may express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data.

ACCREDITATION STATEMENT

Pharmacy
Postgraduate Healthcare Education, LLC is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

UAN: 0430-0000-22-124-H01-P
Credits: 2.0 hours (0.20 ceu)
Type of Activity: Knowledge

TARGET AUDIENCE

This accredited activity is targeted to pharmacists. Estimated time to complete this activity is 120 minutes.

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DISCLAIMER

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

GOAL

To educate pharmacists about depression as a common comorbidity in women with breast cancer and the role that pharmacists can play in the identification, screening, and referral of the mood disorder.

OBJECTIVES

After completing this activity, the participant should be able to:

1. Describe the prevalence of depression among women with breast cancer.
2. Identify specific challenges due to the COVID-19 pandemic restrictions and obstacles faced by young women with breast cancer.
3. Summarize the pharmacogenomic issues surrounding the use of antidepressants in women with breast cancer who are receiving tamoxifen.
4. Discuss the role that pharmacists can play in screening women with breast cancer for depression, educating them about available resources, and providing appropriate referrals.

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ABSTRACT: Approximately one in eight women will develop breast cancer (BC) in her lifetime, and depression and suicide are higher in this group than in the general population. The necessary COVID-19 pandemic social restrictions resulted in delays in treatment and heightened fears of BC recurrence and disease progression. Young women are particularly vulnerable to depression and face additional challenges compared with older women with BC. Information about the potential gene-drug interaction between tamoxifen (a selective estrogen receptor modulator, which is one of the mainstays of adjunctive hormonal therapy for BC) and some selective serotonin reuptake inhibitors is available. Pharmacists should be actively involved in screening patients with BC for depression, informing them about resources that are available, and making referrals to other team members as appropriate.

In the United States, breast cancer (BC) is the most common type of cancer in women (except for some types of skin cancer), accounting for 30% of all cancers diagnosed in this group.^1,2 In 2022, it is estimated that there will be 290,560 new cases of BC in the U.S., along with 43,780 deaths.³ According to the National Cancer Institute (NCI), in 2019 there were an estimated 3,771,794 women living with BC in the U.S.⁴ BC accounts for 15% of all new cancer cases and 7.1% of cancer deaths among women, with black women dying from the disease at a higher rate than white women.^4,5

In the U.S., approximately one in eight women will develop BC in her lifetime, with many suffering from concomitant depression.⁶

Statistics on Depression and BC

Global estimates put the prevalence of depression among BC survivors at nearly 32.2%.⁷ One of the most comprehensive studies was a serial, retrospective, crosssectional analysis conducted between January 1, 2002, and December 31, 2014, using data from the Healthcare Cost and Utilization Project National Inpatient Sample, which is the largest all-payer inpatient discharge database in the U.S. This study characterized the type and number of comorbidities with depression in both female and male patients with BC. Among patients hospitalized with BC, 41% of women had metastatic disease, compared with 46% of men. The prevalence of depression was 10.5% among women and 7.5% among men. Comorbidities were more common in men than women. Among hospitalized women with BC, depression was most common in whites and those aged 40 to 69 years, whereas in men, it was more common in Native Americans, Hispanics, and those aged 18 to 49 years.

The investigators also noticed a shift in the prevalence of depression, with rates increasing from 6.5% in non-metastatic disease and 5.9% for metastatic disease in women in 2002 to 15.7% to 14.8%, respectively, in 2014. This represents an increase in diagnosed depression of 6% per year in women. For men, the prevalence of depression was 4.7% for nonmetastatic disease and 4.6% for metastatic disease in 2002, and this increased to 13.8% to 9.8%, respectively, in 2014: a 10% increase per year during that period.⁸

Several studies have attempted to quantify rates of depression in various populations with BC. In a study of Medicare beneficiaries, depression rates varied based on type of malignancy, with 3.9% of women with BC diagnosed with depression compared with 5.8% of women with colorectal cancer.⁹ However, another study found that depression was most often identified in patients with BC compared with the other cancer types, including colorectal cancer (27.4% vs. 18.6%, respectively). They also found that the incidence of depression has increased among patients with late-stage cancer of any type from 15.3% in 2001 to 24.1% in 2013. Although not specific for BC, the highest incident of postdiagnosis depression was in whites, and the lowest incidence was among Hispanics. In general, depression was significantly more common in women versus men (22.7% vs. 16.3%, respectively).¹⁰ The prevalence of depressive symptomatology was 53% in a group of Latina BC survivors.¹¹

Assessment of Depressive Symptoms in Cancer Patients

More emphasis has been placed on the mental health well-being of cancer survivors in recent years. While not specific for BC, the American Society of Clinical Oncology (ASCO) has recommendations for the screening, assessment, and care of depressive symptoms in adults with cancer (see TABLE 1).¹²

The NCI has developed a Physician Data Query (PDQ), which is a monograph-like document to assist with the management of depression in patients with cancer. While also not specific to BC, it does address BC throughout. It covers an overview; assessment and diagnosis; intervention for depression in cancer; and the prevalence, assessment, and management of suicide risk in cancer patients.¹³

The National Comprehensive Cancer Network (NCCN) has developed a Distress Thermometer to screen for distress and rate it on a scale of 0 to 10. Distress is described as an unpleasant experience of mental, physical, social, or spiritual nature. There is also an accompanying Problem List that asks about problems in five different life domains: practical (e.g., childcare, food, housing, insurance/financial, transportation, work/ school, and treatment decisions); family problems; emotional problems; spiritual/religious concerns; and physical problems.¹⁴ A PDF of the NCCN Distress Thermometer and Problem List can be found at www.nccn.org.

