Clinical features, assessment, and diagnosis of unipolar depressive disorders in patients with cancer

INTRODUCTION — Depressive syndromes such as major depression and minor depression are more common in patients with cancer than the general population [1]. However, treating these depressive disorders in patients with cancer can be beneficial [2].

The misconception that all patients with cancer are or should be depressed can trivialize the suffering and disability associated with comorbid depression, and can foster the underdiagnosis and undertreatment of depression [3]. Low-income, ethnic minority cancer patients may be at particular risk for undertreatment of depressive disorders [4].

This topic reviews the clinical features, assessment, and diagnosis of unipolar depressive disorders in patients with cancer. The clinical features and diagnosis of other psychiatric disorders in cancer patients are discussed separately, as are the clinical features and diagnosis of unipolar depression in palliative care and the management of depressive disorders in cancer patients. (See "Clinical features and diagnosis of psychiatric disorders in patients with cancer: Overview" and "Assessment and management of depression in palliative care" and "Management of psychiatric disorders in patients with cancer", section on 'Depression'.)

EPIDEMIOLOGY — The reported prevalence of depression in patients with cancer varies widely, which is likely due to differences in time since diagnosis of cancer, assessment methods, diagnostic criteria, patient populations (eg, sociodemographic factors and stage of cancer), settings (eg, inpatient and outpatient), and interviewer expertise [5]. As an example, identifying cases of depression with clinical interviews is more valid than using depression rating scales or screening instruments. In addition, diagnosing depression in the context of cancer can be difficult because somatic symptoms such as anorexia and anergia may be due to depression, cancer, and/or its treatment. Nevertheless, it is generally thought that the prevalence of depressive syndromes is higher in patients with cancer than the general population [6].

Prevalence — The point prevalence of unipolar major depression in patients with active cancer is approximately 5 to 20 percent [6-10], and the risk of major depression is two to four times greater in patients with cancer than individuals without cancer [1,11-14]. In addition, the increased rate of depression is highest in the first week after diagnosis of cancer and decreases thereafter [15].

Several studies have examined the prevalence of depression in patients with cancer:

●A meta-analysis of 70 studies included patients with cancer (n >10,000) across 14 countries who were interviewed; palliative care patients were excluded. The primary findings were as follows [6]:

•The estimated point prevalence of unipolar major depression was 16 percent; however, heterogeneity across studies was high. In the United States (23 studies), the point prevalence of unipolar major depression in patients with cancer was approximately 22 percent.

•In the nine high-quality studies, the estimated point prevalence of unipolar major depression was only 8 percent, and in the 27 studies published since 2001, the prevalence was 13 percent.

•The point prevalence of any type of depressive syndrome (major depression, minor depression, or persistent depressive disorder [dysthymia]) was approximately 21 percent.

●A 2014 study of cancer patients (n > 4000) who were interviewed found that the point prevalence of unipolar major depression ranged from 6 to 13 percent (depending upon the type [site] of cancer) [8]. This is consistent with a 2013 review, which focused upon higher-quality studies and found that in six studies of outpatients with cancer (number of patients not reported), major depression was present in 5 to 16 percent [7].

●A meta-analysis of 11 studies that conducted diagnostic interviews for depression in patients with cancer (n >1300) estimated that the point prevalence of unipolar major depression was 14 percent; however, heterogeneity across studies was high [9].

Multiple studies suggest that the risk of major depression is two to four times greater in patients with cancer than individuals without cancer [11-14]. As an example, a national registry study identified almost 2,000,000 women with no history of cancer or psychiatric disorders and observed that over 13 years of follow-up, nearly 45,000 women developed breast cancer [1]. The incidence of treatment for depression in the first year after diagnosis of cancer was greater in cancer patients than the general population (relative risk 1.7, 95% CI 1.4-2.1), and use of antidepressants was more than three times greater in women with cancer (relative risk 3.1, 95% CI 3.0-3.2).

The increased risk of depression persists for several years, but progressively dissipates, such that the prevalence of depression in patients who survive cancer eventually appears to be comparable to that in the general population [1]. As an example, a meta-analysis of 14 studies compared the prevalence of clinically significant depressive symptoms in cancer survivors (n >50,000) and in healthy controls (n >200,000); the mean time since cancer diagnosis was seven years [16]. The prevalence of depression in cancer survivors and controls was similar (12 and 10 percent).  

The prevalence of depression in palliative care (including late stage or advanced cancer) is discussed separately. (See "Assessment and management of depression in palliative care", section on 'Prevalence of depression in palliative care'.)

