Depression is a comorbid disabling syndrome that affects approximately 15% to 25% of cancer patients.     Depression is believed to affect men and women with cancer equally, and gender-related differences in prevalence and severity have not been adequately evaluated.  Individuals and families who face a diagnosis of cancer will experience varying levels of stress and emotional upset. Depression in patients with cancer not only affects the patients themselves but also has a major negative impact on their families.
Definitions: Depression is suspected when a number of specific symptoms are observed (affect, sleep disturbance, thought patterns). These are specified in the categorization of psychiatric/behavioral disorders in the Diagnostic and Statistical Manual of Mental Disorders, 4th and 5th editions.   However, there are a number of pathways that may result in the symptom clusters that lead to the consideration of depression, including disruption in serotonin/dopamine pathways, experience of loss or anticipated loss, direct side effects of chemotherapy medications, presence of tumors in the central nervous system, poorly managed pain, disruption of sleep due to medical treatments, and anemia. Assessment and management of these symptoms require understanding of the various pathways and the evidence-based treatment options.
Normally, a patient’s initial emotional response to a diagnosis of cancer is brief, extending over several days to weeks, and may include feelings of disbelief, denial, or despair. This normal response is part of a spectrum of depressive symptoms that range from normal sadness to adjustment disorder with depressed mood to major depression.  Other syndromes described include dysthymia and subsyndromal depression (also called minor depression or subclinical depression). Dysthymia is a chronic mood disorder in which a depressed mood is present on more days than not for at least 2 years. In contrast, subsyndromal depression is an acute mood disorder that is less severe (some, but not all, diagnostic symptoms present) than major depression.
A survey in England of women with breast cancer showed that among several factors, depression was the strongest predictor of emotional and behavioral problems in their children.  Fear of death, disruption of life plans, changes in body image and self-esteem, changes in social role and lifestyle, and financial and legal concerns are significant issues in the life of any person with cancer, yet serious depression or anxiety is not experienced by everyone who is diagnosed with cancer.
Just as patients require ongoing evaluation for depression and anxiety throughout their course of treatment, so do family caregivers. In a study of family caregivers of patients in the palliative phase of illness, both male and female caregivers experienced significantly more anxiety than did a sample of non-caregivers, while there was an increased incidence of Hospital Anxiety and Depression Scale–defined depression among women. 
There are many myths about cancer and how people cope with it, such as the following:
Some people may have more difficulty adjusting to the diagnosis of cancer than others do and will vary in their responses to the diagnosis. Sadness and grief are normal reactions to the crises faced during cancer. All people will experience these reactions periodically. Because sadness is common, it is important to distinguish between normal degrees of sadness and depressive disorders. An end-of-life care consensus panel review article describes details regarding this important distinction and illustrates the major points using case vignettes.  A critical part of cancer care is the recognition of the levels of depression present and determination of the appropriate level of intervention, ranging from brief counseling or support groups to medication and/or psychotherapy. For example, relaxation and counseling interventions have been shown to reduce psychological symptoms in women with a new diagnosis of gynecological cancer. 
Major depression is not simply sadness or a blue mood. Major depression affects approximately 25% of patients and has recognizable symptoms whose diagnosis and treatment are essential because they have an impact on quality of life.   Depression is also an underdiagnosed disorder in the general population. Symptoms evident at the time of a cancer diagnosis may represent a preexisting condition and warrant separate evaluation and treatment.
Depression and anxiety disorders are common among patients receiving palliative care and contribute to a greatly diminished quality of life in these patients.  In the Canadian National Palliative Care Survey, patients receiving palliative care for cancer (N = 381) were evaluated for depressive and anxiety disorders and for the impact of these disorders on quality of life. The primary assessment tool was a modified version of the Primary Care Evaluation of Mental Disorders. A significant number of participants (24.4%; 95% confidence interval, 20.2–29.0) were found to fulfill diagnostic criteria for at least one depressive or anxiety disorder (20.7% prevalence for depressive disorder and 13.1% for anxiety disorder).
Participants diagnosed with a depressive or anxiety disorder had the following characteristics:
They also reported more severe distress about physical symptoms, social concerns, and existential issues, suggesting significant negative impact on other aspects of their quality of life. 
The importance of psychological issues was underscored by another study conducted in terminally ill cancer patients (n = 211) with life expectancies of less than 6 months.  Investigators evaluated patient “sense of burden to others” and its correlation with physical, psychological, and existential issues, using specific validated psychometrics (e.g., visual analog scale). The variables most highly correlated with sense of burden to others included:
In multiple regression analysis, four variables predicted perception of burden to others:
No association between sense of burden to others and actual degree of physical dependency was found, implying that this perception is mainly mediated through psychological distress and existential issues. A subanalysis of patient groups from different settings suggested that these findings were consistent across the inpatient and outpatient settings, with some minor variations. 
The emotional response to a diagnosis of cancer (or cancer relapse) may begin as a dysphoric period marked by increasing turmoil. The individual will experience sleep and appetite disturbance, anxiety, ruminative thoughts, and fears about the future. Epidemiologic studies, however, suggest that at least one-half of all people diagnosed with cancer will successfully adapt.
Markers of successful adaptation to a diagnosis of cancer include the following: 
Some studies suggest an association between maladaptive coping styles and higher levels of depression, anxiety, and fatigue symptoms.   Examples of maladaptive coping behaviors include the following:
One study conducted in a group of 86 mostly late-stage cancer patients suggested that maladaptive coping styles and higher levels of depressive symptoms are potential predictors of the timing of disease progression.  Another study examining coping strategies in women with breast cancer (n = 138) concluded that patients with better coping skills such as positive self-statements have lower levels of depressive and anxiety symptoms.  The same study found racial differences in the use of coping strategies, with African American women reporting and benefiting more from the use of religious coping strategies such as prayer and hopefulness than did Caucasian women. 
Preliminary data suggest a beneficial impact of spirituality on associated depression, as measured by the Functional Assessment of Chronic Illness Therapy—Spiritual Well-Being questionnaire and the Hamilton Depression Rating Scale. 
The following indicators may suggest a need for early intervention:
As shown by a study of adult cancer patients (n = 48) and their adult relatives (n = 99), family functioning is an important factor that impacts patient and family distress. Families that were able to act openly, express feelings directly, and solve problems effectively had lower levels of depression, and direct communication of information within the family was associated with lower levels of anxiety.  Depressive symptoms in spouses of patients with cancer can also have a negative impact on their marital communication. A preliminary study investigated 19 potential predictors of depression in spouses (n = 206) of women with nonmetastatic breast cancer.  Spouses were more likely to experience depressive symptoms if they:
Risk factors may be different, especially pain and other physical symptoms.  When the clinician begins to suspect that a patient is depressed, he or she will assess the patient for symptoms. Mild or subclinical levels of depression that include some, but not all, of the diagnostic criteria for a major depressive episode can cause considerable distress and may warrant interventions such as supportive individual or group counseling, either by a mental health professional or through participation in a self-help support group. 
Evidence-based recommendations have described various approaches to the problems of cancer-related fatigue, anorexia, depression, and dyspnea.  Even in the absence of any symptoms, many patients express interest in supportive counseling; clinicians can accommodate these patients with referrals to qualified mental health professionals. However, when symptoms are more intense, longer lasting, or recurrent after apparent resolution, treatment to alleviate symptoms is essential.    Anxiety and depression in early treatment are good predictors of these same problems at 6 months.  In a study of older women with breast cancer, a recent diagnosis of depression was associated with both a greater likelihood of not receiving definitive cancer treatment and poorer survival. 
The pathophysiology of cancer-related depression remains unclear and probably encompasses many mechanisms. A study of patients with advanced metastatic cancer showed that both plasma interleukin-6 (IL-6) concentrations and hypothalamic-pituitary-adrenal axis dysfunction were markedly higher in patients with clinical depression.  A cut-off value of 10.6 pg/mL for IL-6 yielded a sensitivity of 79% and specificity of 87%, while a cut-off value of 33.5% for cortisol variations yielded a sensitivity of 81% and specificity of 88%. One limitation of this study was that neither pain levels nor fatigue levels were measured, which might independently affect these relationships.
Although the etiology of depression is largely unknown, many risk factors for depression (such as those listed below) are known.
In this summary, unless otherwise stated, evidence and practice issues as they relate to adults are discussed. The evidence and application to practice related to children may differ significantly from information related to adults. When specific information about the care of children is available, it is summarized under its own heading.
