Depression

Summary Type: Supportive care
Summary Audience: Health professionals
Summary Language: English
Summary Description: Expert-reviewed information summary about the diagnosis, assessment, and treatment of depression in adults and children who have cancer.

Depression

Overview

Depression is a comorbid disabling syndrome that affects approximately 15% to 25% of cancer patients.^1,2,3,4 Depression is believed to affect men and women with cancer equally, and gender-related differences in prevalence and severity have not been adequately evaluated.⁵ Individuals and families who face a diagnosis of cancer will experience varying levels of stress and emotional upset. Depression in patients with cancer not only affects the patients themselves but also has a major negative impact on their families. A survey in England of women with breast cancer showed that among several factors, depression was the strongest predictor of emotional and behavioral problems in their children.⁶ Fear of death, disruption of life plans, changes in body image and self-esteem, changes in social role and lifestyle, and financial and legal concerns are significant issues in the life of any person with cancer, yet serious depression or anxiety is not experienced by everyone who is diagnosed with cancer.

Just as patients require ongoing evaluation for depression and anxiety throughout their course of treatment, so do family caregivers. In a study of family caregivers of patients in the palliative phase of illness, both male and female caregivers experienced significantly more anxiety than normal samples, while there was an increased incidence of Hospital Anxiety and Depression Scale–defined depression among women.^7,

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

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

Sadness and grief are normal reactions to the crises faced during cancer. All people will experience these reactions periodically. Because sadness is common, it is important to distinguish between normal degrees of sadness and depressive disorders. An end-of-life consensus panel review article describes details regarding this important distinction and illustrates the major points using case vignettes.⁸ A critical part of cancer care is the recognition of the levels of depression present and determination of the appropriate level of intervention, ranging from brief counseling or support groups to medication and/or psychotherapy. For example, relaxation and counseling interventions have been shown to reduce psychological symptoms in women with a new diagnosis of gynecological cancer.⁹ Some people may have more difficulty adjusting to the diagnosis of cancer than others and will vary in their responses to the diagnosis. Major depression is not simply sadness or a blue mood. Major depression affects approximately 25% of patients and has recognizable symptoms that can and should be diagnosed and treated because they have an impact on quality of life.^10,11, Depression is also an underdiagnosed disorder in the general population. Symptoms evident at the time of a cancer diagnosis may represent a preexisting condition and warrant separate evaluation and treatment.

Normally, a patient's initial emotional response to a diagnosis of cancer is brief, extending over several days to weeks, and may include feelings of disbelief, denial, or despair. This normal response is part of a spectrum of depressive symptoms that range from normal sadness to adjustment disorder with depressed mood to major depression.⁸ Other syndromes described include dysthymia and subsyndromal depression (also called minor depression or subclinical depression). Dysthymia is a chronic mood disorder in which a depressed mood is present on more days than not for at least 2 years. In contrast, subsyndromal depression is an acute mood disorder that is less severe (some, but not all, diagnostic symptoms present) than major depression.

The emotional response to a diagnosis of cancer (or cancer relapse) may begin as a dysphoric period marked by increasing turmoil. The individual will experience sleep and appetite disturbance, anxiety, ruminative thoughts, and fears about the future. Epidemiologic studies, however, suggest that at least one half of all people diagnosed with cancer will successfully adapt. Markers of successful adaptation include maintaining active involvement in daily life; minimizing the disruptions caused by the illness to one's life roles (e.g., spouse, parent, employee); regulating the normal emotional reactions to the illness; and managing feelings of hopelessness, helplessness, worthlessness, and/or guilt.¹² 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.¹³ Recent studies suggest an association between maladaptive coping styles with higher levels of depression, anxiety, and fatigue symptoms.^14,15 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.¹⁵ 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.¹⁴ 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.¹⁴ 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.¹⁶ The following indicators may suggest a need for early intervention: a history of depression, a weak social support system (not married, few friends, a solitary work environment), evidence of persistent irrational beliefs or negativistic thinking regarding the diagnosis, a more serious prognosis, and greater dysfunction related to cancer.

Cancer-related depression is not substantially different from depression in other medical conditions, but treatments may need to be adapted or refined for cancer patients.¹⁷ 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.¹⁸ Even in the absence of any symptoms, many patients express interest in supportive counseling, and clinicians should try to accommodate those patients by a referral to a qualified mental health professional. When symptoms are more intense, longer lasting, or recurrent after apparent resolution, however, treatment to alleviate symptoms is essential.^11,19,20 Anxiety and depression in early treatment are good predictors of these same problems at 6 months.²¹ 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.^22,

¹ Henriksson MM, Isometsä ET, Hietanen PS, et al.: Mental disorders in cancer suicides. J Affect Disord 36 (1-2): 11-20, 1995.

² Bodurka-Bevers D, Basen-Engquist K, Carmack CL, et al.: Depression, anxiety, and quality of life in patients with epithelial ovarian cancer. Gynecol Oncol 78 (3 Pt 1): 302-8, 2000.

³ Lloyd-Williams M, Friedman T: Depression in palliative care patients--a prospective study. Eur J Cancer Care (Engl) 10 (4): 270-4, 2001.

