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. 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 normal samples, 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:
- 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. 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. 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. 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 (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. 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.
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.
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. Some studies suggest an association between maladaptive coping styles with higher levels of depression, anxiety, and fatigue symptoms. 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. 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 (FACIT-Sp) and the Hamilton Depression Rating Scale.
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.
- 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. 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 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.
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 been published describing 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, 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. 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 (HPA) 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.
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.References:
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- 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.
- Lloyd-Williams M, Friedman T: Depression in palliative care patients--a prospective study. Eur J Cancer Care (Engl) 10 (4): 270-4, 2001.
- Derogatis LR, Morrow GR, Fetting J, et al.: The prevalence of psychiatric disorders among cancer patients. JAMA 249 (6): 751-7, 1983.
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- 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.
- 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.
- 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.
- Petersen RW, Quinlivan JA: Preventing anxiety and depression in gynaecological cancer: a randomised controlled trial. BJOG 109 (4): 386-94, 2002.
- Massie MJ, Holland JC: The cancer patient with pain: psychiatric complications and their management. Med Clin North Am 71 (2): 243-58, 1987.
- Lynch ME: The assessment and prevalence of affective disorders in advanced cancer. J Palliat Care 11 (1): 10-8, 1995 Spring.
- 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.
- Chochinov HM, Kristjanson LJ, Hack TF, et al.: Burden to others and the terminally ill. J Pain Symptom Manage 34 (5): 463-71, 2007.
- 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.
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- 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.
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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.
- 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 Table 1):
- "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. 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. For patients with head and neck cancer treated with curative intent, eight 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. 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.
- Cancer-related risk factors:
- Depression at time of cancer diagnosis.
- Poorly controlled pain.
- Advanced stage of cancer.
- Increased physical impairment or discomfort.
- Pancreatic cancer.
- Being unmarried and having head and neck cancer.
- Treatment with certain chemotherapeutic agents:
- 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.
- Additional concurrent life stressors.
- Family history of depression or suicide.
- Previous suicide attempts.
- History of alcoholism or drug abuse.
- Concurrent illnesses that produce depressive symptoms (e.g., stroke or myocardial infarction).
- Past treatment for psychological problems.
- History of depression:
Screening and Assessment for Depression
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:
- A single-item interview. 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?" 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.
- The Hospital Anxiety and Depression Scale. The Hospital Anxiety and Depression Scale may have limited utility in certain patient populations such as early-stage breast cancer and palliative care.
- The Psychological Distress Inventory.
- The Edinburgh Depression Scale.
- The Brief Symptom Inventory.
- The Zung Self-Rating Depression Scale.
- The Distress Thermometer.
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.
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 (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 should undergo a more thorough psychosocial evaluation.
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. 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.
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 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. 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. 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 for the development of breast cancer.
Clinical interviewTable 1. Suggested Questions for the Assessment of Depressive Symptoms in Adults With Cancera QuestionSymptomaAdapted from Roth et al. Depressive symptomsHow well are you coping with your cancer? Well? Poorly?Well-beingHow are your spirits since diagnosis? During treatment? Down? Blue?MoodDo you cry sometimes? How often? Only alone?MoodAre 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?HopelessnessDo you feel you can influence your care, or is your care totally under others' control?HelplessnessDo you worry about being a burden to family/friends during cancer treatment?GuiltDo you feel others might be better off without you? WorthlessnessPhysical 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? FatigueDo 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?InsomniaHow is your appetite? Food tastes good? Weight loss or gain?AppetiteHow is your interest in sex? Extent of sexual activity? LibidoDo you think or move more slowly than usual?Psychomotor slowing
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.
- Uncontrolled pain.[Level of evidence: II]
- Metabolic abnormalities:
- Sodium/potassium imbalance.
- Vitamin B12 or folate deficiency.
- Endocrine abnormalities:
- Hyperthyroidism or hypothyroidism.
- Adrenal insufficiency.
- Medications:[Level of evidence: I];[Level of evidence: II]
- Endogenous and exogenous cytokines, i.e., interferon-alfa and aldesleukin (interleukin-2 [IL-2]).
- 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.
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. 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.[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 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. 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 further information.)References:
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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. 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.
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.
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. 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. 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 coexisting medical or psychiatric illness. The dropout rates 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 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.
- 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.[Level of evidence: I]
- 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.[Level of evidence: I]
- 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.[Level of evidence: I] 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.
Suicide risk of antidepressant medication
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. 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 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 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 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.[Level of evidence: I] 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 boxed 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 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, 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.[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 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.
Antidepressant medication selection
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). Table 2 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.Table 2. Antidepressant Medications for Ambulatory Adult Patients Drug Class/Generic Name (Proprietary Name)/DosagesaSide Effects/CommentsALT = alanine aminotransferase; BP = blood pressure; EKG = electrocardiogram; MAOIs = monoamine oxidase inhibitors; SSRIs = selective serotonin reuptake inhibitors; TCAs = tricyclic antidepressants.aConsult complete prescribing information for appropriate administration schedules. bTCAs prolong cardiac conduction through His-Purkinje system similar to Type IA antiarrhythmic agents (e.g., quinidine). They are specifically contraindicated in patients with bundle-branch disease and second- or third-degree heart block. Their effects on conduction correlate with dosage and serum concentrations and for those agents with positive chronotropic and adrenergic-stimulating properties, TCAs can cause reentry arrhythmias. Persons at greatest risk are those with preexisting cardiac conduction defects and those who have taken an overdose.cPlasma concentrations are most useful for guiding treatment in elderly patients who are (1) experiencing signs and symptoms of toxicity, (2) unresponsive to treatment, (3) suspected of being noncompliant with planned treatment, or (4) receiving other medications that may interact or otherwise alter antidepressant medication pharmacokinetics. dTCAs and other antidepressants may cause sexual dysfunction characterized as decreased libido, penile erectile