There are two major classifications of symptoms for major depression: neurovegetative and emotional-cognitive. In cancer patients whose neurovegetative symptoms may be affected by the disease process or treatment, assessing the emotional-cognitive symptoms of their depression is likely to be more diagnostic and prevent false-positive results. Symptoms include the following:
Cognitive symptoms may express themselves as repeated and ruminative thoughts such as “I brought this on myself,” “God is punishing me,” or “I’m letting my family down,” and as fatalistic expectations concerning prognosis, despite realistic evidence to the contrary. Such thinking may predominate or may alternate with more realistic thinking, yet remain very stressful. Some individuals will share negativistic thoughts freely, and family members may be aware of them. Other patients will not volunteer such thinking but will respond to brief inquiries such as the following (other examples are listed in Table 1):
It is possible for a physician or nurse to ask these types of questions without becoming engaged in providing counseling themselves. Merely asking these questions will express concern and increase the likelihood that the patient will be receptive to suggestions for further counseling.
These questions can be followed by a statement such as, “Many people with cancer sometimes have these feelings. You are not alone. But talking to someone else about them can greatly help. I'd like to suggest that you consider doing that. Would you be willing to talk to someone who has a lot of experience helping people cope with the stress of having cancer?”
It is preferable at this time both to encourage patients to seek out someone already known to them and to inform them about other resources in the community. Particularly for patients who have completed cancer treatment and who have manageable physical symptoms, higher perceived availability of social support has been associated with fewer depressive symptoms.  In some instances, referral to a cleric or therapist may also be appropriate. Most therapists can address general issues of grief or fears about death; some will specialize in clinical health psychology, medical social work, or even working primarily with cancer patients. For the hesitant patient, suggesting multiple resources will increase the likelihood that some assistance will be sought. For other patients, a formal direct referral may be appropriate.
Evaluation of depression in people with cancer includes careful assessment of the following:
Limited data suggest that depressive symptomatology in cancer patients undergoing cytokine therapy with interferon-alfa and interleukin-2 may be mediated by changes in availability of neurotransmitter precursors.  For patients with head and neck cancer treated with curative intent, the following eight pretreatment variables can be used to predict which patients are likely to become depressed up to 3 years after treatment:  
A prospective study of terminally ill Japanese patients who were assessed for psychiatric illness by structured clinical interview at the time of registration (baseline) and again at admission to a palliative care unit (follow-up) found that 5 (42%) of the 12 patients diagnosed with adjustment disorder at baseline progressed to major depression at follow-up. Only the Hospital Anxiety and Depression Scale was significantly predictive of psychiatric diagnoses at follow-up.  Heightened awareness of this facilitates early diagnosis and the use of appropriate interventions.  In the medically ill, early manifestations of delirium may be mistaken for anxiety or depression. These disorders should be considered among the differential diagnoses in individuals who present with depressive symptoms.
Because of the common underrecognition and undertreatment of depression in people with cancer, screening tools can be used to prompt further assessment.  Among the physically ill, in general, instruments used to measure depression have not been shown to be more clinically useful than an interview and a thorough examination of mental status. Simply asking the patient whether he or she is depressed may improve the identification of depression.
The following screening tools are commonly used:
One study of women with newly diagnosed breast cancer (n = 236) successfully utilized brief screening instruments such as the Distress Thermometer and the Patient Health Questionnaire to identify women requiring further assessment to detect clinically significant levels of distress and psychiatric symptoms. 
In a study of 321 women with newly diagnosed stage I to stage III breast cancer, the ability of the single-item Distress Thermometer to specifically predict depression, as measured by a self-report questionnaire of the nine Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) symptoms for major depressive disorder, was investigated. Sensitivity and specificity characteristics were evaluated, and the optimal cutoff score of 7 was identified, resulting in a sensitivity of 0.81 and a specificity of 0.85 for detecting depression. Therefore, individuals scoring 7 or above will undergo a more thorough psychosocial evaluation. 
The Impact Thermometer, a modification of and accompaniment to the Distress Thermometer, has improved specificity for the detection of adjustment disorders and/or major depression, as compared with the Distress Thermometer. The revised tool has a screening performance comparable to that of the Hospital Anxiety and Depression Scale and is brief, potentially making it an effective tool for routine screening in oncology settings.  The Mood Evaluation Questionnaire, a cognitive-based screening tool for depression, has moderate correlation with the structured clinical interview for the DSM, 3rd revised edition (DSM-III-R) and good acceptability in the palliative care population. With further validation, it may become a useful alternative in this population because it can be used by clinicians who are not trained in psychiatry. 
It is important that screening instruments be validated in cancer populations and used in combination with structured diagnostic interviews.  A pilot study of 25 patients used a simple, easily reproduced visual analog scale suggesting the benefits of a single-item approach to screening for depression. This scale consists of a 10-cm line with a sad face at one end and a happy face at the other end, on which patients make a mark to indicate their mood. Although the results do suggest that a visual analog scale may be useful as a screening tool for depression, the small patient numbers and lack of clinical interviews limit conclusions. Furthermore, although very high correlations with the Hospital Anxiety and Depression Scale were reported (r = 0.87), no indication of cut-offs was given. Finally, it is emphasized that such a tool is intended to suggest the need for further professional assessment. However, if validated further, this simple approach could greatly enhance assessment and management of depression in cognitively intact advanced-cancer patients.  
Other brief assessment tools for depression can be used. To help patients distinguish normal anxiety reactions from depression, assessment includes discussion about common symptoms experienced by cancer patients. Depression is reassessed over time.  Because of the increased risk of adjustment disorders and major depression in cancer patients, routine screening with increased vigilance at times of increased stress (e.g., diagnosis, recurrences, progression) is recommended.  General risk factors for depression are noted in the list above. Other risk factors may pertain to specific populations, for example, patients with head and neck cancer  and women at high risk of developing breast cancer. 
|How well are you coping with your cancer? Well? Poorly?||Well-being|
|How are your spirits since diagnosis? During treatment? Down? Blue?||Mood|
|Do you cry sometimes? How often? Only alone?||Mood|
|Are there things you still enjoy doing, or have you lost pleasure in things you used to do before you had cancer?||Anhedonia|
|How does the future look to you? Bright? Black?||Hopelessness|
|Do you feel you can influence your care, or is your care totally under others' control?||Helplessness|
|Do you worry about being a burden to family/friends during cancer treatment?||Guilt|
|Do you feel others might be better off without you?||Worthlessness|
|Physical symptoms (evaluate in the context of cancer-related symptoms)|
|Do you have pain that isn't controlled?||Pain|
|How much time do you spend in bed?||Fatigue|
|Do you feel weak? Fatigue easily? Rested after sleep? Any relationship between how you feel and a change in treatment or how you otherwise feel physically?||Fatigue|
|How is your sleeping? Trouble going to sleep? Awake early? Often?||Insomnia|
|How is your appetite? Food tastes good? Weight loss or gain?||Appetite|
|How is your interest in sex? Extent of sexual activity?||Libido|
|Do you think or move more slowly than usual?||Psychomotor slowing|
|aAdapted from Roth et al. |
Organic Mood Syndromes or Mood Syndromes Related to Another Medical Condition (MSRAMC), as they are referred to in the DSM, 5th edition (DSM-5),  often mimic the mood syndromes in their presentation. The assumption is made (perhaps based on their time course or laboratory data) that an organic or medical factor has a role in the etiology of the syndrome. The DSM-5 suggests that prominent cognitive abnormalities may be accompanying factors and therefore are useful in making the diagnosis. Consideration should be given to obtaining laboratory data to assist in detection of electrolyte or endocrine imbalances or the presence of nutritional deficiencies. Clinical experience suggests that pharmacotherapy is more advantageous than psychotherapy alone in the treatment of depression that is caused by medical factors, particularly if the dosages of the causative agent(s) (i.e., steroids, antibiotics, or other medications) cannot be decreased or discontinued. 
To make a diagnosis of depression, the clinician confirms that these symptoms have lasted at least 2 weeks and are present on most days. The diagnosis of depression in people with cancer can be difficult because of the problems inherent in distinguishing biological or physical symptoms of depression from symptoms of illness or toxic side effects of treatment. This is particularly true of individuals who are receiving active treatment or those with advanced disease.
The following cognitive symptoms are probably the most useful in diagnosing depression in people with cancer:
One German study comparing cancer patients who had a current affective disorder with those who had a single depressive symptom found loss of interest, followed by depressed mood, to yield the highest power of discrimination between the two groups on multivariate analysis. 
The evaluation of depression in people with cancer also includes:
More than 90% of patients indicate that they prefer to discuss emotional issues with their physician, but more than one-quarter of patients feel that the physician must initiate any discussion of that topic. 
Suicidal ideation, when it occurs, is frightening for the individual, the health professional, and the family. Suicidal statements may range from an offhand comment resulting from frustration or disgust with a treatment course—“If I have to have one more bone marrow aspiration this year, I’ll jump out the window”—to a reflection of significant despair and an emergent situation—“I can no longer bear what this disease is doing to all of us, and I am going to kill myself.” Exploring the seriousness of the thoughts is imperative. If the suicidal thoughts are believed to be serious, it is imperative that a referral to a psychiatrist or psychologist is made immediately and attention is given to the patient’s safety. Refer to the Suicide Risk in Cancer Patients section of this summary for more information about suicide.