Risk factors — The following factors may be associated with an increased risk of suffering unipolar major depression following a diagnosis of cancer:

●Prior history of major depression [17-19]

●Social deprivation (eg, low income and limited education) [8]

●Living alone/unmarried/poor social support [1,19,20]

●General medical comorbidity [1,21]

●Frequent pain [19,20]

●Metastases/advanced disease [19,20]

●Impairment of functioning (eg, self-care or work) [20,22]

Although major depression in the general population is more common among females than males by a ratio of 2:1, the prevalence of cancer-related depression in women and men appears to be comparable [6,19,23]. In addition, neither patient age [6] nor type (site) of cancer [15] is associated with the prevalence of depression in cancer patients.

Other populations at greater risk of developing major depression include patients with far advanced cancers and the terminally ill. (See "Assessment and management of depression in palliative care".)

PATHOGENESIS — The pathogenesis of depressive syndromes in patients with cancer is not known. Factors that may be involved include:

●Patient factors – Perceived psychological stress and emotional impact of the diagnosis, personal or family history of depression, lack of social support, heightened attachment anxiety (insecurity and fear of abandonment), poor communication with medical staff, and maladaptive coping behaviors [5,24,25].

●Disease factors – Advanced stages of cancer, a greater number and severity of physical symptoms (eg, pain), and functional disability are associated with depression. Cancer may also lead to depression by inducing the release of pro-inflammatory immune cytokines (eg, tumor necrosis factor and interleukin 6) and by disrupting neuroendocrine processes (eg, elevating nocturnal secretion of cortisol) [24,25].

●Treatment factors – Depressive syndromes may arise from the neurotoxic effects of drugs that are used to treat cancer, such as glucocorticoids, interferon-alpha, procarbazine, vinblastine, and vincristine [24,26,27]. Treatment-induced tissue destruction may also release depressogenic cytokines [5]. In addition, disfiguring surgery (eg, mastectomy) may lead to depression [25,27].

Information about the pathogenesis of depressive syndromes in the general population of patients is discussed elsewhere. (See "Unipolar depression: Pathogenesis".)

CLINICAL FEATURES — It is important to recognize the potential for confusion engendered by multiple uses of the term “depression.” Depression may refer to a mood state, syndrome, or mental disorder. (See "Unipolar depression in adults: Clinical features", section on 'Definitions of depression'.)

In addition, there is a continuum of pathological depressive conditions, from subsyndromal symptoms to the syndromes of minor depression and major depression. (See "Unipolar depression in adults: Clinical features", section on 'Continuum of severity'.)

Depression often occurs in conjunction with anxiety [28]. As an example, a study of patients in treatment for cancer (n >8000) who completed a self-report survey found that clinically significant symptoms of depression plus anxiety were present in 12 percent [29].

Depressive disorders are associated with undesirable clinical outcomes, including physical distress, prolonged hospitalization, poorer adherence with treatment, diminished quality of life, increased desire to die sooner, increased all-cause and cancer mortality, and completed suicide [5]. (See "Physician-assisted dying" and 'Mortality' below.)

Symptoms — The symptoms of unipolar depressive disorders include [30]:

●Depressed mood (dysphoria)

●Loss of interest or pleasure

●Change in appetite

●Sleep disturbance

●Loss of energy

●Neurocognitive dysfunction

●Psychomotor agitation or slowing

●Excessive guilt

●Suicidal ideation and behavior

Information about each symptom is discussed elsewhere. (See "Unipolar depression in adults: Clinical features", section on 'Symptoms'.)

The symptom of depressed mood is common in oncology settings. Dysphoria can be an appropriate response to a new cancer diagnosis, worsening prognosis, or cancer recurrence. However, depressed mood can also be a sign of psychopathology and indicative of a clinical syndrome necessitating treatment.

Several symptoms of depressive disorders overlap with symptoms of cancer and its treatment, including anergia, anorexia, cognitive impairment, and insomnia [5]. Thus, many clinicians give less emphasis to these symptoms when assessing patients for unipolar depression. (See 'Initial evaluation' below.)

Comorbid psychopathology — Depressive disorders in patients with cancer may be accompanied by comorbid psychopathology, such as anxiety disorders. Comorbidity is discussed separately in the context of the general population of patients with depression. (See "Unipolar depression in adults: Clinical features", section on 'Psychiatric'.)

Course of illness — Episodes of depression in patients with cancer often last at least three months. A prospective observational study included women with breast cancer (n = 122) who were enrolled within eight weeks of diagnosis, followed for up to five years, and suffered an episode of syndromal or subsyndromal depressive and/or anxiety disorders [18]. The episodes lasted at least three months in 66 percent of patients.

