Fremonta Meyer, MD

Globally, breast cancer is the most frequently diagnosed cancer; the lifetime incidence among women is 12%. It represents the leading cause of cancer death among women worldwide.

 To support patients with breast cancer, it is important to understand the trajectory and practical logistics of breast cancer treatment. Psychiatrists should also be aware of possible medication interactions, psychiatric or neurologic adverse effects of treatment, and signs of disease progression-issues that are the focus of this article.

The vast majority of patients (95%) with newly diagnosed breast cancer have no evidence of metastatic disease. For these patients, the treatment approach depends on the stage at presentation. In general, patients with early-stage breast cancer undergo primary surgery (lumpectomy or mastectomy) to the breast and regional nodes with or without radiation therapy (RT). Following definitive local treatment, adjuvant chemotherapy may be offered based on primary tumor characteristics, such as tumor size, grade, number of involved lymph nodes, the status of estrogen and progesterone receptors, and expression of human epidermal growth factor receptor 2. Chemotherapy may last up to 3 months, and radiation therapy generally occurs 5 days a week for 3 to 6 weeks. There are sometimes variations on these treatment schedules (such as several months of neoadjuvant chemotherapy), particularly in the context of clinical trials.

Patients with estrogen-positive breast cancer will subsequently receive endocrine therapy-tamoxifen, ovarian suppression, and/or aromatase inhibitors, depending on menopausal status-to reduce the risk of breast cancer recurrence and mortality. The recommended duration of adjuvant endocrine therapy was recently extended from 5 to 10 years, and the role of ovarian suppression has also expanded in high-risk premenopausal women. Both changes have resulted in a higher proportion of women with secondary infertility and ongoing exposure to hormonal treatments, all of which may erode quality of life and increase the risk of anxiety and mood disturbance.

Pretreatment consultation regarding fertility preservation options reduces long-term regret and dissatisfaction concerning fertility, independent of age or previous parity.

 The American Society of Clinical Oncology recommends routinely offering such consultations to all premenopausal women with breast cancer, particularly those who undergo chemotherapy, given its adverse impact on ovarian reserve.

Adverse prognostic factors in breast cancer are shown in 

. Patients with hormone-receptor–negative cancers tend to experience the majority of recurrences within the first 3 to 5 years after completing treatment, while those with estrogen/progesterone positivity remain at a low risk of recurrence (2% per year) indefinitely. In addition, human epidermal growth factor receptor 2–positive tumors are relatively more trophic to the brain than other types of breast cancer. Among patients with stage IV (metastatic) breast cancer, those with bone-only disease may experience prolonged survival, sometimes on the order of many years.

Psychiatric syndromes in breast cancer patients

Adjustment, depressive, and anxiety disorders are the most common forms of neuropsychiatric illness in patients with breast cancer (

). Risk factors include younger age, receipt of chemotherapy, hormonal disruption (amenorrhea/hot flashes), and marital discord. Symptoms appear to be most prominent at specific points in the course of the illness:

• At completion of active treatment, when patients are confronted with existential angst and fears of recurrence in the setting of less active follow-up with medical providers

• At diagnosis of recurrence or metastasis

6 Psychotherapy Questions for Medically Ill Patients

In patients with breast cancer, there is a nonlinear decline in the point prevalence of depression and anxiety in the years following diagnosis (50% in the first year; 25% in years 2 to 4; 15% in year 5), with an increase to 45% within 3 months of diagnosis of a recurrence.

 Thus, it is appropriate to reassure patients that their symptoms are likely to improve as they progress through survivorship. Although up to 80% of patients experience some PTSD symptoms related to breast cancer in the year after diagnosis, rates of acute stress disorder and PTSD after breast cancer are similar to those of the general population (2% to 4%).

Delirium, brain metastases, and leptomeningeal disease with neuropsychiatric symptoms can also occur in this population. These conditions are more often seen in patients with stage IV breast cancer, although patients with aggressive triple-negative or human epidermal growth factor receptor 2–positive tumors are also at elevated risk. Psychiatrists who are caring for a patient with high-risk breast cancer should watch for potential symptoms of CNS disease, such as headaches, vision changes/diplopia, cognitive or personality changes, and gait dysfunction.