The most common form of depressive symptomatology in people with cancer is an adjustment disorder with depressed mood, sometimes referred to as reactive depression. This disorder is manifested when a person has a dysphoric mood that is accompanied by the inability to perform usual activities. [Level of evidence: II] The symptoms appear to be prolonged and in excess of a normal and expected reaction but do not meet the criteria for a major depressive episode. When these symptoms significantly interfere with a person's daily functioning, such as attending to work or school activities, shopping, or caring for a household, they are treated in the same way that major depression is treated (i.e., with crisis intervention, supportive psychotherapy, and medication, especially with drugs that quickly relieve distressing symptoms). Basing the diagnosis on these symptoms can be problematic when the individual has advanced disease and the illness itself is undermining functioning.
It is also important to distinguish between fatigue and depression, which are often interrelated. The different mechanisms that give rise to these conditions can be treated separately.  In more advanced illness, focusing on despair, guilty thoughts, and a total lack of enjoyment of life is helpful in diagnosing depression. (Refer to the PDQ summary on Adjustment to Cancer: Anxiety and Distress for more information.)
The decision to initiate therapy for depression depends on the probability that the patient will recover spontaneously in the next 2 to 4 weeks, the degree of functional impairment, and the severity and duration of the depressive symptoms.  It is important to assess the nature of emotional distress and factors contributing to the depression symptomatology (e.g., psychosocial factors, demoralization, and comorbid symptoms such as pain or fatigue). Decisions about interventions depend on the severity of depression and on factors driving depression symptomatology.  Studies have shown that treatment of severe major depression is optimized by a combination of pharmacotherapy and psychotherapy.  Thus, even if a primary care physician or oncologist undertakes the treatment of depressive symptoms pharmacologically, a referral for psychotherapy or supportive counseling should be considered.
For the following reasons, referral of individuals for a psychiatric consultation should be considered:   
There is a dearth of randomized, placebo-controlled trials assessing the risks and benefits of antidepressants in patients with cancer and depression or depressive symptoms. Furthermore, these studies are limited by methodological challenges and a lack of broad representation of children, adolescents, older adults, and minority groups.  However, a systematic review and meta-analysis of the available studies suggest that antidepressants, regardless of their class (e.g., selective serotonin reuptake inhibitors [SSRIs] or tricyclic antidepressants [TCAs]), are more effective than placebo in treating depression in patients with cancer.  Evidence also suggests that the efficacy of antidepressant treatment is related to the presence of clinically significant depression symptomatology,  suggesting that antidepressants be reserved for patients presenting with clinical depression.
A survey of prescribing patterns in outpatient oncology settings over a 2-year period found that antidepressants were prescribed for about 14% of patients.  In a systematic review of newer pharmacotherapies for depression in adults, the response rate for treatment of depression with antidepressants was found to be approximately 54%.  The efficacy of the newer pharmacotherapies is similar to that of older antidepressants for general medical patients, including older adults and those with medical or psychiatric comorbidities.  The rates of dropout due to adverse effects are approximately 11% for newer antidepressants and 16% for older antidepressants. 
Because of the relative paucity of data regarding antidepressant use in oncology settings, there is considerable variability in practice patterns related to prescribing antidepressants for cancer patients. Although studies generally indicate that about 25% of all cancer patients are depressed, one study found that only 16% of cancer patients were receiving antidepressant medication. 
Antidepressants are divided into several classes on the basis of their underlying mechanisms. Most inhibit uptake of neurotransmitters; some also have a direct impact on cell receptors (refer to Table 2).
|SSRIs||• Most commonly used in patients with cancer because of better safety-tolerability profiles than other antidepressants.|
|• Most-common side effects: GI (e.g., nausea, diarrhea, constipation) and sexual dysfunction (e.g., delayed ejaculation, anorgasmia, decreased libido).|
|• Risk of hyponatremia and bleeding.|
|• Risk of serotonin syndrome and risk of serotonin discontinuation syndrome with abrupt discontinuation.|
|Medication||Starting Dose (mg/day)||Maintenance Dose (mg/day)||Comments|
|– Citalopram||10–20||20–40||Minimal drug-drug interactions.|
|Better safety-tolerability profile than other antidepressants.|
|Potential for QTc prolongation (dose increase limited in patients with cardiac issues).|
|– Escitalopram||5–10||10–20||S-enantiomer of citalopram.|
|Minimal drug-drug interactions.|
|Better safety-tolerability profile than other antidepressants.|
|– Fluoxetine||10–20||20–60||Minimal risk of serotonin discontinuation syndrome due to long half-life.|
|Significant inhibitor of CYP2D6.|
|– Fluvoxamine||25–50||100–300||Better anxiolytic properties than other SSRIs.|
|Significant inhibitor of CYP1A2 and CYP3A4.|
|– Paroxetine||10–20||20–60||High risk of serotonin discontinuation syndrome.|
|Modest anticholinergic properties.|
|Significant inhibitor of CYP2D6.|
|– Sertraline||25–50||100–200||Higher risk of GI side effects.|
|Dose-dependent inhibition of CYP2D6.|
|– Vilazodone||10||20–40||Risk of GI side effects.|
|Possibly less risk of sexual dysfunction, but evidence inconclusive.|
|SNRIsb||• Known for positive impact on certain comorbidities, specifically pain syndromes and hot flashes. Commonly used in depressed patients with these comorbidities.|
|• Risk of hypertension and other cardiac issues. Baseline ECG recommended in some cases.|
|• Risk of headaches and excessive sweating.|
|• Risk of GI side effects, hyponatremia and bleeding.|
|• Risk of serotonin syndrome and risk of serotonin discontinuation syndrome with abrupt discontinuation.|
|Medication||Starting Dose (mg/day)||Maintenance Dose (mg/day)||Comments|
|– Desvenlafaxine||50||50–100||Active metabolite of venlafaxine.|
|Minimal drug-drug interactions.|
|Positive impact on hot flashes.|
|– Duloxetine||30||30–60||First-line treatment in patients with comorbid neuropathic pain (in doses as high as 120 mg).|
|Higher risk of GI side effects and hypertension.|
|Risk of hepatotoxicity.|
|– Levomilnacipran||20||40–120||More-potent noradrenergic effects, activating effects.|
|Useful for comorbid cognitive and pain symptoms.|
|Increased risk of cardiovascular side effects, sweating, and urinary hesitancy.|
|– Venlafaxine (IR and XL)||37.5–75||150–225||First-line treatment in patients with comorbid hot flashes.|
|Higher risk of serotonin discontinuation syndrome.|
|Minimal drug-drug interactions.|
|NDRIs||Baseline ECG recommended in some cases.|
|Medication||Starting Dose (mg/day)||Maintenance Dose (mg/day)||Comments|
|– Bupropion (IR, SR, and XL)||100–150 (SR and XL)||150–450||Stimulating effects and lack of sexual dysfunction.|
|Dose-dependent seizure risk (rare), insomnia, headaches, and weight loss.|
|SR and XL commonly used to avoid anxiogenic effects and higher seizure risk associated with IR.|
|Medication||Starting Dose (mg/day)||Maintenance Dose (mg/day)||Comments|
|– Mirtazapine||7.5–15||30–45||Frequently used in cancer patients with comorbid insomnia and cachexia. Known for its antinausea effects.|
|Decreased elimination in elderly.|
|Sedation, weight gain, and dizziness.|
|Risk of hepatotoxicity and neutropenia.|
|– Trazodone||25–50||50–200||Primarily used as adjunct to other antidepressants. Useful for comorbid insomnia and anxiety.|
|Marked sedation and anxiolytic effects.|
|Risk of orthostatic hypotension, dizziness, and priapism (rare).|
|TCAs||• Not commonly used as first-line agents due to high risk of cardiotoxicity and neurotoxicity. Baseline ECG recommended to evaluate for preexisting cardiac conduction abnormalities.|
|• Primarily used as adjunctive treatments at low dosages.|
|• Risk of weight gain and anticholinergic effects such as dry mouth, orthostatic hypotension, dizziness, and sedation.|
|• Useful in patients with comorbid insomnia and/or headaches.|
|• Certain TCAs have known therapeutic plasma concentrations.|
|• Risk of serotonin syndrome and risk of serotonin discontinuation syndrome with abrupt discontinuation.|
|Medication (only most commonly used TCAs included below)||Starting Dose (mg/day)||Maintenance Dose (mg/day)||Comments|
|– Amitriptyline||10–25||150–300||Marked sedation and anticholinergic effects.|
|– Clomipramine||25||100–250||More serotonergic effects, less sedation, and fewer anticholinergic effects than other TCAs.|
|– Desipramine||25–50||100–300||Mild sedation.|
|Minimal anticholinergic effects.|
|– Doxepin||10–25||75–300||Marked sedation and anticholinergic effects.|
|– Imipramine||25–50||75–300||Moderate sedation.|
|– Nortriptyline||10–25||90–150||Mild sedation.|
|Moderate anticholinergic effects.|
|MAOIs||• Primarily used for treatment-refractory depression.|
|• Involvement of psychiatric prescribers and pharmacy consultation strongly recommended because MAOIs carry serious risks of side effects, drug-drug interactions, and drug-food interactions.|
|• Common side effects include orthostatic hypotension, dizziness, anticholinergic side effects, and headaches.|
|• Serious risk of serotonin syndrome and hypertensive crisis.|
|• Low-tyramine diet required.|
|• Medications: phenelzine, selegiline, and tranylcypromine.|
|Psychostimulants as adjunctive treatments to antidepressants||• Used for stimulating/energy-enhancing effects, especially in patients with prominent fatigue symptoms.|
|• Risk of anxiety, agitation, insomnia, anorexia, and psychosis.|
|• Risk of hypertension and arrhythmia (baseline ECG recommended); can lower seizure threshold.|
|• Risk of tolerance, abuse, and dependence liability.|
|• Medications: dextroamphetamine and methylphenidate.|
|Other adjunctive treatments||• Antipsychotic medications.|
|• Buspirone primarily used as adjunct to treat comorbid anxiety symptoms.|
|CYP = cytochrome P450 enzyme; ECG = electrocardiogram; GI = gastrointestinal; IR = immediate release; MAOI = monoamine oxidase inhibitor; NDRI = norepinephrine-dopamine reuptake inhibitor; SNRI = serotonin-norepinephrine reuptake inhibitor; SR = sustained release; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant; XL = extended release.|
|aAll antidepressants carry a boxed warning about the risk of suicidal thinking and behavior, risk of mania, and risk of drug-drug interaction when combined with MAOIs (refer to the MAOIs section of this summary for more information).|
|bRefer to the Serotonin-norepinephrine reuptake inhibitors (SNRIs) section of this summary for more information about side effects associated with SNRIs.|
The following sections describe the major antidepressant classes, their underlying mechanisms of action, their safety/tolerability profiles, and their potential use in cancer patient populations.  