⁴ Derogatis LR, Morrow GR, Fetting J, et al.: The prevalence of psychiatric disorders among cancer patients. JAMA 249 (6): 751-7, 1983.

⁵ Miaskowski C: Gender differences in pain, fatigue, and depression in patients with cancer. J Natl Cancer Inst Monogr (32): 139-43, 2004.

⁶ Watson M, St James-Roberts I, Ashley S, et al.: Factors associated with emotional and behavioural problems among school age children of breast cancer patients. Br J Cancer 94 (1): 43-50, 2006.

⁷ Grov EK, Dahl AA, Moum T, et al.: Anxiety, depression, and quality of life in caregivers of patients with cancer in late palliative phase. Ann Oncol 16 (7): 1185-91, 2005.

⁸ Block SD: Assessing and managing depression in the terminally ill patient. ACP-ASIM End-of-Life Care Consensus Panel. American College of Physicians - American Society of Internal Medicine. Ann Intern Med 132 (3): 209-18, 2000.

⁹ Petersen RW, Quinlivan JA: Preventing anxiety and depression in gynaecological cancer: a randomised controlled trial. BJOG 109 (4): 386-94, 2002.

¹⁰ Massie MJ, Holland JC: The cancer patient with pain: psychiatric complications and their management. Med Clin North Am 71 (2): 243-58, 1987.

¹¹ Lynch ME: The assessment and prevalence of affective disorders in advanced cancer. J Palliat Care 11 (1): 10-8, 1995 Spring.

¹² 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.

¹³ Edwards B, Clarke V: The psychological impact of a cancer diagnosis on families: the influence of family functioning and patients' illness characteristics on depression and anxiety. Psychooncology 13 (8): 562-76, 2004.

¹⁴ Reddick BK, Nanda JP, Campbell L, et al.: Examining the influence of coping with pain on depression, anxiety, and fatigue among women with breast cancer. J Psychosoc Oncol 23 (2-3): 137-57, 2005.

¹⁵ Beresford TP, Alfers J, Mangum L, et al.: Cancer survival probability as a function of ego defense (adaptive) mechanisms versus depressive symptoms. Psychosomatics 47 (3): 247-53, 2006 May-Jun.

¹⁶ Nelson CJ, Rosenfeld B, Breitbart W, et al.: Spirituality, religion, and depression in the terminally ill. Psychosomatics 43 (3): 213-20, 2002 May-Jun.

¹⁷ 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.

¹⁸ Meyer TJ, Mark MM: Effects of psychosocial interventions with adult cancer patients: a meta-analysis of randomized experiments. Health Psychol 14 (2): 101-8, 1995.

¹⁹ Massie MJ, Holland JC: Overview of normal reactions and prevalence of psychiatric disorders. In: Holland JC, Rowland JH, eds.: Handbook of Psychooncology: Psychological Care of the Patient With Cancer. New York, NY: Oxford University Press, 1989, pp 273-82.

²⁰ Massie MJ, Shakin EJ: Management of depression and anxiety in cancer patients. In: Breitbart W, Holland JC, eds.: Psychiatric Aspects of Symptom Management in Cancer Patients. Washington, DC: American Psychiatric Press, 1993, pp 470-91.

²¹ Nordin K, Glimelius B: Predicting delayed anxiety and depression in patients with gastrointestinal cancer. Br J Cancer 79 (3-4): 525-9, 1999.

²² Goodwin JS, Zhang DD, Ostir GV: Effect of depression on diagnosis, treatment, and survival of older women with breast cancer. J Am Geriatr Soc 52 (1): 106-11, 2004.

Assessment and Diagnosis

Symptoms and Risk Factors

The symptoms of major depression are as follows:

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

Cognitive symptoms may express themselves as repeated and ruminative thoughts such as “I brought this on myself," "God is punishing me," or "I'm letting my family down,” and as fatalistic expectations concerning prognosis, despite realistic evidence to the contrary. Such thinking may predominate or may alternate with more realistic thinking, yet remain very stressful. Some individuals will share negativistic thoughts freely, and family members may be aware of them. Other patients will not volunteer such thinking but will respond to brief inquiries such as the following (other examples are listed in the Suggested Questions For the Assessment of Depressive Symptoms in Adults With Cancer table):

• “Many people find themselves dwelling on thoughts about their cancer. What kinds of thoughts do you have?”
• “Do you find yourself ever thinking I brought this on myself, God is punishing me? How often? Only a few times a week, or all the time? Do you believe these thoughts are true?”
• “In spite of these thoughts, are you still able to go on with your life and find pleasure in things? Or, are you so preoccupied that you can't sleep, or feel hopeless?”

It is possible for a physician or nurse to ask these types of questions without becoming engaged in providing counseling themselves. Merely asking these questions will express concern and increase the likelihood that the patient will be receptive to suggestions for further counseling.

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

“Many people with cancer sometimes have these feelings. You are not alone. But talking to someone else about them can greatly help. I'd like to suggest that you consider doing that. Would you be willing to talk to someone who has a lot of experience helping people cope with the stress of having cancer?”