dysfunction, and decreased sensation during orgasm and ejaculation. Management consists of waiting for spontaneous resolution with continued therapy, decreasing the antidepressant dose, selecting an alternative antidepressant, or concomitant treatment with medications that treat the dysfunction (e.g., bethanechol for antidepressants with prominent anticholinergic effects).eCommon antimuscarinic or anticholinergic effects include dry mouth, blurred vision, constipation, and urinary retention. Although patients may eventually develop tolerance to these effects with repeated medication use, symptoms may not completely resolve until the drug is discontinued. TCAsCan cause cardiac arrhythmias.EKG at baseline to evaluate for preexisting cardiac conduction abnormalities. Therapeutic drug concentration ranges in plasma have been identified for all agents, but dosage adjustments should be based on a patient's clinical response and not solely on plasma concentrations.bIn responding patients, decrease daily dosages to the lowest effective amount needed to sustain a response.c Can cause sexual dysfunction.May be associated with weight gain.d amitriptyline (Elavil) Marked sedation, dizziness, headache, weight gain, anticholinergic effects,e orthostatic BP changes (postural hypotension); may produce sexual dysfunction. Therapeutic plasma concentrations (parent drug + active metabolite) = 110–250 ng/mL.initial: 10–25 mg as a single daily dose, preferably at bedtime maintenance: 150–300 mg/d clomipramine (Anafranil) Anticholinergic effects, dizziness, drowsiness, headache, weight gain, orthostatic hypotension. initial: 25 mg/d and gradually increase to 100 mg/d the first 2 weeks; may be given at bedtime maintenance: 100–250 mg/d maximum desipramine (Norpramin)Mild sedation, increased appetite, nausea, minimal anticholinergic effects,e orthostatic BP changes. Therapeutic plasma concentrations = 125–300 ng/mL. initial: 25–50 mg/d as a single daily dose, preferably at bedtime maintenance: 100–300 mg/d as a single daily dose; In elderly patients, daily doses >150 mg are not recommended doxepin (Sinequan) Moderate to heavy sedation, dizziness, headache, weight gain, moderate anticholinergic effects,e postural hypotension. Optimal antidepressant effect is characteristically delayed by 2–3 weeks, but onset of antianxiety effect is comparatively rapid. Therapeutic plasma concentrations (parent drug + active metabolite) = 100–200 ng/mL.initial: 10–25 mg/d as a single daily dose, preferably at bedtime maintenance: 75–300 mg/d as a single daily dose, preferably at bedtime imipramine (Tofranil) Moderate to heavy sedation, dizziness, headache, weight gain, moderate anticholinergic effects,e moderate to marked orthostatic BP changes; may produce sexual dysfunction (both genders). Therapeutic plasma concentrations (parent drug + active metabolite) = 200–350 ng/mL. initial: 25–50 mg/d as a single daily dose, preferably at bedtime maintenance: 75–200 mg/d as a single daily dose, preferably at bedtime nortriptyline (Pamelor, Aventyl) Mild to moderate sedation, constipation, nausea, increased appetite, mild to moderate anticholinergic effects.e Is the TCA least likely to produce postural hypotension. Therapeutic plasma concentrations = 50–150 ng/mL. initial: 10–25 mg, 3–4 times daily maintenance: 30–50 mg, 3 times daily, daily doses >150 mg are not recommendedSSRIs Have few anticholinergic and cardiovascular adverse effects. Life-threatening and fatal reactions have occurred in patients who receive within 2 weeks of using MAOIs. Sexual dysfunction has been reported to be associated with use. There is limited experience with long-term use. citalopram (Celexa) Ejaculation disorder and other sexual dysfunctions, insomnia, dry mouth, nausea, somnolence. In vitro studies indicated that CYP3A4 and CYP2C19 are the primary enzymes involved in citalopram metabolism. Is a relatively weak inhibitor of CYP2D6.initial: 10 mg/d maintenance: 10–40 mg/dfluoxetine (Prozac) Anxiety, nervousness, insomnia, anorexia, mild bradycardia, sinoatrial node slowing, weight loss, solar photosensitivity, hyponatremia, sexual dysfunction; may alter glycemic control in diabetic patients. Substantially inhibits CYP2D6 and may inhibit the clearance of other drugs metabolized by cytochrome P450 CYP2D6 isozymes. Probably inhibits CYP2C9/10, moderately inhibits CYP2C19, and mildly inhibits CYP3A4. Fluoxetine metabolism is impaired in elderly patients. initial: 10–20 mg/d maintenance: 20–80 mg/d escitalopram (Lexapro)Nausea, vomiting, diarrhea, constipation, upset stomach, loss of appetite, dizziness, drowsiness, trouble sleeping, back pain, dry mouth.initial: 10 mg/dmaintenance: 10–20 mg/dfluvoxamine (Luvox) Nausea, sexual dysfunction, headache, nervousness, insomnia, drowsiness.initial: 50 mg at bedtime, adjust in 50 mg increments at 4- to 7-day intervalsmaintenance: 100–300 mg/d paroxetine (Paxil) Anxiety, nervousness, insomnia, mild weight loss, headache, solar photosensitivity, hyponatremia, sexual dysfunction. Substantially inhibits and may interact with other drugs metabolized by cytochrome P450 CYP2D6 isozyme. Paroxetine metabolism is impaired in elderly patients.initial: 10–20 mg/dmaintenance: 20–50 mg/d sertraline (Zoloft) Anxiety, nervousness, insomnia, mild weight loss, headache, solar photosensitivity, hyponatremia, sexual dysfunction. Produces mild inhibition of and may interact with drugs metabolized by cytochrome P450 CYP2D6 isozymes with little, if any, effect on CYP1A2, CYP2C9/10, CYP2C19, or CYP3A3/4.initial: 25–50 mg/d maintenance: 50–200 mg/d MAOIs tranylcypromine (Parnate)Orthostatic hypotension, drowsiness, hyperexcitability, headache. Low-tyramine diet required. initial: 10 mg twice daily, increase by 10-mg increments at 1- to 3-week intervals maintenance: 10–40 mg/dphenelzine (Nardil)Orthostatic hypotension, drowsiness, hyperexcitability, headache. Low-tyramine diet required.initial: 15 mg 3 times a day maintenance: 15–90 mg/dselegiline (EMSAM)Application site reaction, orthostatic hypotension, diarrhea, headache, insomnia, dry mouth. Any dosages higher than 6 mg/24 h require low-tyramine diet.initial: 6-mg patch/24 h (20-mg patch topically every 24 h)maintenance: 6-mg patch/24 h (20-mg patch topically every 24 h). May increase at increments of 3 mg/24 h at 2-week intervals up to 12 mg/24 h.ATYPICAL ANTIDEPRESSANTSIn general, serum drug concentrations do not correlate with antidepressant response. bupropion (Wellbutrin, also approved for the treatment of smoking cessation as Zyban)Initially activating dose-related seizure-inducing potential; contraindicated in patients with CNS involvement, a history of seizure, and concomitant conditions predisposing to seizure and in patients taking other drugs that lower seizure threshold. Mild to moderate sedation, mild to moderate anticholinergic effects,e mild orthostatic BP changes, agitation, insomnia, headache, confusion, dizziness, seizures, weight loss. initial: 75 mg/d maintenance: 200–450 mg/d not to exceed 150 mg/dose trazodone (Desyrel) Mild to moderate sedation; negligible anticholinergic effects; mild to moderate orthostatic BP changes, particularly in elderly patients; dizziness; headache; confusion; muscle tremors; may produce priapism. Taking with food can decrease gastrointestinal upset. Therapeutic plasma concentrations = 800–1,600 ng/mL. initial: 50 mg/d maintenance: 150–600 mg/d mirtazapine (Remeron) A tetracyclic antidepressant. Elimination is decreased in elderly persons. Somnolence, dizziness, increased appetite and weight gain, constipation, hypertension, edema, confusion, increased nonfasting triglycerides and cholesterol, significantly increased hepatic ALT, orthostatic hypotension. When used concomitantly with drugs that reduce seizure threshold (e.g., phenothiazines), may increase risk of seizure.initial: 7.5–15 mg/d maintenance: 15–45 mg/d venlafaxine (Effexor) Dose-related sustained hypertension, headache, dizziness, insomnia, nausea, constipation, abnormal ejaculation. Life-threatening and fatal reactions have occurred in patients who receive within 2 weeks of using MAOIs.initial: 75 mg/d maintenance: 150–375 mg/d duloxetine (Cymbalta)Nausea, dry mouth, constipation, decreased appetite, fatigue, sleepiness, increased sweating, decreased sexual drive or ability, urinary hesitation.initial: 30 mg/dmaintenance: 30–60 mg/dPSYCHOSTIMULANTS Restlessness, agitation, insomnia, nightmares, psychosis, anorexia; may exacerbate preexisting cardiac disease. Should be administered early in a patient's daily waking cycle. Sometimes used adjuvantly to antagonize opioid analgesics' sedative effects. dextroamphetamine (Dexedrine) Drug tolerance, abuse, and dependence liability. Arrhythmia, nervousness, restlessness, insomnia. Contraindicated in patients with advanced arteriosclerosis, symptomatic cardiovascular disease, moderate to severe hypertension, and glaucoma.initial: 2.5–5 mg/dmaintenance: 10–30 mg/d methylphenidate (Ritalin, Methylin) Drug tolerance, abuse, and dependence liability. Hypertension, tachycardia, nervousness, insomnia, anorexia, drowsiness, dizziness. May decrease convulsive threshold in patients with history of seizure disorders.initial: 2.5–10 mg/d maintenance: 20–60 mg/d dexmethylphenidate (Focalin)Dry mouth, tremor or muscle spasms, nervousness, trouble sleeping, headache, drowsiness, nausea, insomnia, increased sweating, dizziness, lightheadedness, changes in sexual function.initial: 10 mg/dmaintenance: 10–20 mg/d
When selecting an antidepressant drug, it is worthwhile to consider that side effects may have a clinical advantage. For example, some TCAs, such as amitriptyline, and atypical antidepressants, such as mirtazapine and trazodone, produce sedation and may be useful for agitated patients and for those who have difficulty getting to sleep. Consequently, treatment is often initiated as a single daily dose administered at bedtime. Although most patients will develop tolerance to antidepressants' sedative effects with continued treatment, the need for soporific agents may diminish with improvement in depressive symptoms.