SSRIs block the reabsorption of serotonin (also called 5-hydroxytryptamine or 5-HT) by the presynaptic neurons by blocking the serotonin transporters. This causes more serotonin to be available to bind to the receptors of the postsynaptic neuron. Medications such as citalopram, escitalopram, and paroxetine work primarily by serotonin transporter blockade. Other SSRIs have additional mechanisms underlying their antidepressant effects. For example, fluoxetine binds to a specific serotonin receptor called the 5-HT2c receptor, sertraline blocks dopamine transporters, and vilazodone has partial agonism at the 5-HT1a serotonin receptor. The drugs in this class are similar in terms of their effectiveness and predilection to cause certain side effects (e.g., gastrointestinal [GI] side effects and sexual dysfunction). However, they differ in terms of severity of these side effects and can have additional effects related to their impact on other neurobiological systems (e.g., anticholinergic effects, sedation, or insomnia).
SSRIs generally undergo hepatic metabolism and renal elimination, and differ significantly in terms of their half-lives. The half-life of the specific SSRI depends on the half-lives of the parent compound and the metabolite. The serotonin discontinuation syndrome, a syndrome associated with abrupt discontinuation of SSRIs, is related to the half-life of the SSRI and its active metabolites (refer to the Serotonin discontinuation syndrome section of this summary for more information). The shorter the half-life of the SSRI and its metabolites, the higher the risk of serotonin discontinuation syndrome.
The mixed SNRIs increase levels of both 5-HT and norepinephrine (NE) in the synapse by blocking reuptake of these neurotransmitters by their respective transporters. SNRIs include older agents such as TCAs and newer agents such as venlafaxine, desvenlafaxine, duloxetine, and levomilnacipran. TCAs are converted to secondary amine metabolites by demethylation in the liver. Both the primary amines and their secondary amine metabolites are active compounds. The secondary amine active metabolites of imipramine (desipramine) and amitriptyline (nortriptyline) are much more potent NE reuptake inhibitors.
The newer agents—venlafaxine, desvenlafaxine, duloxetine, and levomilnacipran—differ in their blockade of 5-HT and NE transporters, depending on their affinity for these transporters. Venlafaxine is primarily serotonergic at lower dosages, with mixed 5-HT and NE effects at higher dosages. Duloxetine and desvenlafaxine are known to block both 5-HT and NE transporters at low dosages, while levomilnacipran has the highest noradrenergic effects at lower dosages compared with other SNRIs. These differential 5-HT and NE effects may be associated with differential efficacy and side effect profiles in different patient populations (e.g., serotonergic effects may be more beneficial in the treatment of depression with comorbid anxiety), while noradrenergic effects may be more beneficial in the treatment of depression with atypical features such as hypersomnia, lack of energy, and lack of motivation.
Many of the SNRIs are also known for their positive impact on pain syndromes, including neuropathic pain associated with chemotherapy. Like SSRIs, SNRIs can cause GI and sexual side effects. Other side effects associated with SNRIs result from their anticholinergic and antihistamine properties. These are much more prominent with TCAs than with the newer agents and include sedation, dry mouth, constipation, dizziness (due to orthostatic hypotension), blurred vision, and urinary retention. SNRIs are also associated with increased risk of headaches and excessive sweating.
The precise underlying mechanisms of these side effects remain unknown. Certain SNRIs, primarily TCAs, have established efficacy in the treatment of headaches. Certain newer SNRIs, specifically venlafaxine and desvenlafaxine, are known to treat hot flashes associated with menopausal symptoms. Other side effects of SNRIs include dose-related diastolic hypertension and increased risk of cardiovascular side effects, primarily resulting from their noradrenergic effects.
TCAs are associated with significant cardiotoxicity and neurotoxicity, including risk of seizures. Use of TCAs requires extreme caution because overdoses of even small amounts of these medications can be fatal. These drugs are primarily used as adjuncts in the treatment of refractory depression and in the treatment of comorbidities such as headaches and neuropathy. The newer SNRIs are safer in overdoses and are used much more frequently as primary treatments, especially in the management of depression with comorbidities such as hot flashes and pain syndromes.
A discontinuation syndrome has been associated with stoppage of serotonergic antidepressants, both SSRIs and SNRIs.  This syndrome is particularly associated with abrupt discontinuation of these medications but can occur in certain cases even with gradual taper. The syndrome includes symptoms such as:
The syndrome is generally self-limiting but in rare cases requires medical attention. The treatment may include re-initiation of serotonergic medications at lower dosages, with gradual taper of these medications over a longer period. Gradual tapering of all serotonergic medications, especially medications with short half-lives such as paroxetine, is strongly recommended to avoid discontinuation syndrome. When taper schedules are recommended, it is also critical to consider individual patient factors such as history of discontinuation syndromes.
Serotonin syndrome  can result from a high dose of one serotonergic medication. More frequently, it is caused by inadvertent concomitant use of two or more serotonergic medications (e.g., serotonergic antidepressants with tramadol, fentanyl, triptans, St. John’s wort, or monoamine oxidase inhibitors [MAOIs]). This syndrome may include the following:
Careful review of all medications is recommended before any serotonergic medication is added to a patient’s medication regimen.
Bupropion is the only medication with this mechanism of action. It blocks the dopamine transporter while its primary metabolite, 6-hydroxybupropion, is a potent NE reuptake inhibitor. Bupropion may be more effective in the treatment of atypical depression (i.e., depression with fatigue and hypersomnia). It is a unique alternative to SSRIs and SNRIs for treating persons with depression and cancer, especially when depression is accompanied by fatigue. Unlike serotonergic antidepressants, bupropion is not associated with sexual dysfunction; therefore, it may be useful in treating patients who wish to remain sexually active and those who have experienced sexual dysfunction with other antidepressants.
Bupropion is available in three formulations based on frequency of administration: immediate release (three times daily), sustained release (twice daily), and extended release (once daily). The sustained- and extended-release formulations are used more frequently because of the ease of administration and less risk of certain side effects, such as anxiety and seizures. The risk of seizures with bupropion is low but can be increased substantially by predisposing factors such as history of seizures, head trauma, brain tumor, and eating disorders. Bupropion should be avoided in patients with malignant diseases involving the brain and histories of cranial trauma or seizure disorder,  and it is contraindicated in persons with a history of bulimia. [Level of evidence: II] Other potential side effects with bupropion include anxiety and insomnia.