It is preferable at this time both to encourage the patient to seek out someone already known to him or her and to inform him or her of other resources in the community. Particularly for patients who have completed cancer treatment and who have manageable physical symptoms, higher perceived availability of social support has been associated with fewer depressive symptoms.² In some instances, referral to a clergy person or therapist may also be appropriate. Most therapists can address general issues of grief or fears about death; some will specialize in clinical health psychology, medical social work, or even working primarily with cancer patients. For the hesitant patient, suggesting multiple resources will increase the likelihood that some assistance will be sought. For other patients, a formal direct referral may be appropriate.

Evaluation of depression in people with cancer should include careful assessment of symptoms, treatment effects, laboratory data results, physical status, and mental status. Although the etiology of depression is largely unknown, many risk factors for depression are known (see list below). Limited data suggest that depressive symptomatology in cancer patients undergoing cytokine therapy with interferon-alfa and interleukin-2 may be mediated by changes in availability of neurotransmitter precursors.³ For patients with head and neck cancer treated with curative intent, 8 pretreatment variables (tumor stage, sex, depressive symptoms, openness to discuss cancer in the family, perceived available support, received emotional support, tumor-related symptoms, and size of the informal social network) can be used to predict which patients are likely to become depressed up to 3 years after treatment.^4,5 A prospective study of terminally ill Japanese patients who were assessed for psychiatric illness by structured clinical interview at the time of registration (baseline) and again at admission to a palliative care unit (follow-up) found that 5 (42%) of the 12 patients diagnosed with adjustment disorder at baseline progressed to major depression at follow-up. Only the Hospital Anxiety and Depression Scale was significantly predictive of psychiatric diagnoses at follow-up.⁶ Heightened awareness of this facilitates early diagnosis and the use of appropriate interventions.⁷ For some cancer populations, such as those status-post stem cell transplantation, preliminary data suggest an association between depressive symptoms and survival. If confirmed, diagnosis and treatment of depression may afford an opportunity to impact mortality as well as quality of life.^8, In the medically ill, early manifestations of delirium may be mistaken for anxiety or depression. These disorders should be considered among the differential diagnoses in individuals who present with depressive symptoms.

Risk Factors for Depression in People With Cancer
• Cancer-related risk factors:
  • Depression at time of cancer diagnosis.^9,10,
  • Poorly controlled pain.^11,
  • Advanced stage of cancer.^11,
  • Increased physical impairment or discomfort.
  • Pancreatic cancer.^12,
  • Being unmarried and having head and neck cancer.^13,
  • Treatment with certain chemotherapeutic agents:
    • Corticosteroids.
    • Procarbazine.
    • L-Asparaginase.
    • Interferon-alfa.^3,14,
    • Interleukin-2.^3,14,15,
    • Amphotericin-B.
• Noncancer-related risk factors:
  • History of depression:
    • Two or more episodes in a lifetime.
    • First episode early or late in life.
  • Lack of family support.^9,
  • Additional concurrent life stressors.^16,
  • Family history of depression or suicide.
  • Previous suicide attempts.
  • History of alcoholism or drug abuse.
  • Concurrent illnesses that produce depressive symptoms (i.e., stroke or myocardial infarction).
  • Past treatment for psychological problems.^17,

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.¹⁸ Among the physically ill, in general, instruments used to measure depression have not been shown to be more clinically useful than an interview and a thorough examination of mental status. Simply asking the patient whether he or she is depressed may improve the identification of depression. In persons with advanced cancer, a single-item interview question has been found to have acceptable psychometric properties and can be useful. One example is to ask “Are you depressed?”¹⁹ Another example is to say, “Please grade your mood during the past week by assigning it a score from 0 to 100, with a score of 100 representing your usual relaxed mood.” A score of 60 is considered a passing grade.²⁰ Other screening tools that have been used and validated in cancer populations include the Hospital Anxiety and Depression Scale,²¹ the Psychological Distress Inventory,²² and the Edinburgh Depression Scale.²³ The Hospital Anxiety and Depression Scale may have limited utility in certain patient populations such as early-stage breast cancer ²⁴ and palliative care.^25,26 The Brief Symptom Inventory, the Zung Self-Rating Depression Scale, and The Distress Thermometer are commonly used screening tools.^27,28,29 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.³⁰ 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.^31,

It is important that screening instruments be validated in cancer populations and used in combination with structured diagnostic interviews.³² 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.^7,33 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.³⁴ Because of the increased risk of adjustment disorders and major depression in cancer patients, routine screening with increased vigilance at times of increased stress (i.e., diagnosis, recurrences, progression) is recommended. General risk factors for depression are noted in the list above. Other risk factors may pertain to specific populations, i.e., patients with head and neck cancer ⁴ and women at high risk for the development of breast cancer.^35,

Clinical interview

Suggested Questions For the Assessment of Depressive Symptoms in Adults With Cancer*

QuestionSymptom*Adapted from Roth et al.^36, How 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.^37,

Possible Medical Causes of Depression in People With Cancer*
• Uncontrolled pain.^11,
• Metabolic abnormalities:
  • Hypercalcemia.
  • Sodium/potassium imbalance.
  • Anemia.
  • Vitamin B12 or folate deficiency.
  • Fever.
• Endocrine abnormalities:
  • Hyperthyroidism or hypothyroidism.
  • Adrenal insufficiency.
• Medications:^{3,15,38,39,40,}
  • Steroids.
  • Endogenous and exogenous cytokines, i.e., interferon-alfa and aldesleukin (interleukin-2, IL-2).^41,
  • Methyldopa.
  • Reserpine.
  • Barbiturates.
  • Propranolol.
  • Some antibiotics (e.g., amphotericin B).
  • Some chemotherapeutic agents (e.g., procarbazine, L-asparaginase).