Many women are offered the choice of either a mastectomy (with or without reconstruction) or a lumpectomy for management of early-stage breast cancer. Difficulty in navigating these and other treatment choices may be a distinct aspect of breast cancer treatment that leads to high rates of anxiety.

A major incentive for the development of breast-conserving surgery was to reduce the presumed emotional impact of radical mastectomy. However, studies have not found lumpectomy to be a psychosocial panacea-women demonstrate similar levels of depression and sexual dysfunction in the months after surgery, regardless of the specific procedure. Women who undergo lumpectomy do tend to have less body image disturbance.

 For those who undergo mastectomy, psychological distress (including depression and anxiety) is apparent immediately and 1 year after surgery, regardless of reconstruction or timing of reconstruction (immediate vs delayed).

Lymphedema-to which patients are mainly predisposed by prior axillary lymph node dissection rather than by type of breast surgery-represents an additional risk factor for depression and anxiety.

Insomnia is extremely common during breast cancer chemotherapy, particularly because of circadian rhythm disruptions, daytime inactivity, and corticosteroid tapers for nausea related to chemotherapy. It may be managed with trazodone, zolpidem, or lorazepam as needed. Note that oncology providers often prescribe lorazepam on an as-needed basis for nausea and insomnia; duplicate prescribing should be avoided.

Gabapentin may help hot flashes associated with insomnia. Melatonin may also be used for initial insomnia, particularly given some evidence that it may inhibit tumor growth.

 Although mirtazapine is an appealing option, many breast cancer patients gain considerable weight over the course of chemotherapy and adjuvant endocrine therapy, which limits the role of this medication.

For patients who present with functionally impairing depressive or anxious symptoms during chemotherapy, concurrent initiation of an antidepressant is reasonable. In addition to improving depression and anxiety, SSRIs and SNRIs (but not bupropion or mirtazapine) reduce hot flashes by approximately 50% in breast cancer survivors.

 For patients who take tamoxifen as part of their adjuvant therapy, psychiatrists must be aware of possible drug interactions in choosing an antidepressant. The research in this area is continuously evolving, and collaboration with the treating oncologist is beneficial in providing the best possible care for your patient.

Potent inhibitors of CYP P450 isoenzyme 2D6, such as paroxetine or fluoxetine, may hinder metabolism of tamoxifen into one of its most active metabolites, endoxifen (4-hydoxy-

-desmethyl-tamoxifen). Research suggests that breast cancer patients who take paroxetine have a greater risk of recurrence than those who receive no antidepressants or who take other antidepressants.

 This potential association with recurrence is not observed with other antidepressants that also inhibit isoenzyme 2D6, such as fluoxetine and bupropion.

A recent, larger study did not find an association between paroxetine use and increased risk of recurrence/mortality in patients who receive tamoxifen.

 Moreover, the discovery of new tamoxifen metabolites and the finding that other CYP isoenzymes, such as 3A4 and 2C9, are also involved in tamoxifen metabolism calls into question the relative importance of endoxifen and CYP 2D6 status in mediating the clinical effects of tamoxifen on target tissues.

Given the evolving recommendations, the best decisions regarding antidepressant therapy and tamoxifen often involve collaboration with the oncologist to allow for full consideration of breast cancer recurrence risk, severity of depressive symptoms, and effect of depressive recurrence on overall health and quality of life. 

 lists common antidepressants and their relative levels of CYP 2D6 inhibition.

Patients often attribute worsening mood symptoms to tamoxifen; however, there is limited support for this in the literature. Placebo-controlled trials of tamoxifen reveal that it does not increase rates of MDD.

 Case reports of tamoxifen-induced major depression may be confounded by chemotherapy-induced amenorrhea. Some data suggest that the same patient factors that prompt a recommendation for tamoxifen-chemotherapy and estrogen receptor positivity-are independent risk factors for depression after a diagnosis of breast cancer.

Despite the lack of group data, tamoxifen may contribute to depressive symptoms in a subgroup of patients who are sensitive to hormonal fluctuations, including those with histories of premenstrual dysphoric disorder and/or postpartum depression. Interestingly, tamoxifen is a protein kinase C inhibitor, similar to lithium and valproate, and has antimanic effects.