The antidepressants in this category have multiple pharmacological properties, including combinations of blockade of monoamine transporters and direct receptor agonist or antagonist properties.  
Mirtazapine is an alpha-2 adrenergic receptor antagonist, blocks several serotonin receptors (5-HT2a, 5-HT2c, and 5-HT3), and is a potent H1 histamine receptor antagonist. Its blockade of presynaptic alpha-2 adrenergic receptors causes the release of NE which, in turn, causes the release of 5-HT. This increase in NE and 5-HT and blockade of 5-HT2c and 5-HT3 receptors have been associated with mirtazapine’s antidepressant effects. The potent antihistaminic effects of mirtazapine can cause significant sedation; in addition, its blockade of histaminic and 5-HT2c receptors has been associated with increased appetite/weight gain, and its blockade of 5-HT3 receptors causes mild antiemetic effects. Mirtazapine has minimal risk of drug-drug interactions because it does not have significant impact on cytochrome P450 enzymes. The sedation and increased appetite/weight gain side effects can be beneficial in patients with cancer struggling with insomnia and cachexia.
Mirtazapine is frequently used for cancer patients, specifically for the treatment of depression with comorbid insomnia and weight loss. It is also useful in this patient population because of its minimal risk of drug-drug interactions, mild antiemetic effects, and minimal impact on sexual function. Mirtazapine is associated with agranulocytosis/neutropenia and increased liver enzymes in rare cases. Monitoring of blood counts and liver enzymes is necessary, especially when patients are at risk of these side effects because of comorbid conditions and other cancer treatments. In rare cases, mirtazapine carries the risk of serotonin syndrome (refer to the Serotonin syndrome section of this summary for more information), primarily when taken in combination with other potent serotonergic medications; it is not associated with serotonin discontinuation syndrome.
Trazodone is a 5-HT2a and 5-HT2c receptor antagonist and weak serotonin reuptake inhibitor. It can be very beneficial as an adjunct in the treatment of depression with comorbid insomnia and anxiety. It has potent sedative effects even at low dosages because of its blockade of histamine, 5-HT2c receptors, and alpha-1 receptors. Trazodone is primarily used at low dosages (25–150 mg) to treat insomnia with or without depression/anxiety. Only high dosages (150–600 mg) of trazodone are associated with antidepressant effects. However, such high dosages carry a high risk of side effects, especially risk of significant daytime sedation, dizziness due to orthostatic hypotension, and other cardiovascular risks.
MAOIs increase all three monoamines (dopamine, serotonin, and NE) simultaneously because of their inhibition of MAO enzymes. The older MAOIs cause irreversible inhibition of both MAO-A and MAO-B enzymes. These medications can be highly effective, especially in the treatment of refractory depression and anxiety symptoms. However, MAOIs are primarily used as last resort because of their risk of serious side effects, multiple drug-drug interactions, and the significant dietary restrictions patients must adhere to when using these medications.
Several classes of medications are contraindicated or used with extreme caution with MAOIs because of the risk of serious and even lethal interactions. Such classes include sympathomimetics, anesthetics, other noradrenergic agents, serotonergic agents, and dopaminergic agents. Opioids with serotonergic properties, such as meperidine and methadone, should also be avoided with MAOIs. Patients taking MAOIs must follow strict dietary restrictions to avoid potentially fatal hypertensive crises. Avoidance of foods containing significant amounts of tyramine (e.g., aged cheese and meats) is critical when these medications are taken. The hypertensive crisis with MAOIs is related to the rapid increase in NE levels due to lack of tyramine processing by the MAO enzymes.
Selegiline, a reversible MAOI, is available as a transdermal patch. At low dosages, it is primarily a selective MAO-B inhibitor and therefore does not require dietary restrictions (up to 9-mg doses). Because of selegiline’s transdermal delivery, at higher doses it still bypasses most of the MAO-A enzyme in the gut while inhibiting both MAO-A and MAO-B in the brain needed for antidepressant effects. However, patients receiving high doses are required to follow dietary restrictions because of the potential for inhibition of MAO-A enzyme in the gut. Higher doses carry warnings for drug-drug interactions and other side effects similar to those for older MAOIs.
In patients with cancer, the use of MAOIs is limited to highly refractory cases due to additional cancer and cancer treatment–related risk factors (e.g., cardiovascular comorbidities due to certain cancer treatments and the use of pain medications such as tramadol and methadone). In most cases, MAOIs are prescribed and managed by psychiatric clinicians in this patient population because of the multiple risks noted earlier. At a minimum, significant involvement of psychiatric prescribers is strongly recommended during initiation and management of MAOIs.
A patient may show improvement with the primary antidepressant treatment, but this improvement may be inadequate from a clinical standpoint because of significant residual symptomatology affecting the patient’s well-being and functioning. In such cases, certain augmentation strategies may be helpful.  However, before any augmentation strategies are considered, it is critical to ensure the adequacy of the primary antidepressant, especially in terms of dosing and duration. Selection of the augmentation strategy is driven by residual or comorbid symptomatology. The following sections describe certain augmentation agents and strategies.
Benzodiazepines can be used to effectively treat the anxiety that may be associated with depression. In patients receiving antidepressant medications and benzodiazepines concomitantly, the latter drugs may be discontinued after patients’ depressive symptoms begin to abate; however, both agents can be continued safely if needed. Benzodiazepines cannot be stopped abruptly because withdrawal symptoms with possible seizures may occur. The dose of benzodiazepines is tapered slowly, at a rate of approximately 25% every 3 to 4 days.
Clinical experience suggests that analeptic agents (e.g., methylphenidate and dextroamphetamine) are useful at low doses for patients whose symptoms include depressed mood, apathy, decreased energy, poor concentration, and weakness. [Level of evidence: II] They are usually prescribed at low dosages and as adjuncts to antidepressants. Analeptic agents are particularly useful for patients with advanced cancer who have a limited life expectancy (weeks to a few months). Psychostimulants often demonstrate antifatigue effects within a few days of starting treatment. They can be helpful in countering the sedating effects of opioids.
Adverse effects associated with analeptic agents include neuropsychiatric side effects such as insomnia, mood lability, and even psychotic symptoms. They are also associated with adverse cardiovascular effects and increased risk of seizures. Considering risks and benefits is critical when the use of these medications is being contemplated. These medications, in appropriate cases and when used in optimal dosages, can have a significant positive impact on a patient’s quality of life, especially for those with advanced cancers.
Medical and psychiatric comorbidities (e.g., neuropathy, menopausal symptoms, and trauma symptoms) may play a role in depression severity. Such conditions frequently have a bidirectional interaction with depression, with one exacerbating the other and vice versa. Medications other than antidepressants that can treat medical/psychiatric comorbidities may play a crucial role in the management of depression in patients with psychiatric comorbidities. For example, gabapentin can be used as an adjunct to antidepressants to target comorbid neuropathic pain, menopausal symptoms, and anxiety symptoms.
Evidence from the non-cancer (general psychiatry) literature suggests a role for other medications and medication classes as adjuncts to antidepressants in treatment-refractory cases.  Such medications and medication classes include antipsychotic medications, thyroid hormone, lithium, buspirone, and certain combination strategies for different antidepressant classes. Some of these medications (e.g., antipsychotic medications and lithium) are associated with a significant burden of side effects. Referral and/or extensive involvement of psychiatric clinicians is strongly recommended for treatment-refractory cases, especially if these medications and medication classes are considered as adjuncts.
Several general, cancer-related, and cancer treatment–related factors play an important role in the choice and management of antidepressants in cancer patients.   The general risks-benefits-alternatives principle is even more crucial in the selection of depression treatment for this patient population. Furthermore, full informed consent and patients’ active involvement in decisions about their treatments is critical in the selection and management of depression treatment and for the success of any antidepressant trial.
The predominance or lack of specific symptoms of depression (e.g., fatigue, insomnia, and cognitive difficulties) and related psychiatric comorbidities (e.g., anxiety disorders) play a role in the selection of an antidepressant.  For example, patients with fatigue as the predominant part of their depressive symptomatology may benefit from a trial of bupropion. The side effects of antidepressants may be clinically advantageous in some cases. For example, the sedation and weight gain associated with mirtazapine or certain TCAs may benefit depressed patients with comorbid insomnia and weight loss.
Patients with cancer frequently struggle with multiple physical and psychological adverse effects related to their cancer and cancer treatments. It is critical to select antidepressants to avoid further worsening of their health status, either by addition of side effects due to antidepressants or exacerbation of existing issues. For example, patients with cancer may be struggling with issues concerning their sexual function. Antidepressants exacerbating sexual dysfunction can heighten distress, which can worsen depression. Some patients may struggle with the GI side effects of their cancer and cancer treatments. Certain antidepressants with known risks for significant GI side effects such as nausea and diarrhea (e.g., sertraline and duloxetine) may need to be avoided in these patients.
