Purpose of This PDQ Summary
Overview
Assessment and Diagnosis

Symptoms and Risk Factors Screening and Assessment for Depression         Clinical interview Diagnosis

Intervention

Pharmacologic Intervention         Overview         Suicide risk of antidepressant medication         Interferon-related depression         Antidepressant medication selection         Selective serotonin reuptake inhibitors         Discontinuation of antidepressants         Side effects         Drug-drug interactions         Atypical antidepressants         Benzodiazepines         Psychostimulants         Monoamine oxidase inhibitors         St. John's wort         Antidepressant effects Psychotherapy         Overview         Empirical studies of the efficacy of psychotherapy

Suicide Risk in Cancer Patients

Demographics and Statistics Etiology/Pathophysiology

Assessment, Evaluation, and Management of Suicidal Patients

Assessment Management Effect on Family and Health Care Providers Assisted Dying, Euthanasia, Decisions Regarding End of Life

Pediatric Considerations for Depression

Assessment and Diagnosis of Pediatric Depression         Assessment         Diagnosis Management of Pediatric Depression         Pharmacologic management

Pediatric Considerations for Suicidality

Incidence Etiology/Assessment Management Pharmacologic Management

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Changes to This Summary (12/19/2008)
Questions or Comments About This Summary
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Purpose of This PDQ Summary

This PDQ cancer information summary provides comprehensive, peer-reviewed information for health professionals about cancer-related depression and suicide risk in both the adult and the pediatric population. This summary is reviewed regularly and updated as necessary by the PDQ Supportive and Palliative Care Editorial Board.

Information about the following is included in this summary:

• Assessment.
• Diagnosis.
• Management.

This summary is intended as a resource to inform and assist clinicians and other health professionals who care for cancer patients during and after cancer treatment. It does not provide formal guidelines or recommendations for making health care decisions. Information in this summary should not be used as a basis for reimbursement determinations.

This summary is also available in a patient version, which is written in less technical language, and in Spanish.

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Overview

Depression is a comorbid disabling syndrome that affects approximately 15% to 25% of cancer patients.[1-4] Depression is believed to affect men and women with cancer equally, and gender-related differences in prevalence and severity have not been adequately evaluated.[5] 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. 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.[6] 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 normal samples, while there was an increased incidence of Hospital Anxiety and Depression Scale–defined depression among women.[7]

There are many myths about cancer and how people cope with it, such as the following:

• All people with cancer are depressed.
• Depression in a person with cancer is normal.
• Treatments are not helpful.
• Everyone with cancer faces suffering and a painful death.

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 consensus panel review article describes details regarding this important distinction and illustrates the major points using case vignettes.[8] 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.[9] Some people may have more difficulty adjusting to the diagnosis of cancer than others and will vary in their responses to the diagnosis. Major depression is not simply sadness or a blue mood. Major depression affects approximately 25% of patients and has recognizable symptoms that can and should be diagnosed and treated because they have an impact on quality of life.[10,11] 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.[12] 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 (PRIME-MD). 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 disorder were significantly younger than the other participants (P = .002), had lower performance status (P = .017), had smaller social networks (P = .008), and participated less in organized religious services (P = .007). 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.[12] 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. Using specific validated psychometrics (e.g., visual analog scale), investigators evaluated patient “sense of burden to others” and its correlation with physical, psychological, and existential issues. The variables most highly correlated with sense of burden to others included depression (r = 0.460, P < .0001), hopelessness (r = 0.420, P < .0001), and outlook (r = 0.362, P < .0001). In multiple regression analysis, four variables emerged predicting perception of burden to others: depression, hopelessness, level of fatigue, and current quality of life. 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.[13]

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.[8] 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.

