Depression and Cancer

Preface

Cancer affects close to one in two men and women across their lifetime, with this risk increasing steadily with age. In many countries, cancer competes with heart disease to become the leading cause of death, while being arguably the major cause of health morbidity, given the many losses, including disfigurement, disability and impairment, associated with the disease and its treatment. Psychological reactions to these losses are many, ranging from demoralization and passivity to anger and memory problems. In addition, depressive disorders are often comorbid with cancer. The likelihood of general practitioners and oncologists seeing patients with depression in the context of their care for people with cancer is extremely high.

The diagnosis of cancer is perceived by many to be their death sentence. The related existential threat initiates substantial suffering, all the moreso if pain is persistent, hopes are dashed, fears fueled, grief intensified and the person feels alone. Such suffering results in much dismay and despair. Whatever the therapy – surgery, radiation, chemotherapy, hormones, vaccines or targeted molecular treatments – the burden of the immediate, long-term and late effects of these regimens adds to the inherent distress. Metaphors of waging war and battlefields fortify against the images of an insidious and uncontrollable spread of disease. In some societies, the word ‘cancer’ remains unspeakable; for others, its prognosis is never acknowledged. The psychological hurdles to adaptation are formidable.

While its diagnosis readily precipitates a mid-life crisis, cancer recurrence induces deep angst as the prospect of cure fades. The very meaning of existence may be called into question. Worldwide, cancer accounts for nearly 14per cent of all deaths, but this rises to 25 per cent in Western societies. No family escapes its experience. The treatment of metastatic cancer models the journey of a chronic medical illness for diseases like breast cancer, whereas for others, like pancreatic malignancy, the focus is essentially palliative and on quality of life. The challenge of holistic care has spawned the birth of a new discipline, named psycho-oncology, drawing its practitioners from psychiatry, psychology, social work and a range of related mental healthcare providers to deliver psychosocial care to cancer patients and their families. In many countries, they work alongside hospice and palliative care practitioners in providing care during the end-of-life; in others, they reach into genetic counseling services, transplant programs, smoking cessation clinics, cancer prevention and screening units, and, of course, cancer survivorship programs. Consultation-liaison psychiatry services almost always have key involvement with oncology and palliative care programs. For all of these psycho-oncology services, the treatment of cancer patients who develop depressive disorders becomes the bedrock of care.

Currently, the USA estimates that over 12 million cancer survivors exist in its society. New hurdles to adjustment are recognized as these patients transition into survivorship. For some, this is the first time that the busyness of a therapeutic schedule eases and the chance to accept their new reality emerges. For others, coping with the morbidity of their treatment challenges their body image, self-worth, sexuality, fertility, fitness or functionality. Whether living with an amputated limb, lymphedema necessitating daily arm compression, xerostomia only ameliorated by the constant sipping of water, or the need for multiple reconstructive surgeries to sustain cosmesis, the rehabilitative challenges after primary cancer treatment are substantial. As we reflect on the life-cycle of the cancer journey, its cumulative experience of grief, transition and loss, the many challenges to optimal adaptation and quality of life become apparent.

Against this background of the ubiquitous burden of a malignant diagnosis and its treatment, this book focuses upon the relationship between cancer and depression. Major human suffering results from this association, suffering that we can effectively assuage. We begin with an appraisal of its prevalence by Mary Jane Massie and colleagues to make explicit the size of this problem. With cancer’s additional dimension of existential threat, both major and sub threshold depressive states enlarge this burden of illness, bringing clinical challenges of definition and recognition to the fore.

The subjective experience of depression in oncology patients results from the interplay of complex gene-environment interactions, involving the biology of the brain with the biology of the cancer and the adaptation of the person. Not only does cancer and its treatment interact often with the hypothalamic-pituitary-adrenal system, but cancers also produce a variety of circulating proteins or cytokines that cross the blood-brain barrier and interact with the mood regulating circuits of the limbic system. Dominique Musselman and her research colleagues elucidate the contribution of these cytokine cas-cades. Adetailed chapteron the pharmacologic treatment of depression by Luigi Grassi and colleagues pays careful attention to the potential for drug-drug interactions, which arise frequently in cancer care.

The psychosocial challenges of cancer to each person’s coping necessitates adaptation through grief and mourning, coming to terms with loss and change, and then moving forward with life. Whenever depression interferes with these processes, its form can span sub-threshold to clinical presentations. Furthermore, the existential realm adds death anxiety, aloneness, loss of meaning and control to this equation, bringing states of demoralization into tension with depression. David Clarke focuses on this in a chapter on psychological adaptation to cancer, while later David Kissane, Gary Rodin and colleagues present the broad range of psychotherapeutic modalities that can be added to our pharmacologic armamentarium to improve outcomes.