Healthy People 2030 has added a research objective intended to increase the mental and physical health–related quality of life of cancer survivors (C-R01). Although there are currently no evidence-based interventions available to address this objective, it has been deemed a high-priority public health issue.¹⁵

Impact of Depression on Health Outcomes in BC

Depression may adversely affect the immune system.¹⁶ Stress may increase susceptibility to inflammationinduced depressive symptoms. Increased levels of inflammation have been associated with increased depressive symptoms in BC.^17,18 A systematic review and meta-analysis of cohort studies found that psychological distress, which manifests as depression and anxiety, was associated with higher cancer-specific mortality risk in patients with BC.¹⁹ A review of data from 145,251 BC patients from the Korean National Health Insurance Service who were diagnosed between 2007 and 2014 found that depression and/or anxiety significantly increased the risk of mortality (hazard ratio [HR]: depression 1.26, anxiety 1.14, depression and anxiety 1.38, respectively). However, antidepressant therapy attenuated this risk.²⁰ Another study using data from the Taiwan National Health Insurance Research Database for 30,659 newly diagnosed BC patients found that depression was associated with a higher rate of recurrence compared with a nondepressed cohort (17.1% vs. 12.5%, respectively; P <.001).²¹

There may be a bidirectional relationship between depression and BC that acts via the immune system. One theory is that depression is due to dysfunction of immune cells and cytokines resulting from alterations to neurotransmitters (including serotonin) that affect blood-brain permeability. There may also be alterations in tryptophan metabolism. A common link may exist between the dysregulation of cytokines or the gastric microbiota, depression, and BC.²² Among the cytokines that have been found to be linked to depression in BC patients are interleukin (IL)-8, IL-6, and IL-2.^23-26 Stress in the form of social environmental adversity (e.g., crime, adverse childhood experiences) is related to depression and anxiety symptoms, which may increase risk by acting as potential modulators of the tumor microenvironment in BC.^27,28 BC itself may serve as a “second wave” of stress, which could affect the development and progression of BC through the hypothalamicpituitary axis.²⁹ Increased psychosocial resilience may help mitigate inflammation-caused depression in BC.³⁰

Depression has also been shown to be directly correlated to pain severity and interference in function among BC survivors.³¹ It may also be involved in chemotherapy-induced memory problems.³² Higher depression scores are associated with worse sleep quality.³³ Having depression prior to a BC diagnosis may affect treatment options and thereby impact prognosis.³⁴

The Total Beck Depression Inventory score may serve as a useful tool to predict 25-year relapse-free survival and overall survival in BC patients.³⁵

Despite the prevailing evidence linking depression to the risk of BC, a meta-analysis involving 11 cohort studies and 182,241 participants concluded that there are insufficient data to support a positive association between depression and BC. It cited methodological concerns, including the use of single depression assessments and numerous different depression scales.³⁶

COVID-19 Effects on Psychosocial Well-Being and BC Treatment Delays

The COVID-19 pandemic and initial mandatory social restrictions have had an adverse effect on the psychosocial well-being of the general population, but more specifically on patients with cancer.³⁷ In an observational longitudinal study of patients undergoing IV antineoplastic therapy, patients with BC experienced greater COVID-19 distress compared with those with other types of cancer (i.e., lung, gastrointestinal, genitourinary, nervous system, head and neck, melanoma, other gynecological cancers, and sarcoma); BC patients made up 26% of the study population.³⁸ The pandemic lockdown restrictions also led to disruptions of care for about one-half of BC survivors.³⁹ Significantly more patients with depression experienced barriers in contacting their general practitioner and BC physician (25.0% and 11.2%, respectively). Interruption of treatment or after-care plans were significantly correlated with depression in one-third (32.7%) of patients. Previously having had depression was independently and significantly associated with depression during the pandemic.⁴⁰

Another study also found that being unable to contact the physician during the pandemic was associated with deterioration in BC patients’ emotional functioning. In those undergoing active BC treatment, there was a significant decline in social functioning during the pandemic. About one-half reported moderate-to-severe loneliness.⁴¹ In a study of older BC survivors, loneliness increased during the pandemic in both patients with BC and those without BC. The loneliness was not explained by either the older adults’ living situation or the availability of a support system. In both groups, loneliness was associated with worsening mental health.⁴²

Depression and anxiety increased death anxiety among BC survivors during the pandemic.⁴³ A scoping review of fear of BC recurrence during the pandemic found that 35.7% of BC patients experienced a clinically significant level of fear. Risk factors for increased fear of BC recurrence were being unmarried, childless, and less financially secure.⁴⁴ This fear may be justified as another study found that there was a significant increase in the prevalence of BC recurrence among those whose treatment was delayed due to COVID-19 restrictions compared with those whose care was not delayed (18.4% vs. 9.0%, P = .018).⁴⁵

For patients with BC, the lockdown had an additional impact of limited access to timely and muchneeded healthcare. Treatment changes, which affected one-fifth of patients (18.8%), and changes in treatment plans due to the pandemic were significantly associated with depression.⁴⁶