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 include maintaining active involvement in daily life; minimizing the disruptions caused by the illness to one's life roles (e.g., spouse, parent, employee); regulating the normal emotional reactions to the illness; and managing feelings of hopelessness, helplessness, worthlessness, and/or guilt.[14]Some studies suggest an association between maladaptive coping styles with higher levels of depression, anxiety, and fatigue symptoms.[15,16] Examples of maladaptive coping behaviors include avoidant or negative coping, negative self-coping statements, preoccupation with physical symptoms, and catastrophizing. 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.[16] 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.[15] 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.[15] Preliminary data suggest a beneficial impact of spirituality on associated depression, as measured by the Functional Assessment of Chronic Illness Therapy—Spiritual Well-Being (FACIT-Sp) and the Hamilton Depression Rating Scale.[17] The following indicators may suggest a need for early intervention: a history of depression, a weak social support system (not married, few friends, a solitary work environment), evidence of persistent irrational beliefs or negativistic thinking regarding the diagnosis, a more serious prognosis, and greater dysfunction related to cancer. 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.[18] 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.[19] Spouses were more likely to experience depressive symptoms if they were older, were less well educated, were more recently married, reported heightened fears over their wife's well-being, worried about their job performance, were more uncertain about their future, or were in less well-adjusted marriages.[19]

Cancer-related depression is not substantially different from depression in other medical conditions, but treatments may need to be adapted or refined for cancer patients.[20] 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.[21] Evidence-based recommendations have been published describing various approaches to the problems of cancer-related fatigue, anorexia, depression, and dyspnea.[22] Even in the absence of any symptoms, many patients express interest in supportive counseling, and clinicians should try to accommodate those patients by a referral to a qualified mental health professional. When symptoms are more intense, longer lasting, or recurrent after apparent resolution, however, treatment to alleviate symptoms is essential.[11,23,24] Anxiety and depression in early treatment are good predictors of these same problems at 6 months.[25] 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.[26]

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 (HPA) axis dysfunction were markedly higher in patients with clinical depression.[27] 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 (VAR) 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.

References

1. Henriksson MM, Isometsä ET, Hietanen PS, et al.: Mental disorders in cancer suicides. J Affect Disord 36 (1-2): 11-20, 1995.  [PUBMED Abstract]
   
   
2. Bodurka-Bevers D, Basen-Engquist K, Carmack CL, et al.: Depression, anxiety, and quality of life in patients with epithelial ovarian cancer. Gynecol Oncol 78 (3 Pt 1): 302-8, 2000.  [PUBMED Abstract]
   
   
3. Lloyd-Williams M, Friedman T: Depression in palliative care patients--a prospective study. Eur J Cancer Care (Engl) 10 (4): 270-4, 2001.  [PUBMED Abstract]
   
   
4. Derogatis LR, Morrow GR, Fetting J, et al.: The prevalence of psychiatric disorders among cancer patients. JAMA 249 (6): 751-7, 1983.  [PUBMED Abstract]
   
   
5. Miaskowski C: Gender differences in pain, fatigue, and depression in patients with cancer. J Natl Cancer Inst Monogr (32): 139-43, 2004.  [PUBMED Abstract]
   
   
6. Watson M, St James-Roberts I, Ashley S, et al.: Factors associated with emotional and behavioural problems among school age children of breast cancer patients. Br J Cancer 94 (1): 43-50, 2006.  [PUBMED Abstract]
   
   
7. Grov EK, Dahl AA, Moum T, et al.: Anxiety, depression, and quality of life in caregivers of patients with cancer in late palliative phase. Ann Oncol 16 (7): 1185-91, 2005.  [PUBMED Abstract]
   
   
8. Block SD: Assessing and managing depression in the terminally ill patient. ACP-ASIM End-of-Life Care Consensus Panel. American College of Physicians - American Society of Internal Medicine. Ann Intern Med 132 (3): 209-18, 2000.  [PUBMED Abstract]
   
   
9. Petersen RW, Quinlivan JA: Preventing anxiety and depression in gynaecological cancer: a randomised controlled trial. BJOG 109 (4): 386-94, 2002.  [PUBMED Abstract]
   