Diagnosis

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.^42,

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.⁴³ 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.⁴⁴ The symptoms appear to be prolonged and in excess of a normal and expected reaction but do not meet the criteria for a major depressive episode. When these symptoms significantly interfere with a person's daily functioning, such as attending to work or school activities, shopping, or caring for a household, they should be treated in the same way that major depression is treated (i.e., consider using crisis intervention, supportive psychotherapy, and medication, especially with drugs that quickly relieve distressing symptoms). Basing the diagnosis on these symptoms can be problematic when the individual has advanced disease and the illness itself is undermining functioning. It is also important to distinguish between fatigue and depression, which are often interrelated. The different mechanisms that give rise to these conditions can be treated separately.¹ In more advanced illness, focusing on despair, guilty thoughts, and a total lack of enjoyment of life is helpful in diagnosing depression. (Refer to the PDQ summary Normal Adjustment and the Adjustment Disorders for further information.)

¹ Jacobsen PB, Donovan KA, Weitzner MA: Distinguishing fatigue and depression in patients with cancer. Semin Clin Neuropsychiatry 8 (4): 229-40, 2003.

² De Leeuw JR, De Graeff A, Ros WJ, et al.: Negative and positive influences of social support on depression in patients with head and neck cancer: a prospective study. Psychooncology 9 (1): 20-8, 2000 Jan-Feb.

³ Capuron L, Ravaud A, Neveu PJ, et al.: Association between decreased serum tryptophan concentrations and depressive symptoms in cancer patients undergoing cytokine therapy. Mol Psychiatry 7 (5): 468-73, 2002.

⁴ de Leeuw JR, de Graeff A, Ros WJ, et al.: Prediction of depression 6 months to 3 years after treatment of head and neck cancer. Head Neck 23 (10): 892-8, 2001.

⁵ Paice JA: Managing psychological conditions in palliative care. Am J Nurs 102 (11): 36-42; quiz 43, 2002.

⁶ Akechi T, Okuyama T, Sugawara Y, et al.: Major depression, adjustment disorders, and post-traumatic stress disorder in terminally ill cancer patients: associated and predictive factors. J Clin Oncol 22 (10): 1957-65, 2004.

⁷ Passik SD, Kirsh KL, Theobald D, et al.: Use of a depression screening tool and a fluoxetine-based algorithm to improve the recognition and treatment of depression in cancer patients. A demonstration project. J Pain Symptom Manage 24 (3): 318-27, 2002.

⁸ Loberiza FR Jr, Rizzo JD, Bredeson CN, et al.: Association of depressive syndrome and early deaths among patients after stem-cell transplantation for malignant diseases. J Clin Oncol 20 (8): 2118-26, 2002.

⁹ Nordin K, Glimelius B: Predicting delayed anxiety and depression in patients with gastrointestinal cancer. Br J Cancer 79 (3-4): 525-9, 1999.

¹⁰ Karnell LH, Funk GF, Christensen AJ, et al.: Persistent posttreatment depressive symptoms in patients with head and neck cancer. Head Neck 28 (5): 453-61, 2006.

¹¹ Ciaramella A, Poli P: Assessment of depression among cancer patients: the role of pain, cancer type and treatment. Psychooncology 10 (2): 156-65, 2001 Mar-Apr.

¹² Green AI, Austin CP: Psychopathology of pancreatic cancer. A psychobiologic probe. Psychosomatics 34 (3): 208-21, 1993 May-Jun.

¹³ Kugaya A, Akechi T, Okuyama T, et al.: Prevalence, predictive factors, and screening for psychologic distress in patients with newly diagnosed head and neck cancer. Cancer 88 (12): 2817-23, 2000.

¹⁴ Capuron L, Ravaud A, Gualde N, et al.: Association between immune activation and early depressive symptoms in cancer patients treated with interleukin-2-based therapy. Psychoneuroendocrinology 26 (8): 797-808, 2001.

¹⁵ Capuron L, Ravaud A, Dantzer R: Early depressive symptoms in cancer patients receiving interleukin 2 and/or interferon alfa-2b therapy. J Clin Oncol 18 (10): 2143-51, 2000.

¹⁶ Green BL, Krupnick JL, Rowland JH, et al.: Trauma history as a predictor of psychologic symptoms in women with breast cancer. J Clin Oncol 18 (5): 1084-93, 2000.

¹⁷ Burgess CC, Ramirez AJ, Richards MA, et al.: Does the method of detection of breast cancer affect subsequent psychiatric morbidity? Eur J Cancer 38 (12): 1622-5, 2002.

¹⁸ Passik SD, Dugan W, McDonald MV, et al.: Oncologists' recognition of depression in their patients with cancer. J Clin Oncol 16 (4): 1594-600, 1998.

¹⁹ Chochinov HM, Wilson KG, Enns M, et al.: "Are you depressed?" Screening for depression in the terminally ill. Am J Psychiatry 154 (5): 674-6, 1997.