A survey was conducted from April 2020 to May 2020 (the first lockdown) of 201 women with BC (median age 53.12 years) who were awaiting treatment at an infusion center. About 47% had been diagnosed with BC more than a year prior. Researchers found that over one-half (54.2%) of patients experienced high distress as indicated by the NCCN’s Distress Thermometer and Problem List. Among the issues that were associated with a high level of distress were those involving childcare, housing, or work or school, and having depression, feeling fear, nervousness, sadness, worry, loss of interest for usual activities, sleep problems, and difficulty getting around. Those diagnosed more than 12 months prior most often had the highest level of distress (25.9% for those diagnosed more than 12 months ago, 13.4% for those diagnosed 6 to 12 months prior, and 14.9% for those diagnosed less than 6 months ago).⁴⁷

A study from Canada found that 63.9% of BC patients experienced at least one stressor during the pandemic. Stressors with the highest degree of concern included obtaining food, medicine, and essentials; postponement or cancellation of cancer treatment; changes in cancer-care trajectory; and postponement of medical tests. The higher the number of stressors and the greater the level of concern, the more significant was the association with depression.⁴⁸

Among the protective factors associated with reduced depression, anxiety, and stress during the lockdown were the possession of personal positive resources such as optimism, hope, self-efficacy (i.e., the belief of being able to perform new or difficult tasks and to achieve the desired results), trait mindfulness (i.e., the predisposition to be mindful in day-to-day life), and courage.⁴⁹

Conversely, a study from the UK that evaluated the impact of COVID-19 on psychological distress among cancer patients (BC patients made up 58.6% of the patient population in 2019 and 41.3% in 2020) found that the pandemic did not adversely affect mental health.⁵⁰ Another group found similar results but also identified a subgroup of BC patients undergoing active treatment who were psychologically susceptible to high levels of distress and lower quality of life due to their “concern often/all the time” about COVID-19.⁵¹

Physical and Psychological Effects of BC in Young Women

Young women with BC face unique physical and psychological challenges, such as infertility/trying to preserve fertility, child-rearing and fear of leaving their children motherless, interference with career trajectory, sexual functioning, financial concerns, and social isolation.^52-57 Factors that add to distress in young women with BC include that the disease is more likely to be hereditary, may be found at a later stage, and may be more aggressive.⁵⁷ Studies that have focused on BC in young women have used different age cutoffs to define this population, ranging from age 18 to 50 or 55 years, adding difficulty in assessing the effect of depression in this group.

In the U.S., about 9% of all new BC cases are diagnosed in women younger than age 45 years.⁵⁷ Whereas the incidence of BC has decreased in older women, recent statistics from the CDC show that the incidence has increased for women aged 20 to 39 years.²

Rates of depression in young women with BC range from 18% to 43%, are higher compared with rates in older women (age >50 years), and are more elevated than in the general population.^58,59 Rates of anxiety symptoms are even higher, occurring in up to 69% of young women.^58,60 Others have confirmed that anxiety, rather than depression, appears to be more common in this population.⁶¹ Some studies have found that depression and anxiety symptoms are at their highest early on in the course of disease, especially when first diagnosed and while undergoing treatment.⁶² Others have indicated that quality of life and psychological distress, including depression, are dynamic over the first year following surgery in young women. Monitoring of psychosocial status should be ongoing.⁶¹ In a study of 54 young women with metastatic BC, investigators found that 20% of patients had a positive screen for depression and 44% had a positive screen for anxiety.⁶³

Concerns over fertility are one of the major sources of distress in young women with BC.^52,54 This is especially true for women who are nulliparous at the time of treatment and for whom treatment results in ovarian failure.⁵⁴ It has been recommended that premenopausal women receiving systemic therapy and who desire to have children consult a reproductive endocrinologist prior to treatment to determine fertility-prevention strategies. Hormonal therapy is not recommended.^64,65 Several recent studies offer reassurance that fertility preservation is safe.^66-68

Young women with chemotherapy-induced infertility score lower in assessments of health-related quality of life and physical functioning than do noncancer patients suffering from infertility.⁶⁹ The Young and Strong study was a multisite, cluster-randomized clinical trial to address fertility concerns. These concerns then served as a surrogate marker for other issues faced by young women with BC. The trial also sought to educate and provide support and reduce psychosocial distress that accompanies a BC diagnosis.⁷⁰ However, the program was not successful in bringing attention to fertility issues.⁷¹ Others have found that an interventional strategy such as a fertility-related decision aid designed to educate young women about fertility-related options helped reduce distress and later regrets.⁷²

A systematic review of health-related quality of life, menopausal symptoms, and fertility concerns among women aged younger than 50 years with BC found that premature menopause, menopausal symptoms, and infertility following treatment were associated with higher levels of distress.⁵⁹ Menopausal symptoms, in particular vasomotor symptoms, appear to mediate depression by causing sleep disturbances. Use of nonhormonal pharmacologic agents such as antidepressants, gabapentin, or nonpharmacological interventions (e.g., cognitive behavioral therapy) may help relieve vasomotor symptoms and the associated depression.⁷³ Additionally, chemotherapy-induced menopause has been associated with both sexual inactivity and sexual dysfunction in young women with BC.⁵⁵