Mortality — Mortality is greater in patients with cancer who are also depressed, compared with cancer patients who are not depressed [31]. One possible explanation is that depression may have adverse pathophysiologic effects (eg, dysregulation of cortisol secretion) [31,32] (see 'Pathogenesis' above). In addition, depressed patients may have difficulty navigating health care systems, may be less inclined to pursue definitive cancer treatment, and may be less adherent with cancer treatment [31,33]. One review estimated that nonadherence is three times greater among depressed cancer patients than nondepressed cancer patients [34]. Depression is also associated with an increased risk of suicide. (See "Clinical features and diagnosis of psychiatric disorders in patients with cancer: Overview", section on 'Suicide'.)

●Cancer mortality – Many prospective studies of patients with cancer indicate that comorbid depression is associated with a small increased risk of cancer mortality [32,35]. As an example, a meta-analyses of 76 prospective observational studies (n >175,000 cancer patients) found that depression predicted increased cancer mortality (relative risk 1.2), and the association persisted after controlling for potential confounding factors (eg, age, sex, and site and stage of cancer) [31].

●All-cause mortality – Among patients with cancer, depressive symptoms are associated with an increased risk for all-cause mortality [33,36,37]. In a registry study that identified patients diagnosed with cancer (n >2700) and controlled for potential confounding factors (eg, age, time since diagnosis, and type of cancer), all-cause mortality was two times greater in cancer patients with clinically significant levels of depression, compared with nondepressed patients (hazard ratio 2.1, 95% CI 1.6-2.7) [38].

SCREENING — We suggest that clinicians screen all patients with cancer for depressive disorders with the self-report, two-item Patient Health Questionnaire (PHQ-2) (table 1) and that screening be implemented with services in place to ensure follow-up for diagnosis and treatment. Patients with cancer should be screened for depression when the initial diagnosis of cancer is made and periodically thereafter as clinically indicated, especially with changes in cancer or treatment status (eg, post-treatment, recurrence, or progression), as well as transition to palliative care. Patients who screen positive (a single “yes” response) should be interviewed to diagnose depression; the interview can be facilitated with the self-administered nine-item Patient Health Questionnaire (PHQ-9) (table 2), which performs well in cancer patients [39]. This approach is consistent with guidelines from the American Society of Clinical Oncology, which are based upon practice guidelines from the Pan-Canadian Guideline on Screening, Assessment and Care of Psychosocial Distress (Depression, Anxiety) in Adults with Cancer [2]. In addition, the US Preventive Services Task Force recommends screening for depression in the general adult population [40]. The rationale for screening is that distress is serious, prevalent, under-recognized, and treatable, and that standardized, valid screening tools are available. Although there is no high-quality evidence that screening for depression in cancer patients improves depression outcomes [41], indirect evidence from other populations suggests that screening can be beneficial. (See "Screening for depression in adults", section on 'Effectiveness of screening' and "Unipolar major depression during pregnancy: Epidemiology, clinical features, assessment, and diagnosis", section on 'Screening'.)

Evidence supporting the use of the PHQ-2 (table 1) to screen for depression in patients with cancer includes a pooled analysis of five studies (900 patients with cancer), which found that sensitivity was 91 percent, specificity 86 percent, positive predictive value 57 percent, and negative predictive value 98 percent [42].

Among multiple reviews that have evaluated self-report depression screening tools, there is no consensus regarding the adoption of any one instrument [43]. Reasonable alternatives to the PHQ-2 and PHQ-9 include the Beck Depression Inventory (21 items), Center for Epidemiologic Studies Depression Scale (20 items), and Hospital Anxiety and Depression Scale (14 total items, including a 7-item depression subscale). Like the PHQ-2 and PHQ-9, the Center for Epidemiologic Studies Depression Scale is in the public domain and thus available free of charge for unlimited clinical use.

Several instruments with fewer than five questions (eg, the single-item Distress Thermometer) are available to screen for depression and are appealing because of their brevity; however, we generally do not recommend them. A pooled analysis of results from seven studies (n >1200 patients with cancer) found that these short instruments performed poorly in detecting possible cases of major depression; the pooled sensitivity was 75 percent and positive predictive value 36 percent [44]. The instruments were better at excluding cases of possible major depression, with a specificity of 81 percent and negative predictive value of 96 percent.

Additional information about screening for depression is discussed separately. (See "Screening for depression in adults".)

ASSESSMENT

When to suspect depression — The presence of major depression in patients with cancer is suggested by the following clues [5,34]:

●Nonadherence with treatment for cancer

●Impairment of social or occupational functioning

●Marked physical or psychological distress

●Negativity

●Irritability

●Hopelessness

●Helplessness

●Worthlessness

●Demoralization (lose confidence or hope)

In addition, if clinicians find themselves feeling bored or hopeless while interviewing patients with cancer, this may also suggest comorbid major depression.