   
10. Massie MJ, Holland JC: The cancer patient with pain: psychiatric complications and their management. Med Clin North Am 71 (2): 243-58, 1987.  [PUBMED Abstract]
    
    
11. Lynch ME: The assessment and prevalence of affective disorders in advanced cancer. J Palliat Care 11 (1): 10-8, 1995 Spring.  [PUBMED Abstract]
    
    
12. Wilson KG, Chochinov HM, Skirko MG, et al.: Depression and anxiety disorders in palliative cancer care. J Pain Symptom Manage 33 (2): 118-29, 2007.  [PUBMED Abstract]
    
    
13. Chochinov HM, Kristjanson LJ, Hack TF, et al.: Burden to others and the terminally ill. J Pain Symptom Manage 34 (5): 463-71, 2007.  [PUBMED Abstract]
    
    
14. Spencer SM, Carver CS, Price AA: Psychological and social factors in adaptation. In: Holland JC, Breitbart W, Jacobsen PB, et al., eds.: Psycho-oncology. New York, NY: Oxford University Press, 1998, pp 211-22. 
    
    
15. Reddick BK, Nanda JP, Campbell L, et al.: Examining the influence of coping with pain on depression, anxiety, and fatigue among women with breast cancer. J Psychosoc Oncol 23 (2-3): 137-57, 2005.  [PUBMED Abstract]
    
    
16. Beresford TP, Alfers J, Mangum L, et al.: Cancer survival probability as a function of ego defense (adaptive) mechanisms versus depressive symptoms. Psychosomatics 47 (3): 247-53, 2006 May-Jun.  [PUBMED Abstract]
    
    
17. Nelson CJ, Rosenfeld B, Breitbart W, et al.: Spirituality, religion, and depression in the terminally ill. Psychosomatics 43 (3): 213-20, 2002 May-Jun.  [PUBMED Abstract]
    
    
18. Edwards B, Clarke V: The psychological impact of a cancer diagnosis on families: the influence of family functioning and patients' illness characteristics on depression and anxiety. Psychooncology 13 (8): 562-76, 2004.  [PUBMED Abstract]
    
    
19. Lewis FM, Fletcher KA, Cochrane BB, et al.: Predictors of depressed mood in spouses of women with breast cancer. J Clin Oncol 26 (8): 1289-95, 2008.  [PUBMED Abstract]
    
    
20. Patrick DL, Ferketich SL, Frame PS, et al.: National Institutes of Health State-of-the-Science Conference Statement: Symptom Management in Cancer: Pain, Depression, and Fatigue, July 15-17, 2002. J Natl Cancer Inst 95 (15): 1110-7, 2003.  [PUBMED Abstract]
    
    
21. Meyer TJ, Mark MM: Effects of psychosocial interventions with adult cancer patients: a meta-analysis of randomized experiments. Health Psychol 14 (2): 101-8, 1995.  [PUBMED Abstract]
    
    
22. Dy SM, Lorenz KA, Naeim A, et al.: Evidence-based recommendations for cancer fatigue, anorexia, depression, and dyspnea. J Clin Oncol 26 (23): 3886-95, 2008.  [PUBMED Abstract]
    
    
23. Massie MJ, Holland JC: Overview of normal reactions and prevalence of psychiatric disorders. In: Holland JC, Rowland JH, eds.: Handbook of Psychooncology: Psychological Care of the Patient With Cancer. New York, NY: Oxford University Press, 1989, pp 273-82. 
    
    
24. Massie MJ, Shakin EJ: Management of depression and anxiety in cancer patients. In: Breitbart W, Holland JC, eds.: Psychiatric Aspects of Symptom Management in Cancer Patients. Washington, DC: American Psychiatric Press, 1993, pp 470-91. 
    