Screening to increase recognition of depression has proven necessary in oncological care because of the unfortunate tendency for clinicians from every discipline to blur the sadness of the predicament with the prevailing mental health reality. Steven Passik covers the range of available measures to screen for depression and the service issues associated with their clinical application.

William Breitbart and colleagues describe the increased rate of suicide among cancer patients in their chapter on the desire for hastened death. Requests for physician-assisted suicide can be a cry for help and clinicians need considerable experience to tease out the many confounding influences that predispose to, precipitate and perpetuate affective disorders.

Depression is a recognised risk factor for shortened survival from cancer, this outcome being partly mediated through patients’ adherence to anti-cancer treatments. Unrecognized depression could bring increased morbidity to bear through this mechanism. Meta-analyses by Robin DiMatteo and Kelly Haskard-Zolnierek about the impact of depression on treatment compliance in medical illness make explicit the inherent issues here.

Finally, the social cost of depression is pronounced, and this burden is felt as muchin cancer care as with other medical illness. The roles of culture and socioeconomic status are pertinent. Noteworthy social disparities exist in cancer survival. The health beliefs occurring in African Americans, Asians, Hispanics or Europeans affect cancer outcomes, asdoes their socioeconomic status. Irrespective of access to cancer care, including in Scandinavian societies where health insurance is universal, those living in poor socioeconomic circumstances die earlier. Using Denmark’s national medical record system, Chris-toffer Johansen and colleagues conclude our book by providing methodologically sound evidence that stress, depression, personality and major life events do not cause the onset of cancer. However, untreated depression and social disparity impact cancer survival, making the treatment of affective disorders a paramount public health concern for every society.

This volume ondepression and cancer is partofa WPA series on the comorbidity of mood disorders with various medical illnesses, including heart disease and diabetes. We are grateful to our authors who have given generously of their time and scholarship, to our publishers at Wiley-Blackwell, and to the WPA, through which we hope that the care of depressed patients will steadily improve. Cancer brings a huge social burden; untreated depression adds enormously to any suffering; we have many tools to ameliorate this and improve patients’ wellbe-ing. Let us help those who become weary of life to renew its vigour and joy, with appreciation for life’s value, meaning and purpose, despite the diagnosis of cancer.

David W. Kissane

Mario Maj

Norman Sartorius

CHAPTER 1

The Prevalence of Depression in People with Cancer

Mary Jane Massie

Department of Psychiatry and Behavioral Sciences, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

Mari Lloyd-Williams and Greg Irving

Academic Palliative and Supportive Care Studies Group (APSCSG), School of opulation, Community and Behavioural Sciences, University of Liverpool, UK

Kimberley Miller

Princess Margaret Hospital, Toronto, ON, Canada

Depression is amongst the main causes of disability worldwide, leading to personal suffering and increased mortality. The US National Comorbidity Survey revealed a 12-month prevalence of major depressive disorder of 6%, with a lifetime prevalence of 16%, while high comorbidity exists with anxiety disorders, substance use disorders and impulse control disorders [1]. In any twelve-month period, more than half the patients with major depressive disorder are diagnosed with an additional anxiety disorder. Patients with comorbid depression and anxiety disorders experience more severe symptoms, have longer time to recovery, use more healthcare resources and have poorer outcome than do those with a single disorder [2]. Seed at et al. [3] found that, across cohorts from 15 countries, women developed depression almost twice as frequently as men.

When comorbid with medical illness, depression increases the symptom burden and functional impairment, and worsens medical outcomes [4]. Early studies of depression in the medically ill used patient self-report and varied measures, with a heterogeneous mix of hospitalized medical and surgical patients, and reported prevalence rates ranging from 20 to 30% [5]. In 1987, a retrospective review of 263 000 patients from 327 hospitals found that 24% of those receiving a psychiatric consultation were depressed [6]. However, Snyder et al. [7], using both clinical interview and DSM-III-R criteria reported less depression (6%), but more adjustment disorder with depressed mood (14%), in 944 medically ill patients referred for psychiatric consultation.

Wells et al. [8] examined Epidemiological Catchments Area Study data regarding mental disorders amongst persons with at least one of eight chronic medical conditions. Six-month and lifetime prevalence rates of mental disorders were increased in those with versus without medical illness (25 and 42% versus 17 and 33%). Thirteen per cent of the chronically medically ill had a lifetime diagnosis of affective disorder versus 8% of those free from medical illness.

Lifetime rates of depression in patients with neurological conditions range from 30 to 50% [9]. Prevalence rates of depression in patients with other medical or systemic illnesses show a variable picture, with the highest rates observed with endocrine disturbances such as Cushing’s disease and surprisingly low rates documented in end-stage renal disease.