When selecting antidepressants, either singly or in combination, consider the following:
- Target specific distressing symptoms.
- Evaluate coexistent medical problems that may be exacerbated by particular antidepressants.
- Minimize side effects and avoid worsening of current health status.
- Determine the patient's ability to swallow solid dosage forms; he or she may be able to take an antidepressant in liquid form (e.g., amitriptyline, nortriptyline, doxepin, fluoxetine). Alternatively, some antidepressants are available as parenteral dosage forms (e.g., amitriptyline and imipramine injection).
- Evaluate the patient's medication profile for potential interactions with antidepressant drugs.
Selective serotonin reuptake inhibitors
The postulated mechanism of action of SSRIs involves the blockade of serotonin neuronal reuptake, leading to desensitization of serotonergic feedback receptors. All currently available SSRIs are equally efficacious; they differ primarily in their safety, tolerability, half-lives, and drug-drug interactions. While some side effects are more common with some SSRIs than with others, side effects and tolerability may differ significantly in individual patients. SSRIs have become the first-line treatment for depressive disorders, owing to their better tolerability side effect profile, especially in comparison with the TCAs. As discussed earlier, antidepressant studies conducted in patients with cancer are done mostly with SSRIs or TCAs. None of the clinical trials have included or focused on children and adolescents being treated for cancer. [Level of evidence: I] Overall, the evidence on the efficacy of SSRIs for treating cancer-related depression remains limited, and more studies are needed to address the efficacy, safety, tolerability, and drug-drug interaction issues in the context of cancer and cancer treatments. The British Committee on Safety of Medicines considered only one of the SSRIs (fluoxetine) to have a favorable balance of risks and benefits, but it is only considered beneficial in approximately one in ten patients. Consistent with this finding, age-stratified analyses of the child and adolescent studies found that for children younger than 12 years with major depression, only fluoxetine showed benefit over placebo.[Level of evidence: I] As noted, none of the children or adolescents in these studies had cancer, so there are no reports available that address whether there are additional increased risks of adverse events associated with the use of SSRIs following exposure to different chemotherapeutic agents and/or central nervous system (CNS) radiation treatment. Frontline, alternative, effective, behavioral, and pharmacologic treatments for depression should be used for children and adolescents being treated for cancer. However, if the risks of depression are significant and SSRIs are considered, consultation from a child psychiatrist or neurologist is essential, and close monitoring of potential adverse events is crucial. No warning has been issued for adult use of SSRIs.
Discontinuation of antidepressants
The optimal duration of antidepressant therapy for patients treated for depressive symptoms (without a depressive disorder) is unknown. Patients with a depressive disorder who achieve a beneficial response to antidepressant pharmacotherapy should continue treatment for a minimum of 4 to 6 months after depression resolves. When patients are discontinuing antidepressant medications, TCA doses should be tapered by approximately 25% per week to avoid cholinergic rebound (e.g., hypersalivation, diarrhea). In patients who experience intolerable adverse effects, however, doses may be tapered quickly. With the exception of fluoxetine, gradual tapering is advised when decreasing doses or discontinuing treatment for all SSRIs. Other antidepressants with short half-lives, such as venlafaxine, also should be tapered gradually. Withdrawal symptoms, both somatic and psychological, frequently emerge after abrupt discontinuation, during intermittent noncompliance, and sometimes during dose reduction; though these symptoms are generally mild, short-lived, and self-limiting, they can be distressing and may lead to missed workdays and decreased productivity. Mild symptoms can often be treated by reassuring a patient that they are usually transient. For more severe symptoms, it may be necessary to reinstate the dosage of the original antidepressant and slow the rate of taper. Symptoms of discontinuation may be mistaken for physical illness or relapse into depression and misdiagnosis may lead to unnecessary, costly tests and treatment. Thus, health care professionals need to be educated about the potential adverse effects of SSRI discontinuation.
TCAs can produce abnormal myocardial conduction; thus, a cardiac history and a recent EKG should be obtained in patients with a history of cardiac problems. Many tricyclic antidepressants have a sedating effect; therefore, treatment typically is started at low doses at bedtime. The main exception is desipramine, which some patients find mildly stimulating and can be administered in the morning to reduce insomnia, if it develops. Daily doses are increased slowly every few days or at weekly intervals until symptoms improve. Many patients become tolerant to the drugs' sedative effects, and total daily doses may be divided and given during patients' waking cycles.
TCAs are still regarded as first-line agents for severe, major depression; however, SSRI use is increasing for that indication because of the effectiveness of SSRIs and the low risk of clinically significant side effects that are associated with TCAs, such as cardiac arrhythmias, hypotension, and anticholinergic effects. In addition, TCAs are highly toxic on overdose. Side effects commonly associated with the SSRIs include nausea, vomiting, diarrhea, somnolence, insomnia, headache, confusion, dizziness, asthenia, and sexual dysfunction. Drug-specific adverse effects associated with fluoxetine include gastric distress, brief periods of anxiety or agitation, and anorgasmia in females. Treatment with sertraline is sometimes complicated by dyspepsia, tremor, and ejaculatory delay in men.
The pharmacokinetic profiles of SSRIs permit them to be given once a day, thus improving patient compliance.[Level of evidence: II] Sertraline and paroxetine have a half-life of approximately 20 hours; thus, steady-state systemic concentrations can be achieved within 1 week after starting treatment and altering dosage or administration schedules. In comparison, repeated dosing appears to inhibit fluoxetine metabolism; consequently, both fluoxetine and its active metabolite, norfluoxetine, may be present in the body for weeks after discontinuing treatment.
Clinicians who prescribe and monitor patients receiving antidepressants should also become familiar with their potential for interactions with other medications. The SSRIs venlafaxine, nefazodone, and mirtazapine are metabolized by cytochrome P450 enzymes; their pharmacokinetics may be altered, or they may affect the clearance of drugs metabolized by the same enzymes. Marked differences exist, however, between the SSRIs and SSRI metabolites with regard to their effects on specific cytochrome P450 enzymes. For example, both fluoxetine and norfluoxetine inhibit CYP3A4 isoenzyme; however, the metabolite is more potent than fluoxetine and in view of its longer half-life the potential for interactions may persist for weeks after fluoxetine is discontinued. Understanding the similarities and differences in their pharmacology can aid clinicians in using these agents optimally and avoiding clinically important pharmacokinetic drug-drug interactions. In addition, since all SSRIs are highly protein-bound to albumin (± alpha-1 acid glycoprotein), clinicians must consider their potential for interactions with other highly protein-bound medications. Sertraline and paroxetine may be preferred in patients with renal or hepatic dysfunction since they are metabolized and excreted as inactive compounds.