Risk factors for depression in young BC survivors include the presence of preexisting depression, having children aged younger than 10 years, and having an income above $100,000.⁵⁸ A prior diagnosis of depression has been associated with reduced family support.⁷⁴ Family and partner support, body image, and the ability to manage children and daily life in general also play a mediating role in depression and/or anxiety.^56,74,75 In a systematic review in young BC survivors, emotional support and self-esteem were negatively associated with depressive symptoms, whereas illness intrusiveness into daily activities, stress, negative body image, pain, reproductive concerns, and poor physical functioning were positively associated with depressive symptoms.⁵⁹ Data from the Young and Strong trial of BC survivors found that income was not associated with a diagnosis of depression.⁷⁶ In young women with metastatic BC, having a college education, a higher physical symptom score, being white, having less social support, and having lower spirituality were associated with higher depression scores.⁶³

The type of surgical procedure (i.e., mastectomy or breast-conserving surgery [lumpectomy]) also affects the level of distress.⁷⁷ Young women who underwent a bilateral mastectomy experienced more sexual and body image distress than those who underwent breast conservation, especially if the mastectomy was not followed by reconstructive surgery.^77,78

Mindfulness meditation and survivorship education have been shown to reduce symptoms of depression. Mindfulness has been associated with additional benefits in relieving fatigue, insomnia, and vasomotor symptoms.⁷⁹ Psychological resilience improves outcomes.⁸⁰ Increasing physical activity and healthy eating may also improve mood in young women with BC.⁸¹

Partners of young survivors are adversely affected by the BC diagnosis.⁸² There appears to be a bidirectional relationship with each partner affected by each other’s level of distress.⁸³

Priority research areas that have been identified for young women with BC include promoting shared decision-making, addressing concerns over body image, fear of recurrence and treatment, and evaluating palliative care options for patients with metastatic disease.⁶²

Guidelines on Tamoxifen and Drug-Drug Antidepressant Interactions

Tamoxifen is one of the mainstays of adjunctive hormonal therapy in BC. Tamoxifen is extensively metabolized by numerous CYP450 enzymes, including CYP3A, CYP2D6, CYP2C9, CYP2C19, and CYP2B6. N-desmethyltamoxifen, which is tamoxifen’s major metabolite with equipotent activity to tamoxifen, is primarily formed by CYP3A. Although considered minor metabolites, endoxifen and 4-hydroxytamoxifen have 100fold greater affinity for the estrogen receptor and 30- to 100-fold greater potency in suppressing estrogen-dependent cell proliferation than tamoxifen.

CYP2D6, which undergoes polymorphism resulting in various metabolizer states (i.e., poor metabolizer [PM], intermittent metabolizer [IM], and ultrarapid metabolizer [UM] status), is involved in the formation of endoxifen and 4-hydroxytamoxifen. CYP2D is responsible for catalyzing the formation of endoxifen from N-desmethyltamoxifen. Phase 2 enzymes, such as SULT1A1, UGT2B7, and UGT1A4, are associated with tamoxifen clearance from plasma.⁸⁴

The ABCB1 transporter, which is also subject to polymorphism, is thought to play a role in the metabolism of tamoxifen. The ABCB1 gene encodes for p-glycoprotein, an efflux transporter that extrudes drug molecules and xenobiotics at the blood-brain barrier (BBB) level. The wildtype of the ABCB1 transporter increases efflux of substrate antidepressants at the BBB. ABCB1 genotype has been linked to antidepressant treatment response.⁸⁵ ABCB1 polymorphisms may affect the outcome of tamoxifen adjuvant treatment in premenopausal BC patients^86-89

The Clinical Pharmacogenetics Implementation Consortium (CPIC) developed guidelines to address the effect of CYP2D6 polymorphism on tamoxifen’s metabolism.^90,91 Metabolism of N-desmethyltamoxifen to endoxifen via CYP2D6 varies depending on phenotype. Low endoxifen concentrations have been associated with an increased risk of BC recurrence in women who are on tamoxifen as adjunctive therapy for BC. However, the use of CYP2D6 metabolizer phenotype as a predictor of clinical outcome is controversial.^92,93 There is no established “lower limit” of circulating endoxifen that is associated with treatment failure. Only low levels of endoxifen are needed to block all receptors. Even when alterations in CYP2D6 metabolizer status have occurred resulting in shorter time to recurrence and poorer relapse-free survival, there have been no observed differences in overall survival. However, the studies used to draw this conclusion have been criticized for being flawed.⁹⁴

A systematic review and meta-analysis on the CYP2D6 genotype and tamoxifen response for BC published in 2013 that included 25 studies and 13,629 patients concluded that despite a weak association between CYP2D6 genotype and surrogate endpoints for overall survival, the use of CYP2D6 genotyping to guide tamoxifen prescribing is not recommended.⁹⁵ More recently, in April 2022 another systematic review involving 15 studies came to a similar conclusion that despite data from nearly 100,000 patients on tamoxifen and selective serotonin reuptake inhibitor (SSRI) therapy, including paroxetine, there is no consistent evidence of harm (i.e., BC-specific survival, mortality, quality of life, treatment compliance, and impact of concurrent use of antidepressants and other endocrine therapies) from concomitant use. The authors questioned whether it was time to update evidence-based guidelines to reflect this conclusion.⁹⁶ However, caution is advised since one study demonstrated statistically significant evidence of adverse effects on mortality (HR 1.36, 95% CI 1.15-1.61) included in the systemic review.