PREVALENCE OF DEPRESSION IN CANCER PATIENTS

Using DSM-III criteria through a structured clinical interview, the Psychosocial Collaborative Oncology Group (PSYCOG) was one of the first groups to carefully determine the prevalence of mental disorders in 215 randomly selected hospitalized and ambulatory adult cancer patients in three cancer centers [10]. Forty-seven per cent of the patients evaluated had clinically apparently psychiatric disorders. Of these patients, over two-thirds (68%) had adjustment disorders with depressed oranxious mood, 13% had a major depression, 8%had an organic mental disorder, 7% had a personality disorder, and 4% had a preexisting anxiety disorder. The authors concluded that nearly 90% of the mental disorders observed were reactions too manifestations of disease or treatment. Personality and anxiety disorders can complicate cancer treatment, and were described as antecedent to the cancer diagnosis. This epidemiologically sound study has remained the gold standard for many years.

Many research groups have assessed depression in cancer patients along the years [10–69], and the reported prevalence varies quite widely (major depression 3 to 38%; depression spectrum syndromes 1.5 to 52%). The following databases were searched to retrieve references published between 1965 and 2009: PubMed, Embase, CINAHL (nursing), PsycINFO, Scopus, Science Citation Index/Social Sciences Citation Index, Cochrane Evidence Based Medicine database. The searches were limited to English language references and to studies with more than 100 subjects, where this information was indicated. Table 1.1 shows the 60 studies with more than 100 patients that provided information about the number of patients interviewed and cancer type(s), evaluation methods, and per cent with depression or affective syndromes. Most authors reported patient gender and hospitalization status. The reported prevalence varies significantly because of varying conceptualizations of depression, different criteria used to define depression, differences in methodological approaches to the measurement of depression, and different populations studied.

In early, typically cross-sectional studies, the rate of depression was usually reported for adults with mixed types and stages of cancer. Depression was reported by severity (borderline, mild, moderate, severe, and extreme), or by a symptom such as depressed mood, or by some of these diagnostic categories: major depression, minor depression, depressive disorder, adjustment disorder with depressed mood, or dysthymia, limiting our ability to compare studies. Although many research groups reported the gender and age (usually older) of study subjects, findings usually were not reported by demographic variables, and racial minorities were always underrepresented.

Table 1.1 Representative studies of the prevalence of depression in cancer patients (adapted from Massie [5])TraitAnxietyInventory.

BDI, Beck Depression Inventory; BHS, Beck Hopelessness Scale; BSI, Brief Symptom Inventory; CES-D, Center for Epidemiology Self-report Depression Scale; DIS, Diagnostic Interview Schedule; EORTC-QLQ, European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire; FLIC, Functional Living Index of Cancer; GAIS, Global Adjustment to Illness Scale; GHQ, General Health Questionnaire; HRSD, Hamilton Rating Scale for Depression; HADS, Hospital Anxiety and Depression Scale; HIS-GWB, Rand Health Insurance Study-General Well-Being Schedule; IBQ, Illness Behavior Questionnaire; MADRS, Montgomery-Asberg Depression Rating Scale; MILP, Monash Interview for Liaison Psychiatry; MMPI, Minnesota Multiphasic Personality Inventory; MPAC, Memorial Pain Assessment Card; PHQ, Patient Health Questionnaire; POMS, Profile of Mood States; QOL, Quality of Life questionnaire; RDC, Research Diagnostic Criteria; RDS, Raskin Depression Screen; RSCL, Rotterdam Symptom Checklist; SCID, Structured Clinical Interview for DSM; SCL-25, SCL-90, SCL-90R, Hopkins Symptom Checklist 25, 90, and 90-Revised; SDS, Self-rated Depression Scale; SF-36, Medical Outcomes Study 36-Item Short Form Survey; STAI, State-

A limitation of many studies is that the effects of cancer treatments and non-cancer related variables that affect mood are not accounted for. For example, although drugs can cause depression in some people, research groups usually have not presented data about cytotoxic drug or hormone use when describing their findings.

Several papers from Nemeroff’s group [70–72] acknowledge the many reasons why it is difficult to compare studies (different definitions of depression, cancer type or stage, time since diagnosis, varying cancer treatments, personal history of depression and treatment for depression), but importantly, they underscore several general observations. The severity of medical illness, as manifested by significant pain, declining performance status, or the need for ongoing treatment, is associated with a high risk of comorbid depression. Whether high rates of depression associated with some cancers are due to the path physiologic effect of the tumor (i.e. cytokine or paraneoplastic syndromes associated with breast, pancreas, testis or lung cancers), treatment effects or other unidentified factors remain to be discerned. Nonetheless, we confidently conclude that cancer, exclusive of site, is associated with a rate of depression that is higher than in the general population.