Bupropion is a unique alternative to tricyclics and SSRIs for treating persons with depression and cancer, especially when depression is accompanied by fatigue. Pharmacologically, bupropion is a weak inhibitor of monoamine reuptake and demonstrates a slight preference for dopamine transport inhibition; however, it may be metabolically converted to active substances with amphetamine-like activity that affect both dopamine and norepinephrine reuptake. Bupropion generally does not cause 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 treatment is initiated with doses of 75 mg once daily, preferably in the early part of the day. Patients may initially require a moderate- to long-acting sedative/hypnotic drug at bedtime for the insomnia, agitation, and motor restlessness sometimes associated with bupropion. Risk of seizure with bupropion may be as much as 4 times greater than is associated with other antidepressants. Single doses should not exceed 150 mg, a dose increase should not be greater than 100 mg of bupropion per day, and dose increases should be gradual—at least 3 days after a previous increase in dose. Because the risk of seizure markedly increases in patients receiving bupropion at doses between 450 mg and 650 mg, the total daily dose should not exceed 450 mg. Bupropion is contraindicated in patients with malignant diseases involving the brain and a history of cranial trauma or seizure disorder, and in persons with a history of bulimia. [Level of evidence: II]
Venlafaxine affects both norepinephrine and serotonin reuptake and enhances serotonin neurotransmission. Venlafaxine does not produce the same uncomfortable antimuscarinic and antiadrenergic side effects as the TCAs; however, it does produce side effects similar to those produced by SSRIs, particularly nausea, headache, somnolence, and dry mouth. In some patients, venlafaxine may cause sustained increases in blood pressure; blood pressure should therefore be evaluated before treatment is started, monitored after treatment is initiated, and monitored after doses are increased. Venlafaxine is given twice a day, with food.
The primary actions of the atypical antidepressant trazodone is not well established. Although it antagonizes serotonin reuptake, it is many times weaker in this respect compared with SSRIs. Trazodone is active and is metabolized to compounds that have agonistic activity at some serotonin receptors (5-HT1). It may have additional active metabolites that contribute to its clinical activity.
There is growing clinical experience with mirtazapine in persons with cancer. Pharmacologically, mirtazapine is a noradrenergic and specific serotonergic antidepressant. It competitively antagonizes presynaptic alpha-adrenergic receptors (alpha-2) and serotonin receptors (5-HT2 and 5-HT3), the net result of which enhances norepinephrine release and noradrenergic neurotransmission.;[Level of evidence: I] Sedation is the predominating side effect at subtherapeutic low doses (<15 mg/d), and anecdotal evidence suggests that sedation decreases at higher doses. Its side-effect profile also includes increased appetite, which may cause weight gain, dizziness, dry mouth, and constipation. Although it is a structural analog of mianserin (an antidepressant that is marketed in Europe), mirtazapine has rarely been implicated in producing severe blood dyscrasias, including agranulocytosis, as has mianserin. Little is known about mirtazapine interactions with other drugs, but it is thought to have a lesser risk of clinically significant drug interactions than SSRIs. The initial dose for mirtazapine is 15 mg per day given at bedtime. Doses may be increased at intervals not less than 1 to 2 weeks, up to a maximum daily dose of 45 mg.
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 should never be stopped abruptly because withdrawal symptoms with possible seizures may occur. The dose of benzodiazepines should be tapered slowly at a rate of approximately 25% every 3 to 4 days.
Clinical experience (see Table 3) 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 particularly useful for patients with advanced cancer who have a limited life expectancy (weeks to a few months). Compared with traditional antidepressants such as the TCAs and SSRIs that take 3 to 4 weeks to take effect, the psychostimulants often demonstrate antidepressant effects within a few days of starting treatment. They promote a sense of well-being, decreased fatigue, and increased appetite. Analeptic agents can be helpful in countering the sedating effects of opioids, and in comparison with antidepressants, they are rapidly effective. Adverse effects associated with analeptic agents include insomnia, euphoria, and mood lability. High doses and long-term use may produce anorexia, nightmares, insomnia, euphoria, or paranoia.
Methylphenidate and dextroamphetamine are administered in divided doses early in a patient's waking cycle to avoid sleep disturbances (e.g., insomnia and nighttime arousal). Like benzodiazepines, these medications are adjuncts to antidepressant medications; they may be started concomitant with an antidepressant and discontinued when depressive symptoms abate.Table 3. Clinical Trials of Psychostimulants in Cancer PatientsStudyCommentsDrug(s)OutcomeMeyers et al. 1998 Brain tumor; N = 30methylphenidate (Ritalin)↑ mood, ↑ cognition, ↑ function Olin and Masand 1996 Mixed cancer; N = 59; chart reviewdextroamphetamine (Dexedrine); methylphenidate (Ritalin) ↓ depression, ↑ appetiteBruera et al. 1992 Cancer pain vs. opioid infusion; N = 20methylphenidate (Ritalin); placebo↑ cognition, ↓ sedationFernandez et al. 1987 Mixed cancer; rapid onset; N = 30 methylphenidate (Ritalin; up to 80 mg)↓ depressionBruera et al. 1986 Pain; double-blind cross-over study; N = 24mazindol (Mazanor)↓ pain, ↓ appetite, no effect on mood Joshi et al. 1982 Terminally illamphetamine↑ comfort
Monoamine oxidase inhibitors
The use of monoamine oxidase inhibitors (MAOIs) in the cancer population has been limited because the nutritional requirements of a tyramine-free diet are generally more difficult to accomplish in patients receiving antineoplastic treatments. MAOIs are contraindicated in patients receiving opioids, sympathomimetics, and procarbazine because of the potential for developing hypertensive crisis.
MAOIs may cause adverse reactions when taken with other medications and certain foods. MAOIs impair the metabolism of morphine and other opioids as well as barbiturates and may lead to exaggerated ventilatory depression. Meperidine HCl (Demerol), an opioid, has been associated with hypertension, hyperpyrexia, skeletal muscle rigidity, seizures, and coma when used with MAOIs. Exaggerated effects of antihistamines, anticholinergics, and tricyclic antidepressants may be secondary to impaired metabolism by MAOIs. In addition, the hypoglycemic effects of insulin and oral sulfonylureas may be potentiated by MAOIs.
MAOIs may also interact with specific anesthetic drugs used during surgery. Cancer patients in particular may frequently undergo surgical procedures and should alert their anesthesiologist of all medications. Postoperative pain should not be treated with meperidine HCl. MAOIs should neither be taken with procarbazine, a chemotherapeutic agent used in the treatment of lymphomas and brain tumors, nor used with other antidepressants.
The FDA approved a transdermal antidepressant that may have particular value in the treatment of the depressed cancer patient who is unable to swallow or take medications by mouth. The antidepressant selegiline (sold under the trade name EMSAM) is an irreversible MAOI. The drug has not been evaluated for the treatment of depression in cancer patients.
Many of the usual dietary restrictions (low-tyramine diet) and drug-drug interactions (the product should not be used with meperidine, propoxyphone, or methadone) are germane to selegiline (see Table 4 below). However, according to the package insert, the 20-mg skin patch (which delivers 6 mg of selegiline in a 24-hour period) can be used without the dietary restrictions found on all MAOIs marketed to date. This recommendation is supported by clinical trials and other evidence submitted to the FDA. The two higher doses (a 30-mg patch that delivers 9 mg in 24 hours and a 40-mg patch that delivers 12 mg in 24 hours) carry the usual dietary warning. This drug has not been evaluated in cancer patients for safety and efficacy.Table 4. Tyramine-Containing FoodsaClass of Food and BeverageTyramine-Rich Foods and Beverages To AvoidAcceptable Foods Containing Little or No TyramineOTC = over-the-counter.aAdapted from the EMSAM Medication Guide. The foods and beverages listed above should be avoided beginning on the first day of treatment with selegiline 9 mg/24 h or 12 mg/24 h and should continue to be avoided for 2 weeks after a dose reduction to 6 mg/24 h or following the discontinuation of selegiline 9 mg/24 h or 12 mg/24 h.Meat, poultry, and fishAir-dried, aged, and fermented meats, sausages, and salamis (including cacciatore, hard salami, and mortadella); pickled herring; and any spoiled or improperly stored meat, poultry, and fish (e.g., foods that have undergone changes in color or odor or that have become moldy); spoiled or improperly stored animal liversFresh meat, poultry, and fish, including fresh processed meats (e.g., lunch meats, hot dogs, breakfast sausage, and cooked sliced ham)VegetablesBroad bean pods (fava bean pods)All other vegetablesDairyAged cheesesProcessed cheeses, mozzarella, ricotta cheese, cottage cheese, and yogurtBeveragesAll varieties of tap beer, and beers that have not been pasteurized so as to allow for ongoing fermentationAs with other antidepressants, concomitant use of alcohol with selegiline is not recommended. (Bottled and canned beers and wines contain little or no tyramine.)MiscellaneousConcentrated yeast extract (e.g., Marmite), sauerkraut, most soybean products (including soy sauce and tofu); OTC supplements containing tyramineBrewer's yeast, baker's yeast, soy milk, commercial chain-restaurant pizzas prepared with cheeses low in tyramine
Selegiline is a nonselective MAOI, inhibiting not only the monoamine oxidase B (MAO-B) enzyme in the central nervous system but also monoamine oxidase A (MAO-A) elsewhere in the body. In the digestive tract, MAO-A normally metabolizes tyramine, a dietary amine that is found in high concentrations in foods such as aged cheese and red wine. The breakdown of tyramine in the gut prevents significant amounts of it from being absorbed and circulated throughout the body. Tyramine is a potent pressor—leading to constriction of blood vessels—which ultimately results in increased blood pressure. Large amounts of tyramine can lead to hypertensive crises, resulting in stroke, heart attack, and even death. Because the medication is absorbed from the skin patch and bypasses the gut wall, it is thought that transdermal selegiline will have a significantly reduced effect on MAO-A in the digestive tract. In addition, at lower doses, selegiline is thought to inhibit MAO-B preferentially, while at higher doses both A and B isoenzymes are affected. With significantly reduced inhibition of digestive tract MAO-A, dietary restrictions are not considered necessary for the lower dose. In considering starting this drug, consult with a pharmacist about multiple classes of drug-drug interactions. This drug has not been evaluated in people with cancer.