Psychiatrists play a critical role in devising treatment regimens that will increase the likelihood of tolerating adjuvant endocrine therapy. If depressive symptoms are temporally correlated with tamoxifen use and resolve after discontinuation-and in addition do not respond to concomitant antidepressant therapy-coordination with the oncologist can help determine whether it might be appropriate to consider a switch to aromatase inhibitors in postmenopausal women, or to an ovarian suppression agent plus an aromatase inhibitor in premenopausal women. There are no relevant drug/drug interactions between antidepressants and aromatase inhibitors/ovarian suppression agents. However, some patients may continue to experience mood lability while they take ovarian suppression agents and/or aromatase inhibitors.

Psychotherapy is a crucial component of psychiatric care for patients with breast cancer. Cancer is a life-transforming diagnosis and a traumatic stressor that presents numerous immediate threats, including:

• Treatments that often seem worse than the disease itself

Whenever possible, supportive therapy should be incorporated into medication management visits for breast cancer patients. Unfortunately, early hopes that group therapy might prolong survival in patients with metastatic breast cancer have not been conclusively borne out.

 Still, a recent randomized clinical trial that tested a group-based psychological intervention in patients with regional breast cancer found that patients in the intervention group had significantly reduced risks of breast cancer recurrence and death.

Overall, 5% to 10% of women with breast cancer have genetic mutations, primarily BRCA1 and BRCA2, which are inherited in an autosomally dominant fashion; the rate approaches 20% in women with a family history of breast cancer. BRCA positivity may lead to emotional turmoil, given the need to consider more extensive surgery (bilateral mastectomy and prophylactic oophorectomy) and guilt over potential transmission to children. However, BRCA mutations do not appear to increase the overall risk of psychiatric disorders in patients with breast cancer.

Male breast cancer represents 0.5% to 1% of all breast cancer diagnoses; up to 15% of men with breast cancer harbor a BRCA mutation. Men may experience increased psychological distress because of the strong association between breast cancer and female gender. Furthermore, aspects of their medical care-such as questionnaires asking about menstrual functioning and clinical trials that exclude males-may heighten these feelings. Telephone or on-line support groups offer promise in combating isolation among male breast cancer patients.

Because of the high prevalence of breast cancer in the general population-with potentially further increases in the risk of worse outcomes as a result of mental illness-virtually every practicing psychiatrist will at some point treat a patient with a breast cancer diagnosis or recurrence. Adjustment, anxiety, and depressive disorders are the most common neuropsychiatric illnesses across the stages of the disease. Cognitive disorders due to brain metastases, leptomeningeal disease, and delirium warrant consideration in the setting of advanced cancer. A working knowledge of the practical logistics of breast cancer treatment, communication with the patient’s oncology treatment team when feasible, and encouragement of adjunctive therapy (including group therapy) are critical strategies to facilitate patients’ adjustment to this life-altering diagnosis.

The authors acknowledge the Academy of Psychosomatic Medicine (APM) for helping to bring this article to fruition. The APM is the professional home for psychiatrists providing collaborative care bridging physical and mental health. Over 1200 members offer psychiatric treatment in general medical hospitals, primary care, and outpatient medical settings for patients with comorbid medical conditions. More information on the APM can be found at 

Dr. Meyer is Staff Psychiatrist at the Dana-Farber Cancer Institute and Brigham and Women’s Hospital and is Assistant Professor of Psychiatry, Harvard Medical School, Boston, MA. Dr. Lynn is Staff Psychiatrist and Assistant Professor in the department of psychiatry at the University of Texas (UT) MD Anderson Cancer Center and Adjunct Assistant Professor at Baylor College of Medicine and McGovern Medical School at UT Health Science Center of Houston. The authors report no conflicts of interest concerning the subject matter of this article.

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Articles

To support patients with breast cancer, psychiatrists should be aware of possible medication interactions, psychiatric or neurologic adverse effects of treatment, and signs of disease progression--issues that are the focus here. 

Breast Cancer: What Psychiatrists Need to Know

[[{"type":"media","view_mode":"media_crop","fid":"29494","attributes":{"alt":"psycho-oncology","class":"media-image media-image-right","id":"media_crop_8701231950864","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"3053","media_crop_rotate":"0","media_crop_scale_h":"151","media_crop_scale_w":"150","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"float: right;","title":" ","typeof":"foaf:Image"}}]]Strictly speaking, psycho-oncology is a “sub-sub-specialty.” That is, psycho-oncology is a specialized niche of psychosomatic medicine, or medical psychiatry. Psycho-oncologists include psychiatrists, psychologists, social workers, and other mental health practitioners who possess cancerrelated expertise in a variety of areas, including differential diagnosis, psychotherapy, psychopharmacology, and palliative/supportive care.