    
25. Nordin K, Glimelius B: Predicting delayed anxiety and depression in patients with gastrointestinal cancer. Br J Cancer 79 (3-4): 525-9, 1999.  [PUBMED Abstract]
    
    
26. Goodwin JS, Zhang DD, Ostir GV: Effect of depression on diagnosis, treatment, and survival of older women with breast cancer. J Am Geriatr Soc 52 (1): 106-11, 2004.  [PUBMED Abstract]
    
    
27. Jehn CF, Kuehnhardt D, Bartholomae A, et al.: Biomarkers of depression in cancer patients. Cancer 107 (11): 2723-9, 2006.  [PUBMED Abstract]
    
    

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Assessment and Diagnosis

Symptoms and Risk Factors

The symptoms of major depression are as follows:

• A depressed mood for most of the day and on most days.
• Diminished pleasure or interest in most activities.
• Significant change in appetite and sleep patterns.
• Psychomotor agitation or slowing.
• Fatigue.[1]
• Feelings of worthlessness or excessive, inappropriate guilt.
• Poor concentration.
• Recurrent thoughts of death or suicide.

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 the Suggested Questions For the Assessment of Depressive Symptoms in Adults With Cancer table):

• “Many people find themselves dwelling on thoughts about their cancer. What kinds of thoughts do you have?”



• “Do you find yourself ever thinking I brought this on myself, God is punishing me? How often? Only a few times a week, or all the time? Do you believe these thoughts are true?”



• “In spite of these thoughts, are you still able to go on with your life and find pleasure in things? Or, are you so preoccupied that you can't sleep, or feel hopeless?”

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.

A statement such as the following can then follow these questions:

“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 the patient to seek out someone already known to him or her and to inform him or her of 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.[2] In some instances, referral to a clergy person 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 should include careful assessment of symptoms, treatment effects, laboratory data results, physical status, and mental status. Although the etiology of depression is largely unknown, many risk factors for depression are known (see list below). 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.[3] For patients with head and neck cancer treated with curative intent, 8 pretreatment variables (tumor stage, sex, depressive symptoms, openness to discuss cancer in the family, perceived available support, received emotional support, tumor-related symptoms, and size of the informal social network) can be used to predict which patients are likely to become depressed up to 3 years after treatment.[4,5] 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.[6] Heightened awareness of this facilitates early diagnosis and the use of appropriate interventions.[7] For some cancer populations, such as those status-post stem cell transplantation, preliminary data suggest an association between depressive symptoms and survival. If confirmed, diagnosis and treatment of depression may afford an opportunity to impact mortality as well as quality of life.[8] 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.

Risk Factors for Depression in People With Cancer

• Cancer-related risk factors:
  • Depression at time of cancer diagnosis.[9,10]
  • Poorly controlled pain.[11]
  • Advanced stage of cancer.[11]
  • Increased physical impairment or discomfort.
  • Pancreatic cancer.[12]
  • Being unmarried and having head and neck cancer.[13]
  • Treatment with certain chemotherapeutic agents:
    • Corticosteroids.
    • Procarbazine.
    • L-Asparaginase.
    • Interferon-alfa.[14,3]
    • Interleukin-2.[15,14,3]
    • Amphotericin-B.



• Noncancer-related risk factors:
  • History of depression:
    • Two or more episodes in a lifetime.
    • First episode early or late in life.
  • Lack of family support.[9]
  • Additional concurrent life stressors.[16]
  • Family history of depression or suicide.
  • Previous suicide attempts.
  • History of alcoholism or drug abuse.
  • Concurrent illnesses that produce depressive symptoms (i.e., stroke or myocardial infarction).
  • Past treatment for psychological problems.[17]