Initial evaluation — The initial clinical evaluation of patients with a possible diagnosis of unipolar major depression includes a psychiatric history, mental status examination, general medical history, physical examination, and a basic set of laboratory tests (eg, complete blood count, serum chemistry panels, thyroid stimulating hormone, urinalysis, and urine toxicology screen for drugs of abuse) [45,46]. Additional information about the initial assessment is discussed separately. (See "Unipolar depression in adults: Assessment and diagnosis", section on 'Assessment'.)

In particular, the assessment should address current and past suicidal ideation and behavior; identification of suicidality should prompt a referral to a mental health specialist for further evaluation and management. Patients with severe symptoms (eg, suicidal ideation with a specific plan and intent or suicidal behavior) should be directly referred to an emergency department. Additional information about assessing suicidality is discussed separately. (See "Suicidal ideation and behavior in adults".)

We suggest that the assessment emphasize the five mood and cognitive symptoms of major depression (table 3) [19,30]:

●Dysphoria (depressed, sad, or anxious)

●Anhedonia (loss of interest or pleasure)

●Worthlessness or excessive guilt

●Impaired concentration and decision making

●Suicidal ideation and behavior

In addition, major depression may also be characterized by hopelessness and helplessness that is disproportionate to the medical reality and prognosis of the patient’s cancer.

Patients who are not depressed may periodically be sad, but maintain the capacity for experiencing pleasure. They react positively to opportunities to engage in the activities that they enjoy, even though the range of activities available to them may be diminished. There is nothing inherent to the cancer or its treatment that robs one of the capacity to feel pleasure.  

Patients may state that they are burdening and inconveniencing their families and causing them pain. Such beliefs are less likely to represent a symptom of depression than if patients suffer with guilty recrimination (eg, “God is punishing me”), feel that their lives have never had any worth, or that they are being punished for evil things that they have done.

The diagnosis of major depression can be made with more confidence if the patient has at least three of the five mood and cognitive symptoms, especially suicidality. Focusing more upon mood and cognitive symptoms is consistent with the approach taken when diagnosing major depression in the context of other general medical disorders. (See "Unipolar depression in adults: Assessment and diagnosis", section on 'Unipolar major depression'.)

Somatic (neurovegetative) symptoms of depression include anergia, anorexia, and disturbances in psychomotor activity and sleep [30]. However, these symptoms may also be caused by cancer and its treatment [19]. Cancer can cause fatigue, unrelieved pain may cause insomnia and depression, and chemotherapy may lead to loss of appetite and weight.

Despite the overlap between symptoms of depression and cancer, the somatic symptoms of depression should not be ignored; multiple studies suggest that assessing somatic symptoms is useful when evaluating cancer patients for depressive disorders [47]. As an example, a prospective study assessed patients (n = 279) for unipolar major depression or minor depression up to three times within the first nine months of being diagnosed with cancer [48]. All depressive symptoms were more common in depressed patients than nondepressed patients, and the diagnostic accuracy of somatic symptoms was at least as good as that for mood and cognitive symptoms. In addition, asking about specific somatic symptoms may help begin a dialogue about depression with patients who may otherwise resist discussions of emotional issues.

Passive wishes for death to come soon and thoughts of hastening death arise commonly in cancer patients throughout the disease course. Careful assessment is needed to evaluate whether such thoughts are associated with a suicidal plan and/or behavior. Frequently, suicidal thoughts represent a wish to talk about fears of dying or other concerns about the future, and can be remediated by increased clinical attention. The presence of a suicidal plan and/or behavior should prompt immediate referral for a psychiatric evaluation.

The presence of risk factors for depression may also help clinicians rule in a depressive disorder in patients with cancer. (See 'Risk factors' above.)

Assessment of patients for depressive disorders in the context of palliative care and in the general population is discussed separately. (See "Assessment and management of depression in palliative care", section on 'Assessment and diagnosis' and "Unipolar depression in adults: Assessment and diagnosis", section on 'Assessment' and "Unipolar minor depression in adults: Epidemiology, clinical presentation, and diagnosis", section on 'Assessment'.)

DIAGNOSIS

Criteria — Among patients with cancer, the criteria for diagnosing unipolar depressive disorders, including unipolar major depression (table 3) and unipolar minor depression (table 4), are the same criteria that are used in the general population [30]. (See "Unipolar depression in adults: Assessment and diagnosis", section on 'Diagnostic criteria and classification'.)