The presence or absence of certain medical comorbidities can drive antidepressant selection.  For example, medications such as citalopram, which carries a warning about QTc prolongation, or potent noradrenergic antidepressants such as levomilnacipran may need to be avoided in patients with significant cardiovascular comorbidities. In patients with depression with comorbid chemotherapy-related neuropathy, duloxetine may be beneficial because it targets both depression and neuropathic symptoms. Similarly, patients with depression and menopausal symptoms may benefit from a trial of venlafaxine because it is known to treat both.
Antidepressants, even from the same class, can have significant pharmacological differences. They can differ in their absorption; half-lives, including half-lives of their active metabolites; and metabolism via and impact on different cytochrome P450 enzymes. These differences can play an important role, depending on cancer types and cancer treatments.
Consideration of pharmacodynamic and pharmacokinetic interactions with concomitant medical and psychiatric medications is critical when an antidepressant is being contemplated. For example, highly sedating antidepressants, such as mirtazapine, are not desirable in combination with sedating concomitant medications, such as opioids and benzodiazepines. Potent 2D6 cytochrome P450 enzyme inhibitors, such as paroxetine and duloxetine, are not recommended for patients receiving tamoxifen because of concerns about their impact on the efficacy of tamoxifen (because of the inhibition of tamoxifen’s conversion to endoxifen, its active metabolite).
Information collected from patients and family members about experience with antidepressants (i.e., positive responses or negative experiences such as side effects) can be crucial in the selection of an antidepressant. Genetic background (e.g., serotonin transporter polymorphism) shared by the patient and biological family members may play a role in responsiveness to specific medications or medication classes. Information about successful or failed antidepressants for biological family members can play an important role in antidepressant selection.
The availability of antidepressant formulations may play a crucial role in antidepressant selection for certain patient populations with cancer. For example, patients with head and neck cancers may have difficulty swallowing because of the disease, its treatment, or both. In such cases, the use of antidepressants in liquid form (e.g., citalopram and fluoxetine) or parenteral form (e.g., amitriptyline injection) may be necessary.
Certain cancers can affect medication absorption (e.g., GI cancers) or metabolism (e.g., liver and kidney cancers). Antidepressant selection may therefore be driven by the pharmacokinetic profile of individual antidepressants to circumvent any issues. In some cases, antidepressant dosages may need to be adjusted beyond recommended guidelines to derive maximum therapeutic benefit.
Generally, there is a long latency period (3–6 weeks) from initiation of antidepressant medications to the onset of a therapeutic response.  Antidepressant treatment begins at low doses, followed by a period of gradual dose titration to achieve an optimum individualized response. Initial low doses may help to avoid initial side effects, but dose escalation may be required to produce therapeutic effects. For some agents, there is a therapeutic window during which plasma concentrations correlate with a patient’s response to the antidepressant (e.g., nortriptyline). For patients receiving these agents, serial drug concentration monitoring guides therapy and helps provide an adequate therapeutic trial because plasma concentrations lower and higher than the defined therapeutic ranges are associated with treatment failure, suboptimal responses and, in the case of high drug concentrations, unnecessary toxicity.
It is recommended that an antidepressant be continued for at least 1 year for a major depressive episode. Continuation of an antidepressant beyond 1 year depends on several factors, including a patient’s psychological status at that time, their psychiatric history, their cancer and cancer treatment status and, more important, their thoughts about and experience with the antidepressant. As in the initiation, decisions are individualized according to the risks-benefits-alternatives principle and patient choice.
Switching from one antidepressant to another or discontinuing antidepressants is frequently indicated because of intolerable adverse effects or lack of treatment response. Several factors play a role in the strategies employed during switching or stopping an antidepressant. These factors are primarily driven by the risk of serotonin syndrome (refer to the Serotonin syndrome section of this summary for more information) and serotonin discontinuation syndrome (refer to the Serotonin discontinuation syndrome section of this summary for more information). Such factors include antidepressant-dependent factors and patient- or illness-related factors:  
Generally, when antidepressants are switched, either (1) discontinuing one antidepressant followed by initiating the new one or (2) gradual cross-tapering between the two antidepressants is recommended. However, given the lack of controlled evidence, the switching strategy is highly individualized and driven by the pharmacological properties of both antidepressants and specific patient- and illness-related factors.  There are differing opinions about the exact duration and schedule of dose titration because of the lack of evidence from controlled trials in this area. 
Switching from a serotonergic antidepressant with a longer half-life (or one that has an active metabolite with a longer half-life, e.g., fluoxetine) to another serotonergic antidepressant may carry the risk of developing serotonin syndrome, depending on when one medication is stopped and the second one is started. (Refer to the Serotonin syndrome section of this summary for more information.) The risk of serotonin syndrome in these cases will also depend on the doses of both medications and the schedule of cross-taper. 
For the discontinuation of serotonergic antidepressants, it is strongly recommended that antidepressants be tapered gradually to minimize the risk of serotonin discontinuation syndrome. (Refer to the Serotonin discontinuation syndrome section of this summary for more information.)
As with switching antidepressants, specific medication-related factors and patient- or illness-related factors need to be considered when patients are tapered off antidepressants, but the precise taper strategy is highly individualized. The half-life of antidepressants is a critical factor in stopping antidepressants. Generally, the shorter the half-life of an antidepressant, the higher the risk of discontinuation syndrome. (Refer to Table 3 for a list of antidepressants and the risk of serotonin discontinuation syndrome.)
|Fluoxetine||+||Very long half-life; generally, no taper required|
|Desvenlafaxine||+||~2% risk; no taper required for most patients|
|Clomipramine||++||Most serotonergic TCA|
|Bupropion||+||Minimal to no risk|
|Mirtazapine||+||Minimal to no risk|
|Trazodone||++||Doses <150 mg/d carry minimal to no risk|
|MAOI = monoamine oxidase inhibitor; SNRI = serotonin-norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant; + = low risk; ++ = moderate risk; +++ = high risk.|
|aRisk based on half-life of antidepressant.|
Educating patients about what to expect, close clinical monitoring, and frequent reassurance are crucial during the switching or discontinuing of antidepressants. Consultation with pharmacy or psychiatric services is generally recommended for switching or stopping. In a minority of cases, despite gradual tapering, patients may experience severe withdrawal symptoms, sometimes lasting several weeks. In such cases, immediate consultation with psychiatric services is strongly recommended.
Most antidepressant prescribing is directed at the treatment of an existing depressive disorder or significant depressive symptoms. However, one study supports the use of antidepressants to prevent depression in patients receiving high-dose interferon for adjuvant therapy of malignant melanoma. [Level of evidence: I] The rationale for this approach is that treatment with high-dose interferon is associated with a particularly high rate of depression in this patient population, and proinflammatory cytokines implicated in the biological changes that result in depression may be directly reduced by antidepressants.
In a double-blind study of patients receiving high-dose interferon, 2 of 18 patients in the paroxetine group developed depression during the first 12 weeks of therapy, compared with 9 of 20 patients in the placebo group (relative risk [RR] = 0.24; 95% confidence interval [CI], 0.08–0.93). Moreover, there were significantly fewer treatment discontinuations in the paroxetine group (5% vs. 35%, RR = 0.14; 95% CI, 0.05–0.85).  Further study is required to confirm these findings and to determine whether prophylactic use of antidepressants has benefit in other treatment settings.
Over the past few years, significant concerns have been raised about the risk of suicidal thinking and behavior with the use of antidepressants in children, adolescents, and young adults. In October 2004, the FDA mandated pharmaceutical companies to add a boxed warning to the labeling of all antidepressants suggesting increased risk of suicidality in pediatric patients who were taking antidepressants. The FDA revised this boxed warning in May 2007 to include young adults younger than 25 years.  The new, carefully worded warning emphasizes that the risk of suicidality is associated with both antidepressants and depression. In addition to raising concerns about increased suicidality in children, adolescents, and young adults, the warning acknowledges a significant protective effect of antidepressants in adults aged 65 years and older.
The meta-analysis that led to the initial boxed warning in pediatric patients concluded that the antidepressants are associated with a twofold increase in suicidal ideation and behavior compared with the placebo in children and adolescents.  A major meta-analysis published in the Journal of the American Medical Association re-analyzed the data from the child and adolescent studies (including seven studies not included in the initial meta-analysis), using a random-effects model. [Level of evidence: I] While this re-analysis found an overall increased risk of suicidal ideation/suicidal behavior consistent with the initial meta-analysis, the pooled risk differences were found to be smaller and statistically insignificant.