The CPIC guidelines make recommendations on the use of endocrine therapy based on CYP2D6 phenotype. CYP2D6 PMs (i.e., those who have deficit CYP2D6 activity) have lower endoxifen concentrations compared with normal (extensive) metabolizers. Since this can increase the risk of BC recurrence, aromatase inhibitors (AIs; e.g., anastrozole, letrozole, exemestane) are recommended alternatives for postmenopausal women. For premenopausal women who are PMs, the guidelines recommend the use of AIs along with ovarian-function suppression. Switching from tamoxifen to anastrozole is not associated with an increased risk of BC recurrence. The guidelines do not recommend the use of a higher dose of tamoxifen (i.e., 40 mg/day) unless AIs are contraindicated because this dosage does not normalize endoxifen concentrations. In patients who are IMs or IMs/normal metabolizers, AIs are also recommended with or without ovarian suppression based on menopausal status, and the 40-mg/day dosage of tamoxifen should only be used if AIs are contraindicated. Patients should also avoid CYP2D6 inhibitors of any type (weak or strong inhibitors). Normal and ultra CYP2D6 metabolizers (i.e., those with genetically elevated CYP2D6 activity) should receive the recommended standard dosage of tamoxifen (20 mg/day), but they should avoid moderate-to-strong CYP2D6 inhibitors.^90,91 Evidence shows that there has been a shift in prescribing patterns away from the concomitant use of strong CYP2D6-inhibitory antidepressants with tamoxifen.^97,98

Concern arises in the management of depression in patients with BC since several antidepressants are CYP2D6 inhibitors. Paroxetine, fluoxetine, and bupropion are strong inhibitors; duloxetine is a moderate inhibitor; and escitalopram, citalopram, venlafaxine, sertraline, fluvoxamine, and mirtazapine are weak inhibitors of CYP2D6, with the latter two presumably having no CYPD2D6 activity.^99,100 Those who are CYP2D6 PMs already have higher concentrations of drugs such as paroxetine since the antidepressant is also metabolized via CYP2D6, which could lead to greater CYP2D6 inhibition of endotoxifen concentrations.^101,102

While paroxetine reduces tamoxifen’s active metabolite, endoxifen, the use of citalopram with tamoxifen has not been associated with BC recurrence (compared with nonusers of citalopram).^103-106

Based on results of a population-based cohort study, coadministration of paroxetine and tamoxifen resulted in an increased risk of death from BC (mean follow-up 2.38 years). Absolute risk of BC death increased 25%, 50%, and 75% in proportion to the time on tamoxifen. Overlapping paroxetine administration was associated with 24%, 54%, and 91%, respectively, increased risk of BC-related death.¹⁰⁷ However, a large, longitudinal cohort study involving administrative claims data of 16,887 BC survivors found that concomitant administration of tamoxifen and antidepressants, including paroxetine, did not increase the risk of subsequently developing BC over the 14-year study period.¹⁰⁸ These findings were confirmed in a case-control study involving 18,432 BC patients with estrogen-positive disease without distant metastases (445 BC patients died due to BC) who were followed for about 10 years. Nonadherence, which was defined as <80% overlap between an SSRI and tamoxifen and was based on data from 9,104 women, was associated with worse BC survival (odds ratio [OR] 4.07, 95% CI 3.27-5.06).¹⁰⁹

Some have suggested that continuous SSRI use is associated with lower survival in cancer patients in general (i.e., breast, melanoma, prostate, lung, and colorectal cancers), especially during the first 2 years following a cancer diagnosis.¹¹⁰ Another study based on data from a cancer registry from 1990 to 2008 of 4,216 women with BC did not find that antidepressant use increased the risk of recurrence.¹¹¹

The FDA has evaluated the scientific evidence for genetic polymorphisms or genetic variant–inferred phenotypes that are likely to affect drug metabolism resulting in either altered efficacy or adverse event profile. For the tamoxifen-CYP2D6 drug-gene interaction pair, the FDA has determined that the pharmacogenetic association demonstrated by the available data results in only a potential impact on pharmacokinetic properties, although it cautions that CYP2D6 IMs or PMs have lower systemic active metabolite concentrations, but the effect on efficacy is not established. The agency has advised the use of caution when this drug-gene pair is present, but the FDA-approved drug label for tamoxifen does not discuss genetic testing for CYP2D6.^84,102 This is in contrast to a recommendation based on the scope and strength of evidence by the FDA Clinical Pharmacology Subcommittee in 2006 that supported the inclusion of pharmacogenetic information on CYP2D6 in tamoxifen’s labeling to help improve the benefit/risk ratio of the drug.^112,113

CYP2D6 PM status occurs in 3% to 10% of Caucasians, 4.3% to 5.4% of African Americans, 3.8% of South Asians, 0.84% of East Asians, 2.2% to 6.6% of Hispanics, 3.1% of Native Americans, and 2.3% of Middle Easterners.^114-116

Pharmacists can play a role by performing pharmacogenomic testing using this information to help guide antidepressant therapy. This is especially important given the potential drug-drug interaction between tamoxifen and SSRIs. Pharmacogenomic-guided antidepressant treatment has been found to result in greater improvement in depressive symptoms, generalized anxiety, and disability compared with standard antidepressant treatment.¹¹⁷ However, pharmacogenomicstudies are needed in patients with depression and BC.