The field was developed under the leadership of pioneers such as Avery Weisman, Jimmie Holland, and William Breitbart. These individuals advanced the discipline through clinical work, teaching, research, activism, and creation of professional networks. A clinical psychiatrist and psychoanalyst at Massachusetts General Hospital in the mid-1950s, Dr Weisman oversaw a research initiative, Project Omega. He authored various books, including 

, which continue to serve as foundational learning for trainees in psycho-oncology.

 The Department of Psychiatry and Behavioral Sciences at Memorial Sloan-Kettering Cancer Center (MSKCC) in New York, founded in the late 1970s under the leadership of Dr Jimmie Holland, has contributed a plethora of clinical research to the field, much of which has involved veteran clinician and renowned researcher, Dr William Breitbart.

MSKCC, Dana-Farber Cancer Institute/Brigham and Women’s Hospital in Boston, and Princess Margaret Hospital in Toronto offer accredited PGY-5 fellowship programs in psychosomatic medicine with emphasis on psycho-oncology. Active professional networks include the American Psychosocial Oncology Society, International Psycho-oncology Society, and the psycho-oncology and palliative care special interest group of the Academy of Psychosomatic Medicine.

In 2007, the Institute of Medicine published

 Cancer Care for the Whole Patient: Meeting Psychosocial Health Needs

 This seminal report galvanized the oncology community to address quality of life (including psychological distress) alongside duration of life.

 Even as the breadth of the field expands, the limited supply of psycho-oncology clinicians, particularly in non-urban settings, dictates that many cancer patients in need of mental health services receive care from general mental health providers.

In this article, we introduce select topics in clinical psycho-oncology, including assessment and management of delirium and brain lesions, mood and anxiety disorders, medication adverse effects, and existential death anxiety.

The majority of advanced cancer patients experience delirium in the last 6 months of life. Somewhat unique to oncology, the syndrome often presents in the ambulatory setting. While some cancer or cancer treatment–specific causes of delirium require specialized consideration, remember that “common things occur commonly.” That is, regardless of cancer stage or treatment details, common causes of delirium must be assessed and treated. This includes medical assessment (eg, laboratory tests, urinalysis, chest radiography, blood and urine cultures, brain imaging) and medication review, with special attention paid to opioids and benzodiazepines (both used commonly in cancer patients) and to anticholinergics. These assessments should be followed by serial mental status examinations, preferably using objective measures such as the Montreal Cognitive Assessment.

Cancer patients at particularly high risk for delirium include those undergoing stem cell transplant; immunosuppression increases the risk of infection, including potential reactivation of dormant viruses such as BK, varicella-zoster, and herpes simplex. Patients with primary brain tumors, brain metastases, or leptomeningeal carcinomatosis; those receiving high doses of opioids or benzodiazepines; and those with endorgan failure are also at increased risk.

A common challenging clinical neuropsychiatric scenario is that of a patient with a newly discovered brain lesion. Some lesions may be psychiatrically “silent” and have little effect on mood or behavior, although the risk of mental status changes is high in the setting of larger space-occupying lesions with frontal or temporal localization. Other risk factors include hemorrhage, increased intracranial pressure/obstruction of cerebral spinal fluid flow, seizures, and leptomeningeal invasion. Premorbid psychiatric and cognitive disorders may complicate the interpretation of mental status changes in the setting of brain tumors; in these situations, neuropsychological testing (where available) may be particularly useful diagnostically and therapeutically.

Alice presents with confusion and bizarre behavior. She is 60 years old and has a history of stage III lung cancer. She has no history of psychiatric problems and is not taking medications known to alter mental status. A toxic/metabolic workup is unrevealing. However, a brain MRI scan reveals a large right frontal metastatic lesion with areas of hemorrhage. Resection of the lesion returns the patient’s cognition to baseline, and dexamethasone taper (targeting brain edema) is started immediately following surgery. Three days later, Alice again presents with altered mental status, raising concern for nonadherence with the corticosteroid taper. On evaluation, she reports visual hallucinations and evidences episodic severe distractibility, with poor concentration and memory difficulties on formal testing.