Foods that contain large amounts of tyramine, such as cheese, chicken liver, chocolate, beer, and wine, may provoke hypertension (initially manifesting as headache) and cardiac dysrhythmias.
St. John's wort
There continue to be high levels of enthusiasm for the use of herbs and dietary supplements for controlling symptoms and improving health-related quality of life and well-being. One popular herbal agent that has been used to treat depression is St. John's wort, a plant with Greek origins. The major active constituents in St. John's wort are hypothesized to be melatonin, hypericin, hyperforin, and adhyperforin, although hypericin may not reach sufficient concentrations in humans to have biologic activity. Hypericin is thought to be a monoamine oxidase inhibitor, while hyperforin and adhyperforin are believed to inhibit the reuptake of serotonin, dopamine, and norepinephrine. These mechanisms of action provide the rationale for evaluating St. John's wort for depression management.
During the last 25 years, many trials have compared St. John's wort to placebo, to antidepressants, and sometimes to both placebo and antidepressants. A wide range of results have emerged, from finding no differences between arms, to finding St. John's wort improving outcomes over placebo for moderate depression, to finding St. John's wort preferable to placebo in general, to finding St. John's wort equal to antidepressants in alleviating depressive symptoms.;[Level of evidence: I] Older studies comparing St. John's wort to antidepressant therapy tended to use low doses of antidepressants and did not titrate up by response to the usual doses used for managing depression. The best overview of the research in this area is provided in a meta-analysis of randomized controlled trials. Conclusions from this meta-analysis, which includes 37 trials, are that St. John's wort does not have a clinically important effect on major depressive disorder and that for milder depression, it may have some effect (but it is not large).
Side effects reported in studies of St. John's wort are minimal. One study that compared St. John's wort to sertraline and placebo found that the side effects of St. John's wort that were significantly different from those of placebo included anorgasm, frequent urination, and swelling.[Level of evidence: I] A meta-analysis of randomized controlled trials found that fewer patients withdrew from trials because of adverse effects from St. John's wort, compared with antidepressants.
It is important that a physician knows what drugs a patient is already using before that patient begins taking St. John's wort, which decreases the effectiveness of other concomitantly administered drugs. There are two important cautions when the use of St. John's wort for depression is being considered:
- As an herb, St. John's wort is regulated by the FDA as a food/dietary supplement. Although the FDA issued a final rule establishing regulations to require manufacturers of dietary supplements to prove good manufacturing processes and to correctly label their ingredients, the standardization of products such as St. John's wort with respect to the desired amount of potentially active ingredients is not carried out. Therefore, if hyperforin is the desired ingredient, the amount of hyperforin in any formulation of St. John's wort could differ substantially among brands.
- St. John's wort has been found to be metabolized within the cytochrome P450 system and has effects inhibiting as well as inducing various metabolic pathways. The pathways affected by St. John's wort are CYP3A4, CYP2C9, and CYP2D6. In one study in humans, effects on systemic concentrations of drugs via the CYP3A4 pathway were evident in as few as 14 days. Clinically, this means that the concomitant use of St. John's wort with other drugs could cause lower concentrations of drugs that are needed to have therapeutic effects. With respect to cancer and its treatment, St. John's wort has been shown to decrease concentrations of irinotecan in patients receiving treatment and, in vitro, is suspected of reducing concentrations of docetaxel. Additionally, St. John's wort has been found to affect concentrations of cyclosporin A and tacrolimus, both important for transplant engraftment, as well as concentrations of indinavir for the treatment of HIV.
The bottom line regarding the use of St. John's wort for the management of depression is that despite a more tolerable side effect profile, there is a lack of evidence demonstrating an advantage to using this herbal agent over approved antidepressant therapy. The data do not support a strong effect on major depressive disorder or even on mild to moderate depression. This fact, combined with concerns about drug interactions and lack of standardization, makes St. John's wort an unattractive alternative for depression management.
Table 5 and Table 6 highlight tips that may be useful in determining what medication is best to use for a particular patient. The tables focus on the effects these medications may have beyond their antidepressant effects that may decrease or increase patient distress, such as fatigue, insomnia, and nausea and vomiting.Table 5. Physical Symptom- and Distress-Driven Approach to Choosing an Antidepressanta in Adult Cancer Patients Distressing Symptom SSRI TCA Psychostimulants OtherSSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant; + = use of this medication could relieve the symptom; – = use of this medication could worsen the symptom.aIn general, doses should start low and increase slowly. This list does not indicate absolute indications or contraindications for particular medications. A current Physicians' Desk Reference or another reliable drug information resource and experience should guide clinical decision making.bAlthough all SSRIs have the potential paradoxical side effect of hypersomnia, fluoxetine is particularly activating. Bupropion is also somewhat activating.cSedating antidepressants are useful for insomnia, either alone or in addition to another antidepressant. Trazodone and mirtazapine are often used as sleep aids in combination with another antidepressant. dSome antidepressants are useful in treating neuropathic pain. The most studied of these are the TCAs, particularly amitriptyline. eSedating antidepressants are most useful for anxious/agitated patients. These include the TCAs, trazodone, mirtazapine, and nefazodone. Fatigue +b+ +bInsomniac + +cNeuropathic paind + + Opioid side effects + +Constipation + +Loss of appetite (weight loss) + +Anxiety + + +eDry mouth/stomatitis + –+ Table 6. Factors to Consider in Choosing an Antidepressant For Adult Cancer Patients Comorbid Medical ConditionsSSRI TCA Psychostimulants OtherSSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant; + = use of this medication could relieve the symptom; – = use of this medication may be a less appropriate choice.aIn general, TCAs and psychostimulants can cause and exacerbate cardiac arrhythmia. SSRIs, bupropion, venlafaxine, and nefazodone are generally less likely to cause cardiac problems. EKGs should be obtained before starting TCA medication, and a cardiologist should be consulted if there is concern for cardiac compromise.bThe shorter-acting SSRIs (sertraline and paroxetine) are less problematic than fluoxetine in patients with hepatic dysfunction. There is less potential for adverse drug interactions and fewer problems related to drug accumulation due to a shorter half-life. Sertraline and nefazodone reportedly have less effect on hepatic P450 enzyme activity.cClinicians should consider whether antidepressant doses and administration schedules require modification for their patients with renal or hepatic insufficiency.dThe TCAs are contraindicated in closed-angle glaucoma. Cardiac history + –+a Hepatic dysfunction +b + – Renal dysfunctionc Glaucoma + –d Neuropathic pain + +
It should be noted that electroconvulsive therapy (ECT) is a useful and safe therapy when other interventions have not succeeded in relieving the depressive syndrome that may represent a life-threatening complication of treatable cancer. Experience is limited, however, in using ECT in patients receiving mirtazapine and trazodone, and there are no clinical studies establishing the use of ECT in patients receiving SSRIs. Prolonged seizures have occurred rarely in patients receiving fluoxetine.
