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Abstract Depression is the psychiatric syndrome that has received the most attention in individuals with cancer. The study of depression has been a challenge because symptoms occur on a broad spectrum that ranges from sadness to major affective disorder and because mood change is often difficult to evaluate when a patient is confronted by repeated threats to life, is receiving cancer treatments, is fatigued, or is experiencing pain. Although many research groups have assessed depression in cancer patients since the 1960s, the reported prevalence (major depression, 0%–38%; depression spectrum syndromes, 0%–58%) 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. Depression is highly associated with oropharyngeal (22%–57%), pancreatic (33%–50%), breast (1.5%–46%), and lung (11%–44%) cancers. A less high prevalence of depression is reported in patients with other cancers, such as colon (13%–25%), gynecological (12%–23%), and lymphoma (8%–19%). This report reviews the prevalence of depression in cancer patients throughout the course of cancer. Depression affects 121 million people and is among the leading causes of disability worldwide. Untreated depression leads to personal suffering and increased mortality. Although the prevalence of depression varies considerably globally, the most common symptoms of depression are depressed mood, insomnia, and fatigue, and depressed women out number depressed men 2 to 1. Americans have a one in five chance of developing depression in their lifetimes. Weissman and colleagues reported the lifetime rate of major (nonbipolar) depression to be 8%–17% for American women and 3.5%–8.6% for men (1). The 6-month prevalence of depression in adult Americans is 6%. The point prevalence of depression in “healthy community samples” is 4.5%–9.3% for women and 2.3%–3.2% for men. Although major depression commonly has its onset in the late twenties, one in 10 children have persistent feelings of sadness, one of the hallmarks of depression. The point prevalence of depression in prepubertal children ranges from 1% to 3% and from 3% to 9% in adolescents (2); however, the lifetime prevalence through adolescence is estimated to be as high as 20% (3). Although there is no difference in the prevalence rate between sexes before puberty, females are at higher risk after puberty. Depression in children negatively affects a child's development and often manifests as behavioral problems or somatic complaints. Depression commonly coexists with other syndromes and symptoms, such as anxiety disorders (e.g., posttraumatic stress disorder, panic disorder, generalized anxiety disorder) and pain. The National Comorbidity Survey data show that in a 12-month period, 51% of patients with major depressive disorders are diagnosed with an additional anxiety disorder. Patients with comorbid depression and anxiety disorders experience more severe symptoms, have a longer time to recovery, use more healthcare resources, and have poorer outcome than do those with a single disorder (4). The symptoms of depression and personal suffering resulting from this disorder have been well described. The complex biological underpinnings result from disturbances in neurotransmitters and hypothalamic-pituitary-gonadal axis disregulation. The last two decades have produced exciting science and advances in our understanding of the neurobiology and pathophysiology of depression. Electrophysiologic studies, neuroimaging techniques (i.e., magnetic resonance imaging [MRI]; computed tomography [CT]; single photon emission computed tomography [SPECT]; positron emission tomography [PET]; functional magnetic resonance imaging [functional MRI]), and neuropsychologic studies are providing information about the neuroanatomical substrate of depression as we are learning more about how systemic disease effects vulnerability to depression. Early Studies of Depression in Cancer Patients When significant numbers of mental health professionals began working in oncology settings, they asked oncologists to describe their perceptions of the prevalence of psychiatric disorders in cancer patients. Common responses ranged from “everyone is depressed, and rightfully so, because they have cancer” to “no one is depressed; these are just normal people” and likely were a reflection of the respondent's mood and coping style. One of the first efforts in psychooncology was to obtain objective data on the type and frequency of psychological problems in cancer patients. Using criteria from the Diagnostic and Statistical Manual of Mental Disorders-Third Edition (DSM-III) (5) classification of psychiatric disorders, the Psychosocial Collaborative Oncology Group determined the psychiatric disorders in 215 randomly selected hospitalized and ambulatory adult cancer patients in three cancer centers by structured clinical interview (6). Although 53% of the patients evaluated were adjusting normally to stress, the remainder (47%) had clinically apparently psychiatric disorders. Of this 47% with psychiatric disorders, more than two-thirds (68%) had adjustment disorders with depressed or anxious 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 psychiatric disorders observed were reactions to or manifestations of disease or treatment. Personality and anxiety disorders can complicate cancer treatment and were described as antecedent to the cancer diagnosis. The finding of 4% anxiety disorders was far below what would have been expected in the general population. Thirty-nine percent of those who received a psychiatric diagnosis experienced significant pain. In contrast, only 19% of patients who did not receive a psychiatric diagnosis had significant pain. The psychiatric diagnosis of the patients with pain was predominately adjustment disorder with depressed or mixed mood (69%), but of note, 15% of patients with significant pain had symptoms of a major depression. This early study conducted in 1983 was important for several reasons: first, it was a collaborative research effort by groups at three treatment facilities serving patient populations from different socioeconomic and cultural backgrounds (Baltimore, MD; New York City; and upstate New York); second, it was one of the first reviews of the prevalence of psychiatric disorders cancer patients providing useful data for mental health professionals to use to teach oncologists and oncology staff members about the psychological problems of cancer patients and the importance