Concerns have been raised that the unintended consequence of the warnings will be overly restricted use of antidepressants among those who benefit the most and, hence, an increase in suicidality that the warning seeks to prevent.
In summary, the risks-benefits-alternatives principle favors appropriate use of antidepressants with careful monitoring for suicidality. None of the studies that led to the boxed warning included or focused on patients being treated for cancer. Clinical experience and results of small clinical trials suggest that antidepressants can be safely administered to adult cancer patients, although there are no large controlled clinical trials to support this position. When antidepressants are prescribed for patients with cancer, implementation of a careful monitoring plan should be considered by individuals with expertise, and consultation referral made for patients who do not respond as anticipated or who present other concerns.
Traditionally, depressive symptomatology was managed with insight-oriented psychotherapy, which is quite useful for some people with cancer. For many other people, these symptoms are best managed with some combination of crisis intervention, brief supportive psychotherapy, and cognitive-behavioral techniques.
Psychotherapy for depression has been offered in a variety of forms. Most interventions have been time limited (range, 4–30 hours), have been offered in both individual and small-group formats, and have included a structured educational component about cancer or a specific relaxation component. 
Cognitive-behavioral psychotherapy has been one of the most prominent types of therapies studied. Cognitive-behavioral interventions focus on the following:
Understanding and altering one’s thoughts can change emotional reactions and accompanying behaviors. For example, frequent, intrusive, uncontrollable thoughts about loss, life changes, or death can cause poor concentration and precipitate feelings of sadness, guilt, and worthlessness. In turn, these feelings can result in increased sleep, withdrawal, and isolation. A cognitive-behavioral intervention focuses on the intrusive thoughts, often challenging their accuracy or rationality and noting specific patterns of cognitive distortions. Simultaneously, patients develop specific cognitive coping strategies that are designed to alter emotional reactions and accompanying behaviors. The result is improved coping, enhanced adjustment, and better overall quality of life.
Other goals of psychotherapy include: [Level of evidence: II];   [Level of evidence: I] 
Consultation with a cleric or a member of a pastoral care department may also help some individuals.
Specific goals of these therapies include the following:
Cancer support groups can be useful adjunctive therapies in the treatment of cancer patients.  [Level of evidence: II] Support group interventions have demonstrated significant effects on mood disturbance, use of positive coping strategies, improvement in quality of life, and positive immune responses.  [Level of evidence: I]  Support groups can be found through the Cancer Support Community, the American Cancer Society, and many other community resources, including the social work departments of medical centers and hospitals.
Psychotherapy as a treatment for depression in the general adult mental health population has been extensively researched and found to be effective.  Reviews have also concluded that psychotherapy is an effective intervention for cancer patients experiencing depression. [Level of evidence: II]  In studies designed to prevent the occurrence of depression (i.e., patients not selected because of their depressive symptoms), intervention effects are positive, though small to moderate effect sizes have been reported (effect size range, 0.19–0.54).  However, in those studies in which patients were intentionally selected because they exhibited depressive symptoms, intervention effects were strong (effect size, 0.94).  An effect size of 0.94 indicates that the average patient in the treatment group was advantaged, compared with approximately 82% of patients in the control group.
One well-designed randomized clinical trial of a cognitive-behavioral intervention for depressed cancer patients investigated the effect of problem-solving training on symptoms of depression. [Level of evidence: I] The intervention consisted of 10 1.5-hour weekly individual psychotherapy sessions focused on training to become an effective problem solver. Problem-solving tasks were emphasized, including skills in (a) better defining and formulating the nature of problems, (b) generating a wide range of alternative solutions, (c) systematically evaluating consequences of a solution while deciding on an optimal one, and (d) evaluating outcome after solution implementation. Between-session homework with tasks relevant to each step was assigned, and patients were provided with a written manual and encouraged to refer to it as problems arose. One hundred thirty-two adult cancer patients were randomly assigned to the problem-solving treatment or a wait-list control. Overall results showed both improved problem-solving abilities and clinically significant decreases in symptoms of depression.
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
Epidemiological studies conducted across several countries indicate that cancer is a risk factor for suicide.      One retrospective cohort study (N = 3,594,750) found that patients with cancer had nearly twice the incidence of suicide as did the general population.  Increased rates of suicidal ideation, suicidal behaviors, and suicide attempts have been documented in patients with cancer compared with the general population.    The actual incidence of suicide in cancer patients is probably underestimated because there may be reluctance to report death by suicide in these circumstances and because of methodological issues related to the validity of suicide statistics. 
Certain clinical and sociodemographic risk factors for suicide have been identified in patients with cancer.   As in the general population, suicide risk is higher in male patients with cancer than in female patients.   Older age is another significant risk factor. One group of investigators found that suicide risk increased with age and that older men were at the highest risk.  This study found that the age-adjusted suicide rate was 52.4 per 100,000 person-years among patients aged 80 to 84 years, compared with 22.0 for the same age group in the general population. Notably, the suicide rate for men with cancer in this age group was substantially higher (100.3 per 100,000 person-years) than the suicide rate for women. Race and marital status also play an important role. Single, divorced, or widowed white men carry higher suicide risk than do other patient populations. 
Another consistent risk factor is related to the time since diagnosis. Studies have consistently found higher risk of suicide in the first year after diagnosis, especially in the first 3 to 5 months.    Generally, this risk declines over time. However, for certain cancer types, there is evidence of increased long-term suicide risk many years after the diagnosis.  Certain cancer types have been associated with higher suicide risk, including head and neck cancer, bladder cancer, pancreatic cancer, lung cancer, cancers of the upper digestive tract, brain cancer, and cervical cancer.    Other risk factors include nonlocalized disease and aggressive or advanced cancer with a survival rate of fewer than 5 years.  Certain comorbidities have been associated with higher suicide risk, including substance use; cancer-related pain; and comorbid psychiatric illness, specifically depression and anxiety.  
In a study of Japanese patients (n = 220) who had cancer and who were diagnosed with major depression after being referred for psychiatric consultation, approximately 50% reported suicidal ideation. In a retrospective analysis of predictors of suicidal ideation, researchers found that those with more symptoms of major depression and poorer physical functioning were significantly more likely to report suicidal ideation. 
Risk factors for suicide in the cancer population are as follows: 
Suicide assessment occurs frequently along the cancer continuum. Components of suicide assessment include evaluation of risk factors, patient’s mental state, social context, and nonverbal signs of extreme distress or depression (such as poor eye contact, agitation, or excessive slowing).    Hopelessness is a powerful predictor of suicidal ideation and completed suicides in the general population and in cancer patients.  Certain suicide screening tools such as the Beck Hopelessness Scale, the Suicide Intent Scale, and the Columbia-Suicide Severity Rating Scale are used to screen for suicide risk in the general population and in patients with mental illness.  However, these tools are not validated for cancer patients. 
Other complicating factors in suicide assessment include the demoralization syndrome and desire for hastened death.   The concept of demoralization syndrome involves persistent inability to cope with feelings of hopelessness, helplessness, and loss of meaning of life.  Demoralization syndrome can be assessed using the Demoralization Scale.  Evidence suggests that demoralization syndrome can be present with or without depression symptomatology in cancer patients.  A study conducted in Taiwanese patients (n = 200) found that demoralization was more predictive of suicidal ideation than was depression symptomatology.  The study found that the loss of meaning was a critical factor in the effect of demoralization on suicidal ideation.
The relationships between suicidal ideation and the desire for hastened death, requests for physician-assisted suicide (refer to the Requests for Hastened Death section in the PDQ summary on Last Days of Life for more information), and/or euthanasia are complex and poorly understood.   The desire for hastened death involves a hope for death to come quickly. Such a desire can be psychopathological, as an expression of despair with an exit plan (idea of suicide); a socially driven desire to not be a burden to family or friends;  or a healthy process of closure, i.e., a manifestation of letting go. 
Patients who are found to be suicidal require careful further assessment (refer to Table 4). The risk of suicide increases if the patient reports ideation (i.e., thoughts of suicide) plus a plan (i.e., description of the means). Risk continues to increase to the extent that the plan is lethal.  Lethality is determined by an assessment of how likely death would follow, if the reported plan were carried out.
Factors to consider in assessing lethality include:
For the cancer patient reporting suicidal ideation, it is essential to determine whether the underlying cause is a depressive illness, a desire for hastened death, or an expression of the desire to have ultimate control over intolerable symptoms.  Prompt identification and treatment of major depression is essential in lowering the risk of suicide in cancer patients. Risk factors, particularly hopelessness (which is an even stronger predictive factor for suicidal ideation and completed suicides than is depression), requires careful assessment.  The assessment of hopelessness is not straightforward in the patient with advanced disease with no hope of cure. It is important to assess the underlying reasons for hopelessness, which may be related to poor symptom management, fears of painful death, or feelings of abandonment. 