Several clinical pearls are worth discussing. A clinician confronted with such a patient must consider the neuropsychiatric adverse effects of corticosteroids-including insomnia, irritability, anxiety, depression, hypomania or mania, psychosis, and cognitive impairment.

 In patients with a newly diagnosed and resected brain lesion, neuropsychiatric aberrations may be caused by a combination of clinical factors, including corticosteroids, the possible presence of undiagnosed seizures, and the direct deliriogenic impact of the lesion and its resection. If neuropsychiatric symptoms worsen with corticosteroid taper, consider unchecked inflammation as a possible cause.

In Alice’s case, the clinical examination (most notably, intermittent grossly impaired attention, with pauses in speech production) suggests the possibility of complex partial seizures. Indeed, an electroencephalogram reveals partial status epilepticus, a significant finding because neither adjustment of the corticosteroid dose nor addition of an antipsychotic would have led to symptom resolution. Ultimately, Alice receives 3 antiepileptic medications to control seizures and normalize mental status.

The available evidence for the prevalence of clinical depressive disorders in the cancer population is variable and influenced by study design and method of assessment. A recent systematic review noted the prevalence of depression as 5% to 16% in outpatients, 4% to 14% in inpatients, 4% to 11% in mixed populations, and 7% to 49% in palliative care. Notably, it was found that when studies used expert interviewers (such as psychiatrists and clinical psychologists), prevalence estimates were lower.

 In practice, the most common diagnosis made in the outpatient cancer setting is that of adjustment disorder. The suicide rate is 2 to 3 times that of the general population and is particularly high immediately following a cancer diagnosis.

We recommend using validated tools (eg, Generalized Anxiety Disorder 7-item [GAD-7], Patient Health Questionnaire [PHQ-9]) to screen for major depression and anxiety disorders; however, even results of these screenings can sometimes be misleading. The presence of fatigue, poor appetite, poor concentration, and sleep disturbance that results in high PHQ-9 scores can often be explained by the effects of cancer or its treatment, as opposed to clinical depression. It is therefore also crucial to evaluate psychological constructs such as anhedonia, demoralization, self-esteem, attitude toward the future, hopelessness, helplessness, and meaning. Similarly, a patient can appear to have anxiety disorder as measured by the GAD-7, while the true pathology is akathisia (a movement disorder) as a result of prochlorperazine or metoclopramide, both commonly prescribed for nausea in cancer patients.

The treatment of adjustment, mood, and anxiety disorders in cancer patients is rooted in general psychiatry principles and includes psychotherapy and/or psychopharmacotherapy with antidepressants and, on occasion, stimulants and benzodiazepines. Medications such as venlafaxine XR, sertraline, citalopram, and escitalopram are preferred for the treatment of depression and anxiety because of their limited drug-drug interactions.

Mirtazapine is frequently used for its appetite-stimulating and soporific properties (particularly beneficial in cachectic patients and those with poor sleep) as well as for its very low likelihood of causing or exacerbating nausea (because of its serotonin type 3 antagonist properties). Bupropion also has utility in patients with depression and without prominent anxiety. Historically, there has been concern about prescribing medications with marked cytochrome P-450 (CYP) 2D6 inhibition (eg, paroxetine and fluoxetine) for patients receiving tamoxifen for adjuvant treatment of breast cancer; however, more recent data are mixed regarding a relationship between CYP2D6 activity and cancer recurrence. In patients with carcinoid tumor or syndrome, in whom endogenous serotonin production is elevated, atypical antidepressants such as mirtazapine and bupropion may be theoretically preferred because of their nonserotonergic mechanisms of action. However, in practice, most patients with such tumors tolerate conventional SSRI treatment.

Finally, benzodiazepines are frequently used for anxiety and nausea in cancer patients, but they should be deployed cautiously and usually in short-acting formulations, given their deliriogenic liability (particularly when coadministered with opioids). Haloperidol and atypical antipsychotics, such as quetiapine and olanzapine, given in low doses, are good alternatives for managing anxiety and insomnia, and off-label use may be less problematic in individuals with a limited life expectancy. For individuals with the common symptom cluster of nausea, anxiety, and insomnia, olanzapine may be especially helpful because of its potent antiemetic, anxiolytic, and potentially soporific properties.