²⁰ Akizuki N, Akechi T, Nakanishi T, et al.: Development of a brief screening interview for adjustment disorders and major depression in patients with cancer. Cancer 97 (10): 2605-13, 2003.

²¹ Zigmond AS, Snaith RP: The hospital anxiety and depression scale. Acta Psychiatr Scand 67 (6): 361-70, 1983.

²² Morasso G, Costantini M, Baracco G, et al.: Assessing psychological distress in cancer patients: validation of a self-administered questionnaire. Oncology 53 (4): 295-302, 1996 Jul-Aug.

²³ Lloyd-Williams M, Riddleston H: The stability of depression scores in patients who are receiving palliative care. J Pain Symptom Manage 24 (6): 593-7, 2002.

²⁴ Love AW, Kissane DW, Bloch S, et al.: Diagnostic efficiency of the Hospital Anxiety and Depression Scale in women with early stage breast cancer. Aust N Z J Psychiatry 36 (2): 246-50, 2002.

²⁵ Lloyd-Williams M, Friedman T, Rudd N: An analysis of the validity of the Hospital Anxiety and Depression scale as a screening tool in patients with advanced metastatic cancer. J Pain Symptom Manage 22 (6): 990-6, 2001.

²⁶ Lloyd-Williams M, Spiller J, Ward J: Which depression screening tools should be used in palliative care? Palliat Med 17 (1): 40-3, 2003.

²⁷ Roth AJ, Kornblith AB, Batel-Copel L, et al.: Rapid screening for psychologic distress in men with prostate carcinoma: a pilot study. Cancer 82 (10): 1904-8, 1998.

²⁸ Derogatis LR, Melisaratos N: The Brief Symptom Inventory: an introductory report. Psychol Med 13 (3): 595-605, 1983.

²⁹ Dugan W, McDonald MV, Passik SD, et al.: Use of the Zung Self-Rating Depression Scale in cancer patients: feasibility as a screening tool. Psychooncology 7 (6): 483-93, 1998 Nov-Dec.

³⁰ Akizuki N, Yamawaki S, Akechi T, et al.: Development of an Impact Thermometer for use in combination with the Distress Thermometer as a brief screening tool for adjustment disorders and/or major depression in cancer patients. J Pain Symptom Manage 29 (1): 91-9, 2005.

³¹ Meyer HA, Sinnott C, Seed PT: Depressive symptoms in advanced cancer. Part 1. Assessing depression: the Mood Evaluation Questionnaire. Palliat Med 17 (7): 596-603, 2003.

³² Lynch ME: The assessment and prevalence of affective disorders in advanced cancer. J Palliat Care 11 (1): 10-8, 1995 Spring.

³³ Lees N, Lloyd-Williams M: Assessing depression in palliative care patients using the visual analogue scale: a pilot study. Eur J Cancer Care (Engl) 8 (4): 220-3, 1999.

³⁴ 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.

³⁵ Wellisch DK, Lindberg NM: A psychological profile of depressed and nondepressed women at high risk for breast cancer. Psychosomatics 42 (4): 330-6, 2001 Jul-Aug.

³⁶ 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.

³⁷ Breitbart W, Holland JC: Psychiatric complications of cancer. Current Therapy in Hematology-Oncology 3: 268-74, 1988.

³⁸ Cancer chemotherapy. Med Lett Drugs Ther 29 (736): 29-36, 1987.

³⁹ Drugs of choice for cancer chemotherapy. Med Lett Drugs Ther 33 (840): 21-8, 1991.

⁴⁰ Drugs that cause psychiatric symptoms. Med Lett Drugs Ther 31 (808): 113-8, 1989.

⁴¹ Menzies H, Chochinov HM, Breitbart W: Cytokines, cancer and depression: connecting the dots. J Support Oncol 3 (1): 55-7, 2005 Jan-Feb.

⁴² Reuter K, Raugust S, Bengel J, et al.: Depressive symptom patterns and their consequences for diagnosis of affective disorders in cancer patients. Support Care Cancer 12 (12): 864-70, 2004.

⁴³ Detmar SB, Aaronson NK, Wever LD, et al.: How are you feeling? Who wants to know? Patients' and oncologists' preferences for discussing health-related quality-of-life issues. J Clin Oncol 18 (18): 3295-301, 2000.

⁴⁴ Nordin K, Wasteson E, Hoffman K, et al.: Discrepancies between attainment and importance of life values and anxiety and depression in gastrointestinal cancer patients and their spouses. Psychooncology 10 (6): 479-89, 2001 Nov-Dec.

Intervention

Whether to initiate therapy for depression depends on the probability that the patient will recover spontaneously in the next 2 to 4 weeks, the degree of functional impairment, and the severity and duration of the depressive symptoms.¹ Studies have shown that treatment of major depression is optimized by a combination of pharmacotherapy and psychotherapy. Thus, even if a primary care physician or oncologist undertakes the treatment of depressive symptoms pharmacologically, a referral for psychotherapy or supportive counseling should be considered.