Because of the common underrecognition and undertreatment of depression in people with cancer, screening tools can be used to prompt further assessment.[18] 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. In persons with advanced cancer, a single-item interview question has been found to have acceptable psychometric properties and can be useful. One example is to ask “Are you depressed?”[19] Another example is to say, “Please grade your mood during the past week by assigning it a score from 0 to 100, with a score of 100 representing your usual relaxed mood.” A score of 60 is considered a passing grade.[20] Other screening tools that have been used and validated in cancer populations include the Hospital Anxiety and Depression Scale,[21] the Psychological Distress Inventory,[22] and the Edinburgh Depression Scale.[23] The Hospital Anxiety and Depression Scale may have limited utility in certain patient populations such as early-stage breast cancer [24] and palliative care.[25,26] The Brief Symptom Inventory, the Zung Self-Rating Depression Scale, and the Distress Thermometer are commonly used screening tools.[27-29] 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 (PHQ-9) to identify women requiring further assessment to detect clinically significant levels of distress and psychiatric symptoms.[30] A modification of the Distress Thermometer, the Impact Thermometer, to be used in combination with 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.[31] The Mood Evaluation Questionnaire, a cognitive-based screening tool for depression, has moderate correlation with the structured clinical interview for 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.[32]

It is important that screening instruments be validated in cancer populations and used in combination with structured diagnostic interviews.[33] A pilot study of 25 patients used a simple, easily reproduced visual analog scale suggesting the benefits to 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 should be 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.[34,7] Other brief assessment tools for depression can be used. To help patients distinguish normal anxiety reactions from depression, assessment should include discussion about common symptoms experienced by cancer patients. Depression should be reassessed over time.[35] Because of the increased risk of adjustment disorders and major depression in cancer patients, routine screening with increased vigilance at times of increased stress (i.e., diagnosis, recurrences, progression) is recommended. General risk factors for depression are noted in the list above. Other risk factors may pertain to specific populations, i.e., patients with head and neck cancer [4] and women at high risk for the development of breast cancer.[36]

Organic Mood Syndromes or Mood Syndromes Related to Medical Condition (MSRMC), as they are now referred to in the Diagnostic and Statistical Manual for Mental Disorders, 4th Edition (DSM-IV), 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-IV suggests that prominent cognitive abnormalities may be accompanying factors and therefore are useful in making the diagnosis. The DSM-IV also highlights profound apathy as a sign of MSRMC. 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.[38]

Possible Medical Causes of Depressive Symptoms in People With Cancer*

• Uncontrolled pain.[11]
• Metabolic abnormalities:
  • Hypercalcemia.
  • Sodium/potassium imbalance.
  • Anemia.
  • Vitamin B12 or folate deficiency.
  • Fever.
• Endocrine abnormalities:
  • Hyperthyroidism or hypothyroidism.
  • Adrenal insufficiency.
• Medications:[15,39-41,3]
  • Steroids.
  • Endogenous and exogenous cytokines, i.e., interferon-alfa and aldesleukin (interleukin-2, IL-2).[42]
  • Methyldopa.
  • Reserpine.
  • Barbiturates.
  • Propranolol.
  • Some antibiotics (e.g., amphotericin B).
  • Some chemotherapeutic agents (e.g., procarbazine, L-asparaginase).

To make a diagnosis of depression, the clinician should confirm that these symptoms will have lasted a minimum of 2 weeks and are present on most days. The diagnosis of depression in people with cancer can be difficult due to 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. Cognitive symptoms such as guilt, worthlessness, hopelessness, thoughts of suicide, and loss of pleasure in activities 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.[43]

The evaluation of depression in people with cancer should also include a careful assessment of the person's perception of the illness, medical history, personal or family history of depression or thoughts of suicide, current mental status, and physical status, as well as treatment and disease effects, concurrent life stressors, and availability of social supports. It is important to understand that more than 90% of patients indicate that they prefer to discuss emotional issues with their physician, but over one quarter of patients feel that the physician must initiate any discussion of that topic.[44] 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, a referral to a psychiatrist or psychologist should be made immediately and attention should be given to the patient's safety. Additional information on suicide can be found in the Suicide Risk in Cancer Patients section.

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.[45] 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 should be treated in the same way that major depression is treated (i.e., consider using 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.[1] 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 Normal Adjustment and the Adjustment Disorders for further information.)