To avoid or minimize CYP2D6 inhibition, safe antidepressants include venlafaxine, desvenlafaxine, mirtazapine, escitalopram, and citalopram.^{93,105,106,118-120} For patients on tamoxifen and paroxetine or fluoxetine, switching to escitalopram was found to be safe and resulted in threefold higher endoxifen exposure.¹²⁰ Others have warned that the concomitant use of tamoxifen and SSRIs, in particular paroxetine, escitalopram, and citalopram, has been associated with a significant elevation in the mean QTc-interval, making these latter two drugs less ideal options.¹²¹ Any change in the drug regimen of a patient on tamoxifen and a known CYP2D6 inhibitor should be performed gradually to minimize the risk of SSRI withdrawal and idiosyncratic adverse effects.¹²²

Tamoxifen is also metabolized by CYP3A4, which can be induced by St. John’s wort (SJW), resulting in the possible reduction of the selective estrogen receptor modulator’s effectiveness.¹²³ Pharmacists should conduct thorough medication histories to determine whether depressed BC patients are self-medicating with SJW, and they should counsel them to avoid use until further information is available.

On the flip side, there is evidence, albeit it weak, that tamoxifen may be associated with drug-induced depression as tamoxifen crosses the BBB. However, this iatrogenic effect may be a result of confounding since patients with BC are at a higher risk for depression.^100,124

Breast Cancer and Suicide: 988 Crisis Hotline

BC survivors are at increased risk of suicidal ideations and completed suicides. Suicide risk appears to be 35% to 53% higher than in the general population.^125,126 Unfortunately, there has not been a decrease in the rates of suicide mortality among BC patients for at least 30 years.¹²⁵ These numbers may be underestimations and may go unrecognized because suicide may take the form of withdrawal of therapy, there may be reluctance to report death by suicide, and there are methodological issues related to the validity of suicide statistics.^13,127

Some have reported that the risk of suicide is greatest within the first 3 years following a BC diagnosis, yet others have reported an elevated risk decades later.^125,126 It is imperative to identify risk factors for suicide in this population so that prophylactic measures may be implemented.

A retrospective study was performed of data from the Surveillance Epidemiology and End Results (SEER) database of BC patients who committed suicide. Between 1973 and 2013, 474,128 patients with BC were identified as having died from any cause, of which 773 had committed suicide. Investigator found that age (highest risk was in the aged 30-49 years group with an OR 10.64, P <.001, followed by age <30 years, OR 6.34, P = .002, and 50-69 years, OR 4.7, P <.001), male sex (OR 4.34, P <.001), nonwhite, nonblack race (OR 1.39, P = .046), marital status (OR 1.35 for single persons, P = .024 vs. OR 1.25 for those who were separated/divorced/ widowed, P = .043), having undergone cancer-direct surgery (OR 2.13, P = .007), time since BC diagnosis (OR for first year since diagnosis 4.67, P <.001 and OR for second year since diagnosis 2.35, P <.001) and those with progesterone-receptor positive BC (OR 1.74, P = .004) were risk factors for completed suicide.¹²⁵

Another SEER-based study was published based on data from 2000 to 2014 that involved 4,671,989 patients, of which 1,585 had committed suicide within a year of any cancer diagnosis. When specifically analyzing data on BC, researchers did not observe an increase in suicide risk among those with either localized/regional disease or distant (metastatic) disease.¹²⁸

In the largest and longest international study to date on suicide among BC survivors, investigators gathered data on 723,810 women reported to 16 populationbased BC registries between January 1, 1953, and December 31, 2001. A total of 836 patients had committed suicide. Risk of suicide was found to remain elevated even 25 years or longer after the BC diagnosis. This risk was slightly but not significantly higher in the initial years following the BC diagnosis. Suicidal risk was highest among black women. Worsening disease (i.e., increasing stage of disease) was also associated with increased risk. The cumulative probabilities of committing suicide following 5, 10, 20, and 30 years since BC diagnosis were 0.05%, 0.10%, 0.16%, and 0.20%, respectively. The authors called for long-term psychosocial follow-up of BC survivors.¹²⁹

One study of 284 BC survivors found that the prevalence of suicidal ideations was 10.9% 1 week after breast surgery and increased to 11.4% 1 year post surgery. The authors postulated that the mechanisms for short-term and longer term suicide ideations differed. Depression and physical disability were associated early on with depression, but other factors such as living alone, having anxiety, having an advanced stage of disease, and having the brain-derived neurotropic factor (BDNF) promoter methylation allele had more longterm effects.¹³⁰ Preliminary evidence shows that BDNF gene methylation status may serve as a biomarker for suicidality in BC patients.¹³¹