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

• A primary care physician or oncologist does not feel competent treating the patient for depression because of specific clinical features in the presentation (i.e., if prominent suicidal tendencies are present).
• The depressive symptoms treated by the primary physician are resistant to pharmacologic interventions after 2 to 4 weeks of intervention.
• The depressive symptoms are worsening rather than improving.
• Initiating treatment with antidepressant drugs, titrating drug doses, or continuing treatment is interrupted or made problematic by adverse effects attributable to the medication.
• The depressive symptoms are interfering with the patient's ability to be cooperative with medical treatment.^2,3,4,

Pharmacologic Intervention

Overview

There is a paucity of randomized, placebo-controlled trials assessing the risks and benefits of antidepressants in patients with cancer and depression or depressive symptoms. Furthermore, these studies are limited by methodological challenges and a lack of broad representation of children, adolescents, older adults, and minority groups.⁵ In certain cases of depression in patients with cancer, antidepressant therapy may be indicated. A survey of prescribing patterns in outpatient oncology settings over a 2-year period found that antidepressants were prescribed for about 14% of patients.⁶ In a systematic review of newer pharmacotherapies for depression in adults, the response rate for treatment of depression with antidepressants was found to be approximately 54%.⁷ The efficacy of the newer pharmacotherapies is similar to that of older antidepressants for general medical patients, including older adults and those with coexisting medical or psychiatric illness.⁷ The dropout rates due to adverse effects are approximately 11% for newer antidepressants and 16% for older antidepressants.⁷ Because of the relative paucity of data regarding antidepressant use in oncology settings, there is considerable variability in practice patterns related to prescribing antidepressants in cancer patients. Although studies generally indicate that about 25% of all cancer patients are depressed, one study found that only 16% of cancer patients were receiving antidepressant medication.^8,

Antidepressant Studies
• In adults, a double-blind placebo-controlled trial comparing fluoxetine with desipramine in treating depressive symptoms in 40 women with cancer found both medications to be effective and well tolerated. There were greater improvements on several quality-of-life measures in patients who received fluoxetine.⁹
• One study compared paroxetine with amitriptyline in the management of depression in women with breast cancer. Both treatments were equally effective. Paroxetine was associated with significantly fewer anticholinergic adverse effects than amitriptyline.^10,
• In a randomized controlled trial comparing fluoxetine with a placebo, patients receiving fluoxetine were found to have improved quality of life and decreased depressive symptoms.¹¹ Using a symptom-based approach (similar to the management of other cancer-related symptoms such as pain or nausea), this study assessed for depression by use of a 2-item screening procedure focused on presence of anhedonia (little interest or pleasure in doing things) and depressed or hopeless mood. Most of the sample consisted of patients with mild-to-moderate levels of depressive symptoms regardless of whether they met the diagnostic criteria for depression. Generalization was enhanced by inclusion of a sample of mixed cancer types (e.g., breast, thoracic, genitourinary, gastrointestinal) from a predominantly community cancer care setting, an equal male/female ratio, and a relatively large sample size (n = 163). A subgroup of patients identified as having higher levels of depressive symptoms was most likely to benefit from the treatment.

Interferon-related depression

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.¹² 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). The following table outlines the commonly used antidepressants and highlights starting dosages used in cancer patients. The Side Effects/Comments column identifies drug-specific side effects that may be clinically advantageous or problematic depending on the clinical situation when selecting antidepressant medications and monitoring patients receiving these drugs. Generally, there is a long latency period (3–6 weeks) from initiation of antidepressant medications until the onset of a therapeutic response. In many cases, antidepressant treatment begins at low doses followed by a period of gradual dose titration to achieve an optimum individualized response. Initial low doses may help to avoid initial side effects, but dose escalation may be required in order to see therapeutic effects. For some agents, there is a therapeutic window during which plasma concentrations correlate with a patient's antidepressant response (e.g., nortriptyline). For patients receiving these agents, serial drug concentration monitoring guides therapy and facilitates providing an adequate therapeutic trial, because plasma concentrations less than and greater than the defined therapeutic ranges are associated with treatment failure, suboptimal responses, and in the case of high drug concentrations, unnecessary toxicity.