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 (ranging between 4 and 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 in recent investigations. Cognitive-behavioral interventions focus on altering specific coping strategies aimed at improving overall adjustment and typically focus on specific thoughts and their relationship to emotions and behaviors. 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 end result is improved coping, enhanced adjustment, and better overall quality of life.
Other goals of psychotherapy include enhancing coping skills, directly reducing distress, improving problem-solving skills, mobilizing support, reshaping negative or self-defeating thoughts, and developing a close personal bond with a knowledgeable, empathic health care provider.[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:
- Assist people with cancer and their families by answering questions about the illness and its treatment, clarifying information, correcting misunderstandings, giving reassurance, and normalizing responses to the illness and its effect on their families. Explore the present situation with the patient and how it relates to his or her previous experiences with cancer.
- Assist with problem solving, bolster the patient's usual adaptive defenses, and help the patient and family develop further supportive and adaptive coping mechanisms. Identify maladaptive coping mechanisms and assist the family in developing alternative coping strategies. Explore areas of related stressors (e.g., family role and lifestyle changes), and encourage family members to support and share concerns with each other.
- When the focus of treatment changes from cure to palliation, reinforce strongly that, though curative treatment has ended, the team will aggressively treat symptoms as part of the palliation plan; the patient and family will not be abandoned; and staff members will work very hard to maintain comfort, control pain, and maintain the dignity of the patient and his or her family members.
Cancer support groups can be useful adjunctive therapies in the treatment of cancer patients.[Level of evidence: II] Recent 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 Wellness Community, the American Cancer Society, and many other community resources, including the social work departments of medical centers or hospitals.
Empirical studies of the efficacy of psychotherapy
Psychotherapy as a treatment for depression in the general adult mental health population has been extensively researched and found to be effective. Recent 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 sizes range from 0.19 to 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 training in problem solving 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.
Current Clinical Trials
Check NCI's list of cancer clinical trials for U.S. supportive and palliative care trials about depression that are now accepting participants. The list of trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.References:
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- Barsevick AM, Sweeney C, Haney E, et al.: A systematic qualitative analysis of psychoeducational interventions for depression in patients with cancer. Oncol Nurs Forum 29 (1): 73-84; quiz 85-7, 2002 Jan-Feb.
- Forester B, Kornfeld DS, Fleiss JL: Psychotherapy during radiotherapy: effects on emotional and physical distress. Am J Psychiatry 142 (1): 22-7, 1985.
- Holland JC, Morrow GR, Schmale A, et al.: A randomized clinical trial of alprazolam versus progressive muscle relaxation in cancer patients with anxiety and depressive symptoms. J Clin Oncol 9 (6): 1004-11, 1991.
- Greer S, Moorey S, Baruch JD, et al.: Adjuvant psychological therapy for patients with cancer: a prospective randomised trial. BMJ 304 (6828): 675-80, 1992.
- Worden JW, Weisman AD: Preventive psychosocial intervention with newly diagnosed cancer patients. Gen Hosp Psychiatry 6 (4): 243-9, 1984.
- Lovejoy NC, Matteis M: Cognitive-behavioral interventions to manage depression in patients with cancer: research and theoretical initiatives. Cancer Nurs 20 (3): 155-67, 1997.
- Cain EN, Kohorn EI, Quinlan DM, et al.: Psychosocial benefits of a cancer support group. Cancer 57 (1): 183-9, 1986.
- Montazeri A, Jarvandi S, Haghighat S, et al.: Anxiety and depression in breast cancer patients before and after participation in a cancer support group. Patient Educ Couns 45 (3): 195-8, 2001.
- Fawzy FI, Fawzy NW, Hyun CS, et al.: Malignant melanoma. Effects of an early structured psychiatric intervention, coping, and affective state on recurrence and survival 6 years later. Arch Gen Psychiatry 50 (9): 681-9, 1993.
- Spiegel D, Bloom JR, Yalom I: Group support for patients with metastatic cancer. A randomized outcome study. Arch Gen Psychiatry 38 (5): 527-33, 1981.
- Spiegel D, Glafkides MC: Effects of group confrontation with death and dying. Int J Group Psychother 33 (4): 433-47, 1983.
- Lambert MJ, Ogles BM: The efficacy and effectiveness of psychotherapy. In: Lambert MJ: Bergin and Garfield's Handbook of Psychotherapy and Behavior Change. 5th ed. New York: John Wiley & Sons Inc, 2004, pp 139-93.
- Sheard T, Maguire P: The effect of psychological interventions on anxiety and depression in cancer patients: results of two meta-analyses. Br J Cancer 80 (11): 1770-80, 1999.
- Nezu AM, Nezu CM, Felgoise SH, et al.: Project Genesis: assessing the efficacy of problem-solving therapy for distressed adult cancer patients. J Consult Clin Psychol 71 (6): 1036-48, 2003.
Suicide Risk in Cancer Patients
Demographics and Statistics
Studies indicate that the incidence of suicide in cancer patients can be equal to the incidence in the general population or up to 2 to 10 times as frequent. Some studies suggest that while relatively few cancer patients commit suicide, they are at increased risk for suicide. One population-based study utilizing data from the Cancer Registry of Norway linked to the Register of Deaths at Statistics Norway indicated an increased relative risk of suicide in the decade 1990-1999 within 2 years of diagnosis for males and females; however, the relative risk for females was nonsignificant. For both sexes, the risk was highest in the first months after diagnosis, and there was a significant decrease in relative risk over decades. Passive suicidal thoughts are relatively common among cancer patients. The relationships between suicidal tendency and the desire for hastened death, requests for physician-assisted suicide, and/or euthanasia are complex and poorly understood. Men with cancer are clearly at an increased risk of suicide compared with the general population, with a relative risk as high as 2.3. Overdosing with analgesics and sedatives is the most common method of suicide among persons with cancer, with most cancer-related suicides occurring at home. Reports identify a higher incidence of suicide in patients with oral, pharyngeal, and lung cancers and in HIV-positive patients with Kaposi sarcoma. The actual incidence of suicide in cancer patients is probably underestimated. There may be reluctance to report death by suicide in these circumstances.
Risk factors for suicide in the cancer population are as follows:
- History of psychiatric disorders, especially those associated with impulsive behavior (e.g., borderline personality disorders).
- Family history of suicide.
- History of previous/prior suicide attempts.
- Substance abuse.
- Recent death of a friend or spouse.
- Few social supports.
- Oral, pharyngeal, and lung cancers (often associated with heavy alcohol and tobacco use).
- Advanced stage of disease and poor prognosis.
- Inadequately controlled pain.
- Presence of deficit symptoms (e.g., loss of mobility, loss of bowel and bladder control, amputation, sensory loss, paraplegia, inability to eat and to swallow, exhaustion, fatigue).
- Bolund C: Suicide and cancer: I. Demographic and social characteristics of cancer patients who committed suicide in Sweden, 1973-1976. Journal of Psychosocial Oncology 3 (1): 17-30, 1985.
- Bolund C: Suicide and cancer: II. Medical and care factors in suicides by cancer patients in Sweden, 1973-1976. Journal of Psychosocial Oncology 3 (1): 31-52, 1985.