References

1. Jacobsen PB, Donovan KA, Weitzner MA: Distinguishing fatigue and depression in patients with cancer. Semin Clin Neuropsychiatry 8 (4): 229-40, 2003.  [PUBMED Abstract]
   
   
2. De Leeuw JR, De Graeff A, Ros WJ, et al.: Negative and positive influences of social support on depression in patients with head and neck cancer: a prospective study. Psychooncology 9 (1): 20-8, 2000 Jan-Feb.  [PUBMED Abstract]
   
   
3. Capuron L, Ravaud A, Neveu PJ, et al.: Association between decreased serum tryptophan concentrations and depressive symptoms in cancer patients undergoing cytokine therapy. Mol Psychiatry 7 (5): 468-73, 2002.  [PUBMED Abstract]
   
   
4. de Leeuw JR, de Graeff A, Ros WJ, et al.: Prediction of depression 6 months to 3 years after treatment of head and neck cancer. Head Neck 23 (10): 892-8, 2001.  [PUBMED Abstract]
   
   
5. Paice JA: Managing psychological conditions in palliative care. Am J Nurs 102 (11): 36-42; quiz 43, 2002.  [PUBMED Abstract]
   
   
6. Akechi T, Okuyama T, Sugawara Y, et al.: Major depression, adjustment disorders, and post-traumatic stress disorder in terminally ill cancer patients: associated and predictive factors. J Clin Oncol 22 (10): 1957-65, 2004.  [PUBMED Abstract]
   
   
7. Passik SD, Kirsh KL, Theobald D, et al.: Use of a depression screening tool and a fluoxetine-based algorithm to improve the recognition and treatment of depression in cancer patients. A demonstration project. J Pain Symptom Manage 24 (3): 318-27, 2002.  [PUBMED Abstract]
   
   
8. Loberiza FR Jr, Rizzo JD, Bredeson CN, et al.: Association of depressive syndrome and early deaths among patients after stem-cell transplantation for malignant diseases. J Clin Oncol 20 (8): 2118-26, 2002.  [PUBMED Abstract]
   
   
9. Nordin K, Glimelius B: Predicting delayed anxiety and depression in patients with gastrointestinal cancer. Br J Cancer 79 (3-4): 525-9, 1999.  [PUBMED Abstract]
   
   
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Intervention

Whether 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.[1] Studies have shown that treatment of 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.

Individuals should be referred for a psychiatric consultation for the following reasons:

• A primary care physician or oncologist does not feel competent treating the patient for depression because of specific clinical features in the presentation (i.e., if prominent suicidal tendencies are present).



• The depressive symptoms treated by the primary physician are resistant to pharmacologic interventions after 2 to 4 weeks of intervention.



• The depressive symptoms are worsening rather than improving.



• Initiating treatment with antidepressant drugs, titrating drug doses, or continuing treatment is interrupted or made problematic by adverse effects attributable to the medication.



• The depressive symptoms are interfering with the patient's ability to be cooperative with medical treatment.[2-4]

There is a paucity 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.[5] In certain cases of depression in patients with cancer, antidepressant therapy may be indicated. A survey of prescribing patterns in outpatient oncology settings over a 2-year period found that antidepressants were prescribed for about 14% of patients.[6] 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%.[7] The efficacy of the newer pharmacotherapies is similar to that of older antidepressants for general medical patients, including older adults and those with coexisting medical or psychiatric illness.[7] The dropout rates due to adverse effects are approximately 11% for newer antidepressants and 16% for older antidepressants.[7] Because of the relative paucity of data regarding antidepressant use in oncology settings, there is considerable variability in practice patterns related to prescribing antidepressants in 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.[8]

Antidepressant Studies

• In adults, a double-blind placebo-controlled trial comparing fluoxetine with desipramine in treating depressive symptoms in 40 women with cancer found both medications to be effective and well tolerated. There were greater improvements on several quality-of-life measures in patients who received fluoxetine.[9]



• One study compared paroxetine with amitriptyline in the management of depression in women with breast cancer. Both treatments were equally effective. Paroxetine was associated with significantly fewer anticholinergic adverse effects than amitriptyline.[10]