A longitudinal study involving 431 women with stage I to III BC in which patients were surveyed prior to surgery and again at 1 year following surgery found that suicidal ideation had increased from 4.3% at baseline to 12.8% at the year follow-up, respectively. Risk factors for suicidal thoughts included living in the countryside (OR 2.24, P = .027); having a history of traumatic experiences (OR 7.72, P = .01); being employed (OR 2.55, P = .043); and having symptoms of post-traumatic stress disorder (OR 2.89, P = .05). Protective factors against suicidal ideation included patient age of >55 years (OR 0.32, P = .028); having a paid job in recent years (OR 0.34, P = .037); and being satisfied with the way the patient was informed about their disease (OR 0.18, P = .001).¹³² Chemotherapeutic regimens often include the use of corticosteroids to help manage antineoplastic-induced nausea and vomiting and immune-related adverse effects, for pain relief and appetite stimulation, and to promote a sense of well-being. However, these drugs are also associated with adverse psychological effects, including depression and suicide.¹³³ In addition to corticosteroids, the NCI PDQ identifies other medications associated with contributing to or inducing depression, including endogenous and exogenous cytokines (e.g., interferon-alfa and aldesleukin [IL-2], methyldopa, reserpine [which is no longer available in the U.S.], barbiturates, propranolol, certain antibiotics [e.g., amphotericin B], certain chemotherapeutic agents [e.g., procarbazine, asparaginase], and hormone therapy [e.g., androgen deprivation therapy]).¹³

Several studies have found that women undergoing reconstructive breast surgery following a mastectomy may be at a greater risk of suicide. The authors advise that psychological evaluation and counseling be performed prior to the procedure.^134,135

Upon further analysis of depression as a cause of suicide in BC survivors, it has been suggested that one of the most potent risk factors is hopelessness, which manifests as a negative view of the future, perceived helplessness towards affecting outcomes, and deficits in social problem-solving.^16,136 Preliminary evidence has indicated that behavioral activation treatment (BAT) and problem-solving therapy (PST) may reduce depression and suicidal ideation while decreasing hopelessness in BC survivors; these effects may last for at least a year. These forms of psychotherapy are time-limited and teach positive adaptive behaviors.¹⁶ BAT increases reinforcement for positive, healthy behaviors by decreasing negative reinforcement and extinguishing maladaptive behaviors.¹⁶ PST helps patients with problem identification, efficient problem-solving, and managing associated depressive symptoms.^16,137

A study in Denmark that involved 45,325 women diagnosed with primary early-stage BC between 1998 and 2011 found that women who had used antidepressants prior to their diagnosis were less likely to receive guideline-directed BC treatment and were more likely to only receive a biopsy, not surgery. Further, significantly fewer women who had been pharmacologically treated for depression received guideline systematic adjuvant BC therapy. This group had significantly higher cumulative BC-specific mortality compared with women who had not received the psychotropic (13% vs. 11% women had died of BC within 5 years of diagnosis, respectively). Overall survival (HR 1.21, 95% CI 1.14-1.28) was also reduced in the antidepressant-treated group. The risk of suicide was significantly increased for women who used antidepressants (HR 5.38, 95% CI 2.16-13.37) and those who had a previous hospital contact for depression (HR 19.81, 95% CI 5.32-73.86). Although factors for nonadherence to BC treatment guidelines were not discussed, it raises concern about systemic healthcare system bias against those with mental health issues and/or the ability of those suffering from depression to fully participate in their healthcare decisions.¹³⁸

In September 2020, Congress passed the National Suicide Hotline Designation Act, which required that the Federal Communications Commission (FCC) designate 988 as the universal telephone number for the country’s national suicide prevention and mental health crisis hotline. This legislation was signed into law on October 17, 2020, and went into effect on July 16, 2022.¹³⁹

The enactment of this law was in response to the grim statistic that in the U.S. there is one death by suicide about every 11 minutes and to the realization that mental health crises are often inappropriately managed through the judicial system instead of the healthcare system.^140,141 In addition to the deployment of 988 as the new national hotline number, the legislation also calls for strengthening and expanding the existing crisis network program and providing direct, life-saving services to those in need.¹⁴² There are over 200 crisis centers that are part of a national network available to immediately serve the needs of persons in crisis.¹⁴⁰

SIDEBAR 1 includes links to patient handouts that pharmacists can use to educate their patients about the availability of the new national 988 crisis hotline.

Role of the Pharmacist

Pharmacists can play a major role in screening for depression, in promoting medication adherence, and in suicide prevention for all patients, but especially for those with BC who are at increased risk.^143-157 They can help fill the gap in access to mental health services.^158,159

The American Pharmacists Association (APhA) Foundation issued a white paper advocating for expanding the role of the community pharmacist in managing depression.¹⁶⁰ The APhA Foundation Coordinating Council provided evidence of community pharmacists’ collaborative role in managing patients with depression, and it has advocated that by increasing involvement of community pharmacists in managing patients with depression, pharmacists can improve clinical outcomes and enhance quality of life. Pharmacists can meet the major needs of patients with depression by providing general information about the condition and its treatment; helping patients access appropriate, quality care; providing medication management and support; offering social support and resources; assisting with coordination of care; and increasing pharmacist involvement. The white paper stressed the importance of pharmacistconducted medication therapy management (MTM) reviews.¹⁶⁰

Among the screening tools for depression that the white paper recommended were the Patient Health Questionnaire (PHQ)-9 and the PHQ-2.¹⁶⁰ Pharmacists should take an active role in identifying patients at risk for depression; screening patients for comorbidities and other risk factors; performing MTM, medication counseling, and education; monitoring medication adherence; participating in collaborative practice agreements; providing information on how patients can access patient pharmaceutical assistance programs; serving as a referral and resource for information about depression and social support resources; and being involved in local/regional/national mental health organizations, advisory boards, and other supportive resources.¹⁶⁰

Strategies to enhance pharmacists’ role in managing patients with depression include increasing education about depression in pharmacy school curricula; collaborating with physicians to identify patients at risk; providing patient education; collaborating and communicating with providers; assessing quality of care and patient outcomes; and increasing awareness of the pharmacist’s role and involvement in public and private groups.