Antidepressant Medications for Ambulatory Adult Patients

*Drug Class/Generic Name (Proprietary Name)/DosagesSide Effects/Comments*Consult complete prescribing information for appropriate administration schedules.Notes: aTCAs 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.bPlasma 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. cTCAs 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).dCommon 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. TRICYCLIC ANTIDEPRESSANTS (TCAs)All TCAs can 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.aIn responding patients, decrease daily dosages to the lowest effective amount needed to sustain a response.b TCAs can cause sexual dysfunction.Treatment may be associated with weight gain.c amitriptyline (Elavil) Marked sedation; dizziness; headache; weight gain; anticholinergic effects;d orthostatic blood pressure (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/day clomipramine (Anafranil) Anticholinergic effects; dizziness; drowsiness; headache; weight gain; orthostatic hypotension. initial: 25 mg/day and gradually increase to 100 mg/day the first 2 weeks; may be given at bedtime maintenance: 100–250 mg/day maximum desipramine (Norpramin)Mild sedation; increased appetite; nausea; minimal anticholinergic effects;d orthostatic BP changes. Therapeutic plasma concentrations = 125–300 ng/mL. initial: 25–50 mg/day as a single daily dose, preferably at bedtime maintenance: 100–300 mg/day as a single daily dose; In elderly patients, daily doses >150 mg are not recommended doxepin (Sinequan) Moderately to very sedating; dizziness; headache; weight gain; moderate anticholinergic effects;d postural hypotension. Optimal antidepressant effect is characteristically delayed by 2–3 weeks; however, onset of antianxiety effect is comparatively rapid. Therapeutic plasma concentrations (parent drug + active metabolite) = 100–200 ng/mL.initial: 10–25 mg/day as a single daily dose, preferably at bedtime maintenance: 75–300 mg/day as a single daily dose, preferably at bedtime imipramine (Tofranil) Moderately to very sedating; dizziness; headache; weight gain; moderate anticholinergic effects;d moderate-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/day as a single daily dose, preferably at bedtime maintenance: 75–200 mg/day as a single daily dose, preferably at bedtime nortriptyline (Pamelor, Aventyl) Mild-moderate sedation; constipation; nausea; increased appetite; mild-moderate anticholinergic effects;d 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 recommendedSELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs) SSRIs have few anticholinergic and cardiovascular adverse effects. Life-threatening and fatal reactions have occurred in patients who receive SSRIs within 2 weeks of using monoamine oxidase inhibitor antidepressants. Sexual dysfunction has been reported to be associated with SSRI use. There is limited experience with long-term use. citalopram (Celexa) Ejaculation disorder; other sexual dysfunctions; insomnia; dry mouth; nausea; somnolence. In vitro studies indicated that CYP3A4 and CYP2C19 are the primary enzymes involved in the metabolism of citalopram. Citalopram is a relatively weak inhibitor of CYP2D6.initial: 10 mg/day maintenance: 10–40 mg/dayfluoxetine (Prozac) Anxiety; nervousness; insomnia; anorexia; mild bradycardia; sinoatrial node slowing; weight loss; solar photosensitivity; hyponatremia; sexual dysfunction; may alter glycemic control in diabetic patients. Fluoxetine substantially inhibits CYP2D6 and may inhibit the clearance of other drugs metabolized by cytochrome P450 CYP2D6 isozymes.^13, Fluoxetine probably inhibits CYP2C9/10, moderately inhibits CYP2C19, and mildly inhibits CYP3A4;¹³ fluoxetine metabolism is impaired in elderly patients. initial: 10–20 mg/day maintenance: 20–80 mg/day escitalopram (Lexapro)Nausea, vomiting, diarrhea, constipation, upset stomach, loss of appetite, dizziness, drowsiness, trouble sleeping, back pain, or dry mouth.initial: 10 mg/daymaintenance: 10–20 mg/dayfluvoxamine (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/day paroxetine (Paxil) Anxiety; nervousness; insomnia; mild weight loss; headache; solar photosensitivity; hyponatremia; sexual dysfunction. Paroxetine substantially inhibits and may interact with other drugs metabolized by cytochrome P450 CYP2D6 isozyme.^13, Paroxetine metabolism is impaired in elderly patients. initial: 10–20 mg/daymaintenance: 20–50 mg/day 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.^13,initial: 25–50 mg/day maintenance: 50–200 mg/day MONOAMINE OXIDASE INHIBITORS (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/dayphenelzine (Nardil)Orthostatic hypotension; drowsiness; hyperexcitability; headache. Low tyramine diet required.initial: 15 mg 3 times a day maintenance: 15–90 mg/dayselegiline (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, with a history of seizure, in those with concomitant conditions predisposing to seizure, and in patients taking other drugs that lower seizure threshold. Mild-moderate sedation; mild-moderate anticholinergic effects;d mild orthostatic BP changes; agitation; insomnia; headache; confusion; dizziness; seizures; weight loss. initial: 75 mg/day maintenance: 200–450 mg/day not to exceed 150 mg/dose trazodone (Desyrel) Mild-moderate sedation; negligible anticholinergic effects; mild-moderate orthostatic BP changes, particularly in elderly patients; dizziness; headache; confusion; muscle tremors; may produce priapism; taking trazodone with food can decrease gastrointestinal upset. Therapeutic plasma concentrations = 800–1,600 ng/mL. initial: 50 mg/day maintenance: 150–600 mg/day nefazodone (Serzone) Postural hypotension (although <TCAs); less sexual dysfunction than is reported with SSRIs. Headache; drowsiness; insomnia; agitation; confusion; nausea; tremor. Potential interaction with drugs metabolized by cytochrome P450 isozymes, CYP2D6 and CYP3A4. Check liver function tests at baseline and periodically during therapy. May cause fatal hepatotoxicity.initial: 100 mg twice daily maintenance: 300–600 mg/day mirtazapine (Remeron) A tetracyclic antidepressant. Mirtazapine 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 the seizure threshold (e.g., phenothiazines), mirtazapine may increase the risk of seizure.initial: 7.5–15 mg/day maintenance: 15–45 mg/day venlafaxine (Effexor) Dose-related sustained hypertension. Headache; dizziness; insomnia; nausea; constipation; abnormal ejaculation. Life-threatening and fatal reactions have occurred in patients who received venlafaxine within 2 weeks of using monoamine oxidase antidepressants.initial: 75 mg/day maintenance: 150–375 mg/day duloxetine (Cymbalta)Nausea, dry mouth, constipation, decreased appetite, fatigue, sleepiness, and increased sweating; decreased sexual drive or ability; urinary hesitation.initial: 30 mg/daymaintenance: 30–60 mg/dayPsychostimulants Psychostimulants may cause restlessness, agitation, insomnia, nightmares, psychosis, anorexia; and may exacerbate preexisting cardiac disease. Psychostimulants should be administered early in a patient's daily waking cycle. Psychostimulants are 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-severe hypertension, and glaucoma.initial: 2.5–5 mg/daymaintenance: 10–30 mg/day methylphenidate (Ritalin, Methylin) Drug tolerance, abuse, and dependence liability. Hypertension; may decrease the convulsive threshold in patients with a history of seizure disorders. Tachycardia; nervousness; insomnia; anorexia; drowsiness; dizziness.initial: 2.5–10 mg/day maintenance: 20-60 mg/day 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/daymaintenance: 10–20 mg/day