• In a randomized controlled trial comparing fluoxetine with a placebo, patients receiving fluoxetine were found to have improved quality of life and decreased depressive symptoms.[11] Using a symptom-based approach (similar to the management of other cancer-related symptoms such as pain or nausea), this study assessed for depression by use of a 2-item screening procedure focused on presence of anhedonia (little interest or pleasure in doing things) and depressed or hopeless mood. Most of the sample consisted of patients with mild-to-moderate levels of depressive symptoms regardless of whether they met the diagnostic criteria for depression. Generalization was enhanced by inclusion of a sample of mixed cancer types (e.g., breast, thoracic, genitourinary, gastrointestinal) from a predominantly community cancer care setting, an equal male/female ratio, and a relatively large sample size (n = 163). A subgroup of patients identified as having higher levels of depressive symptoms was most likely to benefit from the treatment.

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. Since 2003, U.S. and European regulators have issued several public health warnings on this topic. The first such advisory issued by the U.S. Food and Drug Administration (FDA) warned about a possible association between antidepressants and suicidal thinking and behavior in children and adolescents. In December 2003, the Medicines and Healthcare Products Regulatory Agency of the United Kingdom issued a letter to doctors advising against the use of antidepressants in anyone younger than 18 years.[12] In October 2004, the FDA mandated pharmaceutical companies to add a “black box” warning to the labeling of all antidepressants suggesting increased risk of suicidality in pediatric patients who were taking antidepressants. The FDA revised this black box warning in May 2007 to include young adults younger than 25 years.[13] 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 sucidality in children, adolescents, and young adults, the warning acknowledges a significant protective effect of antidepressants in adults aged 65 and older. The meta-analysis that led to the initial black box warning in pediatric patients concluded that the antidepressants are associated with a twofold increase in suicidal ideation and behavior compared to the placebo in children and adolescents. A major meta-analysis published in the Journal of the American Medical Association reanalyzed the data from the child and adolescent studies (including seven studies not included in the initial meta-analysis), using a random-effects model. While this reanalysis 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. A study examining U.S. and Dutch data suggests a drop in selective serotonin reuptake inhibitor (SSRI) prescriptions for children and adolescents since the black box warning was issued and a simultaneous increase in suicide rates in this patient population. In summary, the risk-benefit equation favors appropriate use of antidepressants with careful monitoring for suicidality. It is important to note that none of the studies that led to the black box 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, a careful monitoring plan should be implemented by individuals with expertise, and consultation referral should be made for patients who do not respond as anticipated or who present other concerns.

Most antidepressant prescribing is directed at the treatment of an existing depressive disorder or significant depressive symptoms. One study, however, supports the use of antidepressants to prevent depression in patients receiving high-dose interferon for adjuvant therapy of malignant melanoma.[14] 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 this 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.

The choice of antidepressant depends on a patient's medical history and concomitant medical problems, the symptoms referable to depression, previous responses to antidepressant medications, and the side effects associated with the agents available.

The types of medications used to treat depression in patients with cancer include the SSRIs, tricyclic antidepressants (TCAs), and analeptic or CNS stimulant agents (i.e., amphetamines). The following table outlines the commonly used antidepressants and highlights starting dosages used in cancer patients. The Side Effects/Comments column identifies drug-specific side effects that may be clinically advantageous or problematic depending on the clinical situation when selecting antidepressant medications and monitoring patients receiving these drugs. Generally, there is a long latency period (3–6 weeks) from initiation of antidepressant medications until the onset of a therapeutic response. In many cases, 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 in order to see therapeutic effects. For some agents, there is a therapeutic window during which plasma concentrations correlate with a patient's antidepressant response (e.g., nortriptyline). For patients receiving these agents, serial drug concentration monitoring guides therapy and facilitates providing an adequate therapeutic trial, because plasma concentrations less than and greater than the defined therapeutic ranges are associated with treatment failure, suboptimal responses, and in the case of high drug concentrations, unnecessary toxicity.