Diagnosis of depression in the context of palliative care is discussed separately. (See "Assessment and management of depression in palliative care", section on 'Assessment and diagnosis'.)

Missing the diagnosis — Major depression in patients with cancer is often not recognized. One reason is that the somatic symptoms of depression in patients with cancer – changes in appetite, energy, libido, and sleep – may be attributed to normal cancer-related changes or to cancer treatment side effects (see 'Initial evaluation' above). In addition, patients may be reluctant to report depressive symptoms due to stigma.

Differential diagnosis — Somatic symptoms of major depression (table 3), including disturbances in sleep, energy, and appetite, overlap with changes observed in patients with cancer who are not depressed. Depression is distinguished from normal cancer-changes by focusing upon the five mood and cognitive symptoms of depression, which include dysphoria, anhedonia, worthlessness or excessive guilt, impaired concentration and decision making, and suicidal ideation and behavior. Major depression may also be characterized by hopelessness and helplessness that is disproportionate to the medical reality and prognosis of the patient’s cancer. (See 'Initial evaluation' above.)

In addition, symptoms of unipolar depression can overlap with symptoms of other psychiatric disorders. Depressive disorders should also be distinguished from normal sadness that occurs in response to a diagnosis of cancer. The differential diagnosis of unipolar depressive disorders is discussed separately. (See "Unipolar depression in adults: Assessment and diagnosis", section on 'Differential diagnosis'.)

CARETAKERS — Spouses, partners, and other caretakers of patients with cancer may be at increased risk of depressive disorders. A national registry study identified men with no history of hospitalization for unipolar depression or bipolar disorder (n >1,000,000), who were followed for a median of 13 years; the cohort included male partners of women who were diagnosed with breast cancer (n >20,000) during follow-up [49]. After adjusting for potential confounding factors (eg, age, socioeconomic status, and general medical illnesses), the analyses found that the risk of hospitalization for a depression or bipolar disorder was modestly greater in men whose partner was diagnosed with cancer, compared with men whose partner was not diagnosed with cancer (hazard ratio 1.4, 95% CI 1.2-1.6).

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

●Basics topics (see "Patient education: Depression (The Basics)")

●Beyond the Basics topics (see "Patient education: Depression in adults (Beyond the Basics)")

SUMMARY

●Among patients with active cancer who are not in palliative care settings, the point prevalence of unipolar major depression is approximately 5 to 20 percent, and the risk of major depression is two to four times greater in patients with cancer than individuals without cancer. In addition, the increased rate of depression is highest in the first week after diagnosis of cancer and decreases thereafter. Prior history of major depression is associated with an increased risk of suffering unipolar major depression following a diagnosis of cancer. (See 'Epidemiology' above.)

●The symptom of depressed mood is common in oncology settings. Dysphoria can be an appropriate response to a new cancer diagnosis, worsening prognosis, or cancer recurrence. However, depressed mood can also be a sign of psychopathology and indicative of a clinical syndrome necessitating treatment. There is a continuum of pathological depressive conditions, from subsyndromal symptoms to the syndromes of minor depression and major depression. Episodes of depression in patients with cancer often last at least three months. Mortality is greater in patients with cancer who are also depressed, compared with cancer patients who are not depressed. (See 'Clinical features' above.)

●Clinicians are encouraged to screen all patients with cancer for depressive disorders with the self-report, two-item Patient Health Questionnaire (table 1), and that screening be implemented with services in place to ensure follow-up for diagnosis and treatment. Patients who screen positive (a single “yes” response) should be interviewed to diagnose depression; the interview can be facilitated with the self-administered nine-item Patient Health Questionnaire (table 2). (See 'Screening' above.)

●The initial clinical evaluation of patients with a possible diagnosis of unipolar major depression includes a psychiatric history, mental status examination, general medical history, physical examination, and a basic set of laboratory tests. The assessment should emphasize the mood and cognitive symptoms of major depression (table 3), which include dysphoria, anhedonia, worthlessness or excessive guilt, hopelessness, helplessness, impaired concentration and decision making, and suicidal ideation and behavior. Somatic (neurovegetative) symptoms of depression consist of anergia, anorexia, and disturbances in psychomotor activity and sleep; however, these symptoms may also be caused by cancer and its treatment. Patients with severe symptoms (eg, suicidal ideation with a specific plan and intent or suicidal behavior) should be directly referred to an emergency department. (See 'Initial evaluation' above.)

●Among patients with cancer, the criteria for diagnosing unipolar depressive disorders, including unipolar major depression (table 3) and unipolar minor depression (table 4), are the same criteria that are used in the general population. (See 'Criteria' above.)