of hiring mental health professionals trained in the assessment and treatment of people with cancer; third, the researchers found support for an association between psychiatric morbidity and the presence of complaints, such as pain, and highlighted the importance of such correlations; and fourth, the findings helped mental health professionals and hospital administrators consider how best to staff clinical settings to effectively treat the psychological problems of cancer patients. In two other early studies using both DSM-III criteria that were modified to eliminate physical symptoms characteristic of cancer and those that were validated by observer rating scales (Hamilton Rating Scale and Beck Depression Inventory [BDI]), Bukberg and colleagues (7) found a 42% (24% severe, 18% moderate) prevalence among 62 adults (30 female, 32 male) hospitalized on oncology units, and Plumb and Holland (8) found a 33% prevalence of depression among 80 (40 female, 40 male) hospitalized adults with advanced cancer. Prevalence of Depression in Medically Ill Patients To place depression in cancer patients in context, it is helpful to consider the prevalence of depression occurring in association with other medical illnesses. 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% (9). A retrospective review of 263 000 patients from 327 hospitals found that 24% of those receiving a psychiatric consultation were depressed (10). However, Synder and colleagues (11), using both clinical interview and DSM-IIIR criteria, reported less depression (6%) but more adjustment disorder with depressed mood (14%) in 944 medically ill patients referred for psychiatric consultation. Taking a different approach, Wells and colleagues (12) examined Epidemiological Catchment Area Study data regarding psychiatric disorders among persons with at least one of eight chronic medical conditions. Six-month and lifetime prevalence rates of psychiatric disorder were increased in those with medical illness (25% and 42% versus 17% and 33%). Thirteen percent 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% (Table 1) (13). In contrast to neurological disease, 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 (Table 2) (13). Overall, rates of depression in medical illness appear to be lower than those encountered in neurological illness. Some have hypothesized that this may be a function of the extent of the direct structural compromise of the central nervous system in the neurological conditions as opposed to the medical illnesses. To what extent depression in the medically ill is a discrete entity, separate from depression arising in patients without comorbid physical illness is controversial. However, factors, including the absence of the usual female preponderance in affective disorder, no indication of genetic loading, treatment outcome, and long-term course, all favor the idea that these disorders are different. Assessment Methods Depression has been studied in patients with cancer using a range of assessment methods. The methods (self-report, brief screening instruments, and structured clinical interviews) commonly used are the Hospital Anxiety and Depression Scale (HADS), BDI, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, and DSM criteria. In general, the more narrowly the term is defined, the lower the prevalence of depression that is reported. Please see Dr. Trask's comprehensive discussion of the issues and challenges of assessment in this volume (13a). Prevalence of Depression in Cancer Patients Referred for Psychiatric Consultation Studies of the prevalence of depression in cancer patients referred for psychiatric consultation are one source of information about depression in cancer patients. Although one might expect to find a higher rate of depression in those noted to be distressed and referred for psychiatric evaluation, the five studies of depression in oncology patients referred for psychiatric consultation report a prevalence of major depression ranging from 9% to 58% (Table 3) (14–18). Although Massie and Holland (17) reported a low prevalence of depression (9%), an additional 26% of the hospitalized and ambulatory patients studied had adjustment disorder with depressed mood according to DSM-III. Lack of standardization in terms of population studied, disease site and stage, sample size, assessment instruments, cutoff score, type of interview, and diagnostic criteria employed (including major depression verus adjustment disorder with depressed mood versus depressive symptoms) all contributed to the large variance in reported prevalence among these studies. Prevalence of Depression in Cancer Patients Depression, the psychiatric syndrome that has received the most attention in individuals with cancer, has been a challenge to study because symptoms occur on a spectrum that ranges from sadness to major affective disorder and because mood change is often difficult to evaluate when a patient is confronted by repeated threats to life, is receiving cancer treatments, is fatigued, or is experiencing pain. However, depression in cancer has been essential to study because comorbid illnesses complicate the treatment of both and may lead to poor adherence to treatment recommendations and to less desirable outcomes of both conditions. Watson and colleagues' 1999 report (19) that depression is linked to a reduced chance of survival in women with early stage breast cancer supports the need for further study. Many research groups have assessed depression in cancer patients since the 1960s, and the reported prevalence (major depression, 0%-38%; depression spectrum syndromes, 0%-58%) varies significantly (Table 4) (6–8,20–104). These databases were searched to retrieve references published between 1965 and 2002 on the prevalence of depression in cancer: Medline, PreMedline, Embase (Excerpta Medica), PsycINFO (Psychological Abstracts), and CINAHL (Cumulative Index to Nursing and Allied Health Literature). Articles in English were reviewed; Table 4 shows the studies that provided information about the number of patients interviewed and cancer type or types, evaluation methods, and percentage with depression or affective syndromes. Most authors reported patient sex and hospitalization status. Please see Dr. Lawrence's evidence report on cancer-related depression in this monograph (104a). 