Establishing rapport is of prime importance in working with suicidal cancer patients as it serves as the foundation for other interventions. The clinician must believe that talking about suicide will not cause the patient to attempt suicide. On the contrary, talking about suicide legitimizes this concern and permits patients to describe their feelings and fears, providing a sense of control.   A supportive therapeutic relationship is maintained, which conveys the attitude that much can be done to alleviate emotional and physical pain. (Refer to the PDQ summary on Cancer Pain for more information.)
A crisis intervention–oriented psychotherapeutic approach that mobilizes as much of a patient’s support system as possible is initiated.  Contributing symptoms (e.g., pain) are aggressively controlled and depression, psychosis, agitation, and underlying causes of delirium are treated.   These problems are most frequently managed in the medical hospital or at home. Although uncommon, psychiatric hospitalization can be helpful when there is a clear indication and the patient is medically stable. 
|Most people with cancer have passing thoughts about suicide such as, “I might do something if it gets bad enough.”||Acknowledge normality by opening with a statement recognizing that a discussion does not enhance risk|
|Have you ever had thoughts like that? Any thoughts of not wanting to live or wishing your illness might hasten your death?||Level of risk|
|Do you have thoughts of suicide? Have you thought about how you would do it? Do you intend to harm yourself?||Level of risk|
|Have you ever been depressed or made a suicide attempt?||History|
|Have you ever been treated for other psychiatric problems or have you been psychiatrically hospitalized before getting diagnosed with cancer?||History|
|Have you had a problem with alcohol or drugs?||Substance abuse|
|Have you lost anyone close to you recently? (Family, friends, others with cancer.)||Bereavement|
|aAdapted from Roth et al. |
In clinical practice, the goal of management of suicidal patients is to attempt to prevent suicide that is driven by desperation due to poorly controlled symptoms. Prolonged suffering due to poorly controlled symptoms can lead to such desperation. Thus, effective symptom management is critical to decrease psychological distress in suicidal cancer patients.   Patients close to the end of life may be unable to maintain a wakeful state without high levels of emotional or physical pain. This frequently leads to suicidal thoughts or requests for aid in dying. Such patients may require sedation to ease their distress.
At times, it may be important to limit access to potentially lethal medications for patients considered at risk of suicide. When potentially lethal medications are limited, it is important to weigh the impact on symptom management against the impact on suicide risk because poorly controlled symptoms may contribute to risk. Furthermore, suicidal patients will often have other means available to complete suicide attempts and these must also be evaluated. Strategies to lessen suicidal risk include frequent contact to reassess suicidal risk and symptom control, as well as regular delivery of limited quantities of medications facilitating rapid dose titration for effective management of poorly controlled symptoms when necessary. For patients receiving parenteral or intrathecal opioids, programmable pumps with limited access to programming and locked, inaccessible cartridges may provide an element of safety.
Strategies to lessen suicide risk in cancer patients include the following:
Information concerning the incidence of depression in healthy children is limited. One study of children seen in a general practice showed that 38% had problems that required major intervention by a psychiatrist. Another study of children aged 7 to 12 years showed a 1.9% incidence of depression. If applied to the general population of the United States, these results show that 40,000 12-year-olds are depressed. Teachers have estimated that as many as 10% to 15% of their students are depressed. The Joint Commission on Mental Health of Children states that 1.4 million children younger than 18 years need immediate help for disorders such as depression; only one-third of these children receive help for their disorder. 
Most children cope with the emotional upheaval related to cancer and demonstrate not only evidence of adaptation but positive psychosocial growth and development. A minority of children, however, develops the following psychological problems: 
These children require referral to and intervention by a mental health specialist.
In one of the first studies of depression in childhood cancer, 114 children and adolescents were studied, and 59% were found to have mild psychiatric problems.  A study of 17 adolescent and 21 pediatric oncology patients, all of whom were administered a self-report psychosocial life events inventory, showed that the adolescent samples had a mean level of depressive symptoms similar to that of the general population. The pediatric oncology sample demonstrated significantly lower depressive symptoms than the general population. [Level of evidence: II] Forty-one adolescent survivors of childhood cancer were assessed using questionnaires and interviews to determine the psychosocial status of the survivors; most survivors were functioning well, and depression was rare. 
A study of long-term cancer survivors and their mothers, comparing the survivors with a group of 92 healthy children, showed that most former patients were functioning within normal limits. Not surprisingly, children with severe late effects had more depressive symptoms. [Level of evidence: II] One researcher looked at the characteristics of psychiatric consultations in a pediatric cancer center and found that adjustment disorder was the chief psychosocial diagnosis. This finding is similar to results obtained from studies of adult cancer patients. This study also found that anxiety reactions were more common in the younger pediatric patients, and depressive disorders were more common in older patients.  In a study conducted in 1988 with a sample of 30 adolescent cancer patients, the rate of major depression was not higher than the rate for the population at large. [Level of evidence: II] One review reported a 17% incidence of depression using the criteria of the Diagnostic and Statistical Manual of Mental Disorders, 3rd edition. 
Most cancer survivors demonstrate general resiliency and successful psychological adjustment to the disease and its treatment. Despite evidence for successful adaptation, most studies document psychological difficulties in a significant subset of cancer survivors.
The term depression refers to a symptom, a syndrome, a set of psychological responses, or an illness.  Duration and intensity of the behavioral manifestation (e.g., sadness) differentiates the symptoms from the disorder. For example, a sad affect can be a child’s response to trauma and is usually of short duration; however, a depressive illness is characterized by long duration, and is associated with insomnia, irritability, changes in eating habits, and severe impairment of the child’s scholastic and social adjustment. Depression should be considered whenever any behavior problem persists. Depression does not refer to transitory moments of sadness, but rather to a disorder that affects development and interferes with realization of the child’s innate potential. 
Some manifestations of depression in a school-aged child include the following: 
Differentiating these symptoms from behavioral responses to normal developmental stages is important.
Assessment of depression includes determination of the child’s: 
A comprehensive assessment for childhood depression is the basis for accurate diagnosis and treatment. Evaluation of the child and family situation focuses on the pediatric health history, behaviors observed by the practitioner or reported by others (e.g., parents and teachers), interviews with the child, and judicial use of tests such as the Beck Depression Inventory or the Child Behavior Checklist. 
In discussing the diagnosis of childhood depression, experts stress the importance of understanding childhood depression as an entity distinct from depression in adults because developmental issues in childhood are distinctly different from those of adulthood. 
A model of childhood affective disorders uses the following explicit criteria: 
Treatment regimens implemented for childhood depression reflect theoretical models, etiology, and manifestations of the disorder.  Individual and group psychotherapy are commonly utilized as the primary treatment modality and are directed at helping the child to master his or her difficulties and to enable the child to develop in an optimal manner. Play therapy may be used as a means of exploring a younger child’s view of himself or herself, the disease, and its treatment. The child needs to be helped from the beginning to explore and understand, at a level appropriate for his or her developmental age, the diagnosis of cancer and the treatments involved. 
As is the case with depression in adult cancer patients, there are few, if any, revealing trials of antidepressants in children with cancer. One author described rapid clinical response to low doses (<2 mg/kg/d) of imipramine or amitriptyline for eight depressed children with cancer. [Level of evidence: III] Another author described the use of benzodiazepines such as lorazepam, diazepam, alprazolam, and clonazepam for the treatment of anxiety disorders. Trials of benzodiazepines are short term. These drugs are tapered slowly when they are discontinued. 
The combined use of tricyclic antidepressants and neuroleptics in the management of three children with severe symptoms of depression and anxiety has been reported. The children studied were in the terminal phases of their disease and were treated with a combination of low-dose amitriptyline and haloperidol. Levels of anxiety and depression were decreased, and this intervention allowed the patients and their families to deal with issues involved in death and dying. [Level of evidence: III]
Refer to the subsection on Depression and Suicide in the PDQ summary on Pediatric Supportive Care for information on pediatric considerations for suicidality and cautions about the use of selective serotonin reuptake inhibitors.
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Added Switching or discontinuing antidepressants as a new subsection.
This summary is written and maintained by the PDQ Supportive and Palliative Care Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about cancer-related depression and suicide risk in both the adult and the pediatric population. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
This summary is reviewed regularly and updated as necessary by the PDQ Supportive and Palliative Care Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Depression are:
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Supportive and Palliative Care Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”
The preferred citation for this PDQ summary is:
PDQ® Supportive and Palliative Care Editorial Board. PDQ Depression. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/about-cancer/coping/feelings/depression-hp-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389407]
Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.
The information in these summaries should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.
More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.
Date last modified: 2017-11-02
The following organisations have financed parts of our PhD research project on improving the quality of online cancer information.
This site does not accept advertisements.
|Back to the Cancer.gov