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

Significant concern about the potential for suicide as a side effect of selective serotonin reuptake inhibitors (SSRIs) has led the U.S. Food and Drug Administration (FDA) to issue a caution about their use that includes the importance of careful monitoring of potential risks.¹⁴ Before this FDA Health Advisory was issued, clinical experience and the results of small clinical trials suggested that antidepressants can be safely administered to adult cancer patients, although there are no controlled clinical trials to support this position. When SSRIs are prescribed for adult cancer patients, a careful follow-up plan should be implemented by individuals with expertise, and consultation referrals should be made for patients who do not respond as anticipated or who present other concerns.¹⁵ The risk/benefit ratio for use of SSRIs may not be as favorable for children and adolescents. Several multicenter, double-blind, randomized, placebo-controlled clinical trials using SSRIs with children and adolescents with major depressive disorder but not cancer found modest improvements for fluoxetine,^16,17 paroxetine,¹⁸ and sertraline.¹⁹ Balancing these improvements were reports of serious adverse events that included worsening of psychiatric symptoms, increased suicidal ideation and gestures, increased conduct problems or hostility with paroxetine,¹⁸ and suicide and suicide attempts with sertraline.¹⁹ None of these clinical trials have included or focused on children and adolescents being treated for cancer. Risk/benefit concerns have reached the level of international regulatory concern. The Medicines and Healthcare Products Regulatory Agency of Great Britain has recommended that most of the drugs in the SSRI category not be used with children and adolescents,²⁰ and the FDA raised similar concerns in a Talk Paper and subsequently issued a "black box" warning.²¹ The British Committee on Safety of Medicines considered only 1 of the SSRIs (fluoxetine) to have a favorable balance of risks and benefits, but it is only considered beneficial in approximately 1 in 10 patients.²² 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.^23,

Side effects

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.²⁴ 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.

Drug-drug interactions

Clinicians who prescribe and monitor patients receiving antidepressants should also become familiar with their potential for interactions with other medications.²⁵ 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.¹³ 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.²⁶ 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.²⁷

Atypical antidepressants

• Bupropion

  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 with a history of cranial trauma or seizure disorder ²⁸ and in persons with a history of bulimia. ^29,

• Venlafaxine

  Venlafaxine affects both norepinephrine and serotonin reuptake and enhances serotonin neurotransmission.³⁰ Venlafaxine does not produce the same uncomfortable antimuscarinic and antiadrenergic side effects as the TCAs; however, it does produce side effects similar to the 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.

• Trazodone and nefazodone

  The primary actions of the atypical antidepressants trazodone and nefazodone are not well established. Although they both antagonize serotonin reuptake, they are many times weaker in this respect compared with SSRIs. Trazodone is active, and both agents are metabolized to compounds that have agonistic activity at some serotonin receptors (5-HT1). Both agents may have additional active metabolites that contribute to their clinical activity.³⁰ Nefazodone is reported to be useful in patients with agitated depression and may be better tolerated than the SSRIs. Nefazodone can complicate some patients' management because it is a potent inhibitor of hepatic cytochrome P450 3A4 isoenzymes. Its use is, therefore, relatively contraindicated in patients who are receiving methadone and absolutely contraindicated in those receiving terfenadine or astemizole.

• Mirtazapine

  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 (alpha2) and serotonin receptors (5-HT2 and 5-HT3), the net result of which enhances norepinephrine release and noradrenergic neurotransmission.^30,31, Sedation is the predominating side effect at subtherapeutic low doses (<15 mg/day), 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.³² 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.³³ 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.^34, 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

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.

Psychostimulants

Clinical experience suggests that analeptic agents (e.g., methylphenidate and dextroamphetamine) are useful at low doses for patients whose symptoms include depressed mood, apathy, decreased energy, poor concentration, and weakness.³⁵ 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.^36,37,

Clinical Trials of Psychostimulants in Cancer Patients

StudyCommentsDrug(s)OutcomeMeyers et al. 1998 ^38,Brain tumor; N = 30methylphenidate (Ritalin)↑ mood, ↑ cognition, ↑ function Olin and Masand 1996 ^39,Mixed cancer; N = 59; chart reviewdextroamphetamine (Dexedrine); methylphenidate (Ritalin) ↓ depression, ↑ appetiteBruera et al. 1