- Fox BH, Stanek EJ 3rd, Boyd SC, et al.: Suicide rates among cancer patients in Connecticut. J Chronic Dis 35 (2): 89-100, 1982.
- Hem E, Loge JH, Haldorsen T, et al.: Suicide risk in cancer patients from 1960 to 1999. J Clin Oncol 22 (20): 4209-16, 2004.
- Breitbart W, Krivo S: Suicide. In: Holland JC, Breitbart W, Jacobsen PB, et al., eds.: Psycho-oncology. New York, NY: Oxford University Press, 1998, pp 541-7.
- Holland JC: Psychologic aspects of cancer. In: Holland JF, Frie E, eds.: Cancer Medicine. 2nd ed. Philadelphia, Pa: Lea & Febiger, 1978, pp 1175-1203.
Assessment, Evaluation, and Management of Suicidal Patients
Patients who are suicidal require careful assessment (see Table 7). In the assessment of suicide, it is important to recognize that 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 availability of the means, reversibility of the means (once begun can it be stopped), and proximity to help. In the cancer patient reporting suicidal ideation, it is essential to determine whether the underlying cause is a depressive illness 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 for suicide in cancer patients. Risk factors, particularly hopelessness (which is an even stronger predictive factor for suicide than is depression) should be carefully assessed. 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. Of 220 Japanese patients 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.
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 should be maintained, which conveys the attitude that much can be done to alleviate emotional and physical pain. (Refer to the PDQ summary on Pain for more information.) A crisis intervention–oriented psychotherapeutic approach should be initiated that mobilizes as much of a patient's support system as possible. Contributing symptoms (e.g., pain) should be aggressively controlled and depression, psychosis, agitation, and underlying causes of delirium should be treated. (Refer to the PDQ summary on Delirium for more information.) 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.Table 7. Suggested Questions for the Assessment of Suicidal Symptoms in People With CanceraQuestions AssessmentaAdapted from Roth et al. 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 riskHave you ever had thoughts like that? Any thoughts of not wanting to live or wishing your illness might hasten your death? Level of riskDo you have thoughts of suicide? Have you thought about how you would do it? Do you intend to harm yourself?Level of riskHave you ever been depressed or made a suicide attempt? HistoryHave you ever been treated for other psychiatric problems or have you been psychiatrically hospitalized before getting diagnosed with cancer?HistoryHave you had a problem with alcohol or drugs? Substance abuseHave you lost anyone close to you recently? (Family, friends, others with cancer) Bereavement
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 for 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:
- Use medications that work rapidly to alleviate distress (e.g., a benzodiazepine for anxiety or a stimulant for fatigue) while waiting for the clinical effects from antidepressant therapy.
- Pay scrupulous attention to symptom management.
- Limit access as appropriate to quantities of medications that are lethal in overdose.
- Maintain frequent contact with and closely observe the patient.
- Avoid having the patient spend long periods of time alone.
- Mobilize support for the patient.
- Carefully assess the patient's psychological responses at each crisis point over the course of the disease.
Effect on Family and Health Care Providers
When suicide complicates bereavement, the loss can be especially difficult for survivors. A pattern of reactions that includes feelings of abandonment, rejection, anger, relief, guilt, responsibility, denial, identification, and shame may occur. This pattern is modified by such factors as the nature and intensity of the relationship, the nature of the suicide, the deceased person's age and physical condition, the perceived support network, and the survivor's coping skills and cultural/religious background. Assisting survivors through the bereavement period is important. Mutual support groups are helpful in reducing isolation, providing opportunities for venting feelings, and finding ways to cope with the aftermath of suicide. (Refer to the PDQ summary on Grief, Bereavement, and Coping With Loss for further information.)
Staff reactions to the suicide of a patient are similar to those seen in family members, although staff often do not feel that they have the same right to express their feelings. The suicide of a patient may lead a staff member to question his or her professional judgment. It is often helpful for the staff to conduct a psychological autopsy in an attempt to understand why and how the suicide happened, signs and symptoms of risk, and how routines might be altered to prevent similar problems in the future.
Assisted Dying, Euthanasia, and Decisions Regarding End of Life
The principle of respecting and promoting patient autonomy has been one of the driving forces behind the hospice movement and right-to-die issues that range from honoring living wills to promoting euthanasia. These issues can create a conflict between patient autonomy and the physician's obligation to beneficence.
Answers to the questions of euthanasia and physician-assisted suicide belong to the realm of the law, ethics, medicine, and philosophy. Physicians and other health care professionals have essential clinical roles to play in addressing and untangling these issues when working with depressed, terminally ill patients. Additionally, religious and cultural issues may strongly influence this decision-making process. A 1994 survey suggests that hospice physicians favor vigorous pain control and strongly approve of the right of patients to refuse life support even if life is secondarily shortened. However, these physicians strongly oppose euthanasia or assisted suicide, clearly making a sharp distinction between these two interventions. Often patients who specifically request physician-assisted suicide can be prescribed measures that augment their comfort, relieve symptoms, and obviate considering drastic measures. A recent study suggests that agreement with euthanasia is associated with male sex, lack of religious beliefs, and general beliefs about the suffering of cancer patients. A 1995 study of persons with advanced cancer who expressed a consistent and strong desire for hastened deaths suggested that this desire is related to the presence of depression. Patients with the desire to die should be carefully assessed and treated for depression as necessary. Whether their desire to die would persist or decrease with improvement in mood disorder has not yet been studied. It is important to maintain a shared decision-making process from the beginning of the professional relationship. (Refer to the PDQ summary on Last Days of Life for more information.)References:
- Massie MJ, Gagnon P, Holland JC: Depression and suicide in patients with cancer. J Pain Symptom Manage 9 (5): 325-40, 1994.
- Kovacs M, Beck AT, Weissman A: Hopelessness: an indicator of suicidal risk. Suicide 5 (2): 98-103, 1975 Summer.
- Breitbart W, Passik SD: Psychiatric aspects of palliative care. In: Doyle D, Hanks GW, MacDonald N, eds.: Oxford Text Book of Palliative Medicine. New York: Oxford University Press, 1993, pp 609-26.
- Akechi T, Okamura H, Yamawaki S, et al.: Why do some cancer patients with depression desire an early death and others do not? Psychosomatics 42 (2): 141-5, 2001 Mar-Apr.
- Breitbart W, Krivo S: Suicide. In: Holland JC, Breitbart W, Jacobsen PB, et al., eds.: Psycho-oncology. New York, NY: Oxford University Press, 1998, pp 541-7.
- Roth AJ, Holland JC: Psychiatric complications in cancer patients. In: Brain MC, Carbone PP, eds.: Current Therapy in Hematology-Oncology. 5th ed. St. Louis, Mo: Mosby-Year Book, Inc., 1995, pp 609-18.
- Miller RJ: Supporting a cancer patient's decision to limit therapy. Semin Oncol 21 (6): 787-91, 1994.
- Masdeu JC: Physician-assisted suicide and euthanasia. JAMA 276 (3): 196-7, 1996.
- Siegler M: Is there a role for physician-assisted suicide in cancer? No. Important Adv Oncol : 281-91, 1996.
- Back AL, Wallace JI, Starks HE, et al.: Physician-assisted suicide and euthanasia in Washington State. Patient requests and physician responses. JAMA 275 (12): 919-25, 1996.
- Marzuk PM: Suicide and terminal illness. Death Stud 18 (5): 497-512, 1994.
- Suarez-Almazor ME, Belzile M, Bruera E: Euthanasia and physician-assisted suicide: a comparative survey of physicians, terminally ill cancer patients, and the general population. J Clin Oncol 15 (2): 418-27, 1997.
- Howard OM, Fairclough DL, Daniels ER, et al.: Physician desire for euthanasia and assisted suicide: would physicians practice what they preach? J Clin Oncol 15 (2): 428-32, 1997.