While certainly not a psychiatric issue, the management of cancerrelated fatigue is well within the purview of the psycho-oncologist. Individual studies vary; however, the prevalence of fatigue in patients being treated for cancer approaches 100%.

 Validated measures such as the Brief Fatigue Inventory may be used to track a patient’s level of fatigue, although in practice we often use a Likert scale (range, 0-10), in which the patient rates his or her current, average, and most severe levels of fatigue.

While medications may be helpful, a program of exercise has the strongest evidence base supporting its efficacy. Medically ill patients may wake for various physical reasons during the night (cough, pain, dyspnea, sleep apnea, frequent urination, management of tubes/lines, etc). Maintenance of good sleep hygiene is crucial and can help minimize the impact of sleep disruption on the patient’s overall functioning. Blood transfusions often have a robust effect on fatigue, but this benefit may be short-lived in the setting of ongoing cancer treatment.

Erythropoietin-stimulating factors are avoided by many oncologists because of the increased risk of deep venous thrombosis and possible cancer progression. Pharmacological options for cancer-related fatigue (all off-label, non–FDAapproved) include stimulants (such as methylphenidate), modafinil, and armodafinil.

Premorbid psychiatric or substance use disorders

Cancer patients with serious mental illness and/or substance use disorders are monitored closely by the psycho-oncologist, often in collaboration with the individual’s preexisting mental health providers. While case reports document the safe use of clozapine in patients receiving cytotoxic chemotherapy, such patients must be observed carefully in collaboration with the laboratory and dispensing pharmacy. Similarly, patients receiving lithium may require closer monitoring in the setting of chemotherapy fluid shifts. Atypical antipsychotics and valproate are preferred options for de novo management of hypomania/mania in cancer patients. Ensuring adequate treatment of pain and other symptoms in these patients can be challenging. For those with substance use disorders, behavioral contracts, random urine drug screening, and prescription monitoring programs are essential, along with limiting the quantity of opioids and benzodiazepines prescribed at any given time.

Perhaps the greatest challenge facing psycho-oncology practitioners is the management of existential death anxiety, which can occur regardless of the type or stage of cancer and is not infrequently outside a patient’s conscious awareness. Obtaining a detailed narrative regarding the events leading up to cancer diagnosis is critical in understanding coping style and particular triggers for death anxiety. Perhaps the most important service provided by psycho-oncologists is the ability to recognize and address the patient’s defense mechanisms and coping styles, which will ultimately help the patient face mortality.

Despite the many advances in clinical oncology, there unfortunately still exists a cohort of individuals, including children, who will rapidly succumb to their disease. At times, psycho-oncologists bear witness to severe emotional and physical suffering. The field of psycho-oncology offers extensive opportunities for personal/existential growth through meaningful relationships with patients and their families; deep satisfaction in relieving anguish and improving quality of life through psychotherapy and psychopharmacological treatments; and rich collaborations with multidisciplinary oncology teams.

Dr Yuppa is a staff psychiatrist at Dana-Farber Cancer Institute and Instructor in Psychiatry at Harvard Medical School, Boston. Dr Braun is a staff psychiatrist and Chief, Division of Adult Psychosocial Oncology at Dana-Farber Cancer Institute, and Assistant Professor of Psychiatry at Harvard Medical School. Dr Meyer is a staff psychiatrist at Dana-Farber Cancer Institute; Director, Medical Student Education in Psychiatry at Brigham and Women’s Hospital; and Assistant Professor of Psychiatry at Harvard Medical School.

Cancer Care for the Whole Patient: Meeting Psychosocial Health Needs

. Octo-ber 15, 2007. http://www.iom.edu/Reports/2007/Cancer-Care-for-the-Whole-Patient-MeetingPsychosocial-Health-Needs.aspx. Accessed October 7, 2014.

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 Weis J. Cancer-related fatigue: prevalence, assessment and treatment strategies. 

An overview of select topics in clinical psycho-oncology, including assessment and management of delirium and brain lesions, mood and anxiety disorders, medication adverse effects, and existential death anxiety.

Fremonta Meyer, MD

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Breast Cancer: What Psychiatrists Need to Know

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