Cancer types highly associated with depression include brain (41–93%) [57, 63], pancreas (up to 50%) [11], head and neck (up to 42%) [52], breast (4.5–37%) [45, 55], gynecological (23%) [74] and lung (11%) [40]. A large cross-sectional study of 8265 adult outpatients revealed higher levels of mixed anxiety/depression symptoms in patients with stomach (20%), pancreatic (17%), head and neck (15%) and lung (14%) cancers [73]. A lower prevalence of depression is reported in patients with other cancers, such as colon (13%) [11] and lymphoma (8%) [19].

De Florio and Massie reviewed 49 studies of the prevalence of depression in individuals with cancer with a particular emphasis on gender differences [75]. Twenty-three studies found no gender differences in the prevalence of depression at a significance level of p < 0.05. However, 10 research groups found either gender differences in subsets of patients, non-significant trends, or differences in other parameters such as psychiatric morbidity, anxiety and denial.

In their study of 808 cancer patients, Kathol etal. [26] Found women were more depressed than men using Research Diagnostic Criteria;however, this finding did not persist when DSM-III criteria were applied. Sneed et al. [31] found no gender differences in depression, anxiety, hostility, somatization, general psychological distress, or psychological well-being. Fife et al. [76] also found no significant differences in depression in male and female cancer patients; however, they found that women made a more positive adjustment to cancer.

DEPRESSION BY CANCER TYPE

Depression in Women with Breast Cancer

Breast cancer is the cancer most studied in terms of psychosocial effects. The reported prevalence of depression ranges from 4.5% to 37%. One of the larger studies [68], examining 3321 early stage Danish breast cancer patients, recently found a 13.7% prevalence of major depression 12–16 weeks after surgery (17.9% in 18–35 year olds and 11.2% in 60–69 year olds). Independent risk factors for the development of depression included younger age, social status, ethnicity, comorbidity, psychiatric history, physical functioning, smoking, alcohol use and body mass index (BMI). Kissane et al. [39], in 303 early stage and 200 metastatic breast cancer patients, found prevalence rates of major depression of 9.6 and 6.5% respectively. Fatigue, a past history of depression, and cognitive attitudes of helplessness, hopelessness or resignation were significantly associated with depression in both groups.

Some research groups have assessed the duration of psychological distress in breast cancer patients. In a prospective study of 160 women awaiting breast surgery, Morris et al. [12] found a 22% prevalence of depression in women who had a mastectomy for breast cancer. This prevalence persisted at two years, compared to an 8% prevalence of depression in those with benign disease. One five-year observational cohort study of 222 early stage breast cancer patients [77] revealed prevalence rates for depression and anxiety of 33% at diagnosis, 15% after one year and 45% after a recurrence was diagnosed.

Few researchers have correlated patients’ historyof depression with current depression and/or functioning. In a study of 303 relatively young (mean age 46) women with early (Stage I or II) breast cancer at 3 months after breast surgery, using a structured diagnostic interview, Kissane et al. [39] found that a past history of depression was associated with current depression. They also noted that women with few psychological symptoms and good emotional adjustment to cancer may have refused participation in the study, because these women were also being recruited into an intervention study. Pasa-creta [78] reported findings on a homogenous sample of 79 women evaluated with the Diagnostic Interview Schedule and the Center for Epidemiological Studies Depression Scale, three–seven months after their diagnosis of breast cancer. Women with elevated depressive symptoms had more physical symptom distress and more impaired functioning than subjects without depression.

Depression in Women with Gynecological Cancer

In a systematic review which included 18 studies of psychological distress in ovarian cancer patients, Arden-Close et al. [79] found strong evidence for a relationship of younger age, more advanced disease at diagnosis, more physical symptoms and shorter time since diagnosis with increased levels of anxiety and/or depression. In the 12 studies rated as methodologically good, 21–25% of patients scored above the clinical cut-off for depression. In examining depression in ovarian cancer patients, Goncalves et al. [80] noted that persistent clinical depression tended to be not prevalent (6%), and that the highest prevalence was at the beginning of treatment. Neuroticism and the use of antidepressants were independent predictors of depression. For women with gynaecologic cancer, Evans et al. [74] found a 23% prevalence of depression and a 24% prevalence of adjustment disorder with depressed mood.

Depression in Patients with Head and Neck Cancer

Head and neck malignancies carry high risks of morbidity and mortality, with disease and treatment factors contributing substantially to disfigurement and loss of vital functions, such as eating, breathing and communicating. A systematic review of 52 studies found that depression is present throughout the trajectory of illness in patients with oropharyngeal cancers. Depression rates were highest at the