- Suarez-Almazor ME, Newman C, Hanson J, et al.: Attitudes of terminally ill cancer patients about euthanasia and assisted suicide: predominance of psychosocial determinants and beliefs over symptom distress and subsequent survival. J Clin Oncol 20 (8): 2134-41, 2002.
- Chochinov HM, Wilson KG, Enns M, et al.: Desire for death in the terminally ill. Am J Psychiatry 152 (8): 1185-91, 1995.
- Chandler SW, Trissel LA, Weinstein SM: Combined administration of opioids with selected drugs to manage pain and other cancer symptoms: initial safety screening for compatibility. J Pain Symptom Manage 12 (3): 168-71, 1996.
The use of palliative sedation for psychosocial and existential symptoms can be particularly controversial. The clinician may face many ethical and clinical questions—questions that are more easily resolved in the case of palliative sedation for pain and physical symptoms than for depression and psychosocial symptoms.
For example, the ethical basis for the use of terminal sedation (double effect) is less clearly applicable in the case of psychiatric symptoms. Under the principle of double effect, the intended effect (relieving psychological suffering) would be considered allowable as long as any risks or negative effects (i.e., shortened survival) are unintended by the health care professional. The difficulty arises because the principle only discusses the professional's intention, when it is the patient's intention that can be unclear and potentially problematic. Is the depressed patient who no longer wants to suffer depressive symptoms asking only for that relief, or does the patient also intend to ask the professional to shorten his or her life? A clinician who feels uncomfortable in such situations may wish to seek guidance from his or her ethics committee.
Other difficult questions can arise from the potentially negative value that is culturally assigned to detaching oneself, or "zoning out," as a lower form of coping. Should the anxious patient who no longer wants to face the anxiety associated with the end of life and who wants to be sedated be encouraged to work through such issues? Or is it allowable for these patients to have sedation for dealing with their anxiety? How many alternatives should be tried before anxiety is considered unacceptable? When dealing with such requests, professionals should consider their own cultural and religious biases and the cultural and/or religious backgrounds of patients and their families.
Few studies detail the use of terminal sedation for psychosocial symptoms. Four palliative care programs in Israel, South Africa, and Spain participated in one survey. One unique study has described the Japanese experience around the issues of palliative sedation therapy.[Level of evidence: II] A retrospective study at the MD Anderson Cancer Center in Houston included 1,207 patients admitted to the palliative care unit. Palliative sedation was used in 15% of admissions. The most common indications were delirium (82%) and dyspnea (6%). Sedation in these circumstances is often administered on a temporary basis and was reversible in 23% of this group of patients.References:
- Fainsinger RL, Waller A, Bercovici M, et al.: A multicentre international study of sedation for uncontrolled symptoms in terminally ill patients. Palliat Med 14 (4): 257-65, 2000.
- Morita T, Chinone Y, Ikenaga M, et al.: Ethical validity of palliative sedation therapy: a multicenter, prospective, observational study conducted on specialized palliative care units in Japan. J Pain Symptom Manage 30 (4): 308-19, 2005.
- Morita T, Chinone Y, Ikenaga M, et al.: Efficacy and safety of palliative sedation therapy: a multicenter, prospective, observational study conducted on specialized palliative care units in Japan. J Pain Symptom Manage 30 (4): 320-8, 2005.
- Elsayem A, Curry Iii E, Boohene J, et al.: Use of palliative sedation for intractable symptoms in the palliative care unit of a comprehensive cancer center. Support Care Cancer 17 (1): 53-9, 2009.
Pediatric Considerations for Depression
There is limited information concerning the incidence of depression in healthy children. 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 psychological problems including depression, anxiety, sleep disturbances, difficulties in interpersonal relationships, and noncompliance with treatment. These children require referral 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 the majority of 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 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 greater than the rate for the population at large.[Level of evidence: II] One review reported a 17% incidence of depression using the Diagnostic and Statistical Manual for Mental Disorders, 3rd Edition criteria.
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.
Assessment and Diagnosis of Pediatric Depression
The term depression refers to a symptom, a syndrome, a set of psychological responses, or to 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 anorexia, lethargy, sad affect, aggression, weeping, hyperactivity, somatization, fear of death, frustration, feelings of sadness or hopelessness, self criticism, frequent day dreaming, low self-esteem, school refusal, learning problems, slow movements, vacillating hostility towards parents and teachers, and loss of interest in previously pleasurable activities. Differentiating these symptoms from behavioral responses to normal developmental stages is important.
Assessment of depression includes determination of the child's family situation, level of emotional maturity, ability to cope with illness and treatment, age, state of development, previous experience with illness, and personal ego strength.
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, 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. This is due to the fact that developmental issues in childhood are distinctly different from those of adulthood.
A model of childhood affective disorders uses the following explicit criteria:
- Dysphoric mood (children younger than 6 years must also have a sad facial expression).
- At least 4 of the following signs or symptoms present every
day for a period of at least 2 weeks:
- Appetite disturbance.
- Insomnia or hypersomnia.
- Psychomotor agitation or retardation.
- Loss of interest or pleasure in usual activities (children younger than 6 years must also have signs of apathy).
- Fatigue or loss of energy.
- Feelings of worthlessness, self-reproach, or excessive, inappropriate guilt.
- Diminished ability to think or concentrate.
- Recurrent thoughts of death or suicide.
Management of Pediatric Depression
Treatment regimens implemented in 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 should be short term. These drugs should be 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.References:
- Deuber CM: Depression in the school-aged child: implications for primary care. Nurse Pract 7 (8): 26-30, 68, 1982.
- Kazak AE: Psychological issues in childhood cancer survivors. J Assoc Pediatr Oncol Nurses 6 (1): 15-6, 1989.
- O'Malley JE, Koocher G, Foster D, et al.: Psychiatric sequelae of surviving childhood cancer. Am J Orthopsychiatry 49 (4): 608-16, 1979.
- Kaplan SL, Busner J, Weinhold C, et al.: Depressive symptoms in children and adolescents with cancer: a longitudinal study. J Am Acad Child Adolesc Psychiatry 26 (5): 782-7, 1987.
- Fritz GK, Williams JR, Amylon M: After treatment ends: psychosocial sequelae in pediatric cancer survivors. Am J Orthopsychiatry 58 (4): 552-61, 1988.
- Greenberg HS, Kazak AE, Meadows AT: Psychologic functioning in 8- to 16-year-old cancer survivors and their parents. J Pediatr 114 (3): 488-93, 1989.
- Rait DS, Jacobsen PB, Lederberg MS, et al.: Characteristics of psychiatric consultations in a pediatric cancer center. Am J Psychiatry 145 (3): 363-4, 1988.
- Tebbi CK, Bromberg C, Mallon JC: Self-reported depression in adolescent cancer patients. Am J Pediatr Hematol Oncol 10 (3): 185-90, 1988 Fall.
- Kashani J, Hakami N: Depression in children and adolescents with malignancy. Can J Psychiatry 27 (6): 474-7, 1982.
- Archenbach TM, ed.: Manual for the Child Behavior Checklist and Revised Child Behavior Profile. Burlington, Vt: T.M. Achenbach, 1983.
- American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders: DSM-IV-TR. 4th rev. ed. Washington, DC: American Psychiatric Association, 2000.
- Malmquist CP: Major depression in childhood: why don't we know more? Am J Orthopsychiatry 53 (2): 262-8, 1983.
- Pfefferbaum-Levine B, Kumor K, Cangir A, et al.: Tricyclic antidepressants for children with cancer. Am J Psychiatry 140 (8): 1074-6, 1983.
- Coffey BJ: Review and update: benzodiazepines in childhood and adolescence. Psychiatr Ann 23 (6): 332-9, 1993.
- Maisami M, Sohmer BH, Coyle JT: Combined use of tricyclic antidepressants and neuroleptics in the management of terminally ill children: a report on three cases. J Am Acad Child Psychiatry 24 (4): 487-9, 1985.