Among the actions identified by the Council for ways that community pharmacists can enhance their role in the management of depression are creating and implementing a national stigma-reduction program (e.g., Depression Is Real campaign), creating and implementing interdisciplinary depression-care education and certificate programs for pharmacists and other providers; encouraging screening for depression and incorporating it into MTM: increasing awareness of the pharmacist’s role; developing an organizational value-based design that includes best practices for depression; encouraging pharmacists’ involvement in the implementation and screening of quality measures for depression; and collaborating with other professional and community stakeholder organizations to improve the care of patients with depression.¹⁶⁰

The American Society of Health-System Pharmacists (ASHP) issued a policy position statement in 2019 pertaining to the pharmacist’s role in suicide awareness and prevention. It states that pharmacists should be recognized as key providers on the patient care team and that they are integral to suicide awareness and prevention efforts. Potential activities that pharmacists may engage in include ensuring the appropriate use of medications for mental health disorders; identifying and evaluating suicide risk; and making and following up on referrals pertaining to mental health issues. ASHP advocates for mandatory suicide awareness and prevention training for pharmacists and for adequate funding for suicide awareness and prevention efforts.¹⁶¹

The NCI’s PDQ on depression provides screening questions that pharmacists can utilize to assess depressive and suicidal symptoms in patients with cancer.¹³

Health plans are struggling to collect and use patientreported clinical data for quality measurement. One area that poses a challenge in data collection is the lack of routine depression screening and ongoing assessment.¹⁶² The 2023 Centers for Medicare and Medicaid Quality Rating System (QRS) measures address the management of depression. Requirements in 2023 for Antidepressant Medication Management include the percentage of members aged 18 years and older who were treated with antidepressant medication, had a diagnosis of major depression, and remained on an antidepressant medication treatment. Two rates are reported, as follows¹⁶³:

Effective Acute Phase Treatment: The percentage of members who remained on an antidepressant medication for at least 84 days (12 weeks).

Effective Continuation Phase Treatment: The percentage of members who remained on an antidepressant medication for at least 180 days (6 months).

Pharmacists can assist with these data-collection efforts. One strategy to improve pharmacists’ mental health skills is for them to become Mental Health First Aid (MHFA)–certified. MHFA is a national program to teach the skills to respond to the signs of mental illness (including depression and suicidal ideations) and substance use. MHFA uses the acronym ALGEE, which stands for: Assess risk; Listen nonjudgmentally; Give reassurance and information; Encourage appropriate professional help; and Encourage self-help and other support strategies.¹⁶⁴ When pharmacy students underwent MHFA training, it helped to reduce mental health stigma, improve the identification of mental disorders, and improve pharmacists’ confidence in assisting patients with mental health issues.¹⁶⁵ Patients have stated that they are more comfortable discussing their mental health issues with a community pharmacist if the pharmacist is MHFA-certified.¹⁶⁶

Pursuing board certification in psychiatric pharmacy (BCPP) is another path to increasing knowledge regarding the pharmaceutical care of patients with psychiatric-related illnesses and disorders. Currently, there are more than 1,470 BPS board-certified psychiatric pharmacists.¹⁶⁷

While there is a paucity of information on the pharmacist’s role in screening for and managing depression in patients with BC, the literature is replete with evidence of the beneficial effects of screening and referral by pharmacists, including in specific patient populations such as those with cancer (11.7%-15.8% had BC), perinatal women, and patients with diabetes.^{86,143-150,152-154} Further, pharmacists’ involvement in the collaborative care treatment for depression has resulted in improvement of depression symptoms, adherence, reductions in total healthcare costs, and increased antidepressant prescribing.^156,168-171

An important caveat that pharmacists should be aware of is that common assessment tools to screen for depression (i.e., Geriatric Depression Scale–Short Form, the Hospital Anxiety and Depression Scale, and the Center for Epidemiological Studies Depression [CESD] Scale-Revised) may unreliably identify depression in geriatric cancer patients as the established cutoff scores for a positive depression screen may miss 33% to 83% of depressed older patients.^172-174 Among these tests, the CESD shows the most utility. Pharmacists should collaborate with their mental health colleagues if questions arise.¹⁷⁵

More work and support are needed for the benefit of pharmacists’ involvement in depression screening and referral to be fully realized, as many studies have been small and/or pilot studies. A recent systematic review of depression screening by pharmacists in the community found that while pharmacists are successfully able to screen patients, there is little evidence on the clinical and economic impact of these screenings. The authors called for more well-designed studies.¹⁷⁶ These studies should include patients with BC and concomitant depression.

Conclusion

Depression is common in women with BC. Young women with BC are especially at risk for the mood disorder. The use of tamoxifen with strong CYP2D6 inhibitors such as paroxetine and fluoxetine should be avoided. Pharmacists can play a major role in screening BC patients for depression, identifying those at risk for suicide, and making appropriate referrals for follow-up care.

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