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), by a symptom such as depressed mood, or by some of the 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. A limitation of many studies is that the effects of cancer treatments and non-cancer-related variables that affect mood often are not accounted for. For example, although the corticosteroids, vincristine, vinblastine, procarbazine, l-asparaginase, amphotericin B, interferon, and tamoxifen cause depression in some people, research groups usually have not presented data about cytotoxic drug or hormone use when describing their findings. Although Newport and Nemeroff and McDaniel and colleagues (105–107), acknowledged 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), 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 caused by the pathophysiologic effect of the tumor (i.e., paraneoplastic syndromes associated with breast, testis, or lung cancers), treatment effects, or other unidentified factors remains to be described. 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 Cancer types highly associated with depression include oropharyngeal (22%–57%) (36,100), pancreatic (33%–50%) (20,39), breast (1.5%–46%) (67,74), and lung (11%–44%) (84,86). A less high prevalence of depression is reported in patients with other cancers, such as colon (13%–25%) (20,21), gynecological (12%–23%) (37,53,79), and lymphoma (8%–19%) (40,41). Gender Differences A meta-analysis of 58 studies conducted between 1980 and 1994 demonstrated that cancer patients were significantly more depressed than the general population and that there were significant differences among groups with regard to sex, age, and type of cancer (108). DeFlorio and Massie (109) reviewed 49 studies of the prevalence of depression in individuals with cancer with a particular emphasis on gender differences. Among the 49 studies they reviewed, 30 included both males and females. Six research groups did not examine (or report) gender differences; the remaining 23 found no gender differences in the prevalence of depression at a significance level of P<.05. However, 10 research groups found either gender differences in subsets of patients, nonsignificant trends, or differences in other parameters such as psychiatric morbidity, anxiety, and denial. Four studies reported increased depression in the subsets of female patients. Craig and Abeloff (23) found a nonsignificant trend for females to have more psychological symptoms in a study of 30 (63% female) cancer patients. Lloyd and colleagues (30) found significantly higher psychiatric morbidity (anxiety and depression) among women in a study of 40 (38% female) hospitalized and ambulatory patients with different stages of lymphoma. Pettingale and colleagues (46) studied 168 patients with breast cancer or with lymphoma and found that the women with lymphoma had a tendency to be more depressed and were more anxious than were men with lymphoma and women with breast cancer. Women were more anxious than men at 3 months and 1 year follow-up; women with breast cancer were more anxious than were other patients at 1 year. Men were more likely to believe their illness was not under their control. Two studies reported more severe depression in men with cancer. Although Plumb and Holland (28) found no gender differences in overall depression in 80 (50% female) hospitalized patients with advanced cancer, more men than women (12 versus 5) were severely depressed. Males were more likely to have a history of poor impulse control, and females had a history of phobic symptoms. Holland and colleagues (38) found that men with either pancreatic or gastric cancer had depression and distress scores equal or slightly higher than women. Men with pancreatic cancer (but not women) had higher depression scores on the Profile of Mood States than men with gastric cancer. Whether this reflects a gender-based biological mechanism is unknown. Three research groups reported mixed results depending on subsets of patients or diagnostic criteria. In their study of 808 cancer patients, Kathol and colleagues (51) using Research Diagnostic Criteria found that women were more depressed than men; however, this finding did not persist when DSM-III criteria were applied. Baile and colleagues (57) in a study of 45 (43% female) ambulatory patients with head and neck cancer found increased depression in women with early-stage disease and in men with late-stage disease. Sneed and colleagues (60) found no gender differences in depression, anxiety, hostility, somatization, general psychological distress, or psychological well-being in 133 (67% female) patients with mixed cancer diagnoses. However, women with gynecological and breast cancer were found to have less depression, anxiety, hostility, somatization, and psychological distress, and greater psychological well-being, than women and men with other types of cancer. The authors believed this was secondary to their perception that their illness was less serious. Fife and colleagues (110) found no significant differences in depression in male and female cancer patients; however, they found that women made a more positive adjustment to cancer. In a study comparing 46 (45% females) adult twins with a hematological malignancy with their identical twin bone marrow donor, Friedrich and colleagues (42) found that female cancer patients showed more depression and repression of feelings than their nonpatient female twins; no difference was found between the male patients and their nonpatient twins. There was no significant difference in depression between male and female cancer patients. Depression by Cancer Type Depression in Women With Breast Cancer Breast cancer is the cancer most studied in terms of psychosocial effects, and not surprisingly, many studies of the prevalence of depression in cancer are studies of women with breast cancer. The reported prevalence ranges from 1.5% to 46%. Longitudinal studies of depression in women with breast cancer. Some research groups have assessed the duration of psychological distress in breast cancer patients and survivors. In a prospective study of 160 women awaiting breast surgery, Morris and colleagues (24) found a 22% prevalence of depression in women who had a mastectomy for breast cancer. This prevalence persisted at 2 years compared with an 8% prevalence of depression in those with benign disease. Meyer and Aspergren (49) found a 30% rate of anxiety or depressive symptoms in a study of 58 ambulatory women who were 5 years posttreatment for breast cancer. Women who had partial mastectomy followed by radiation had better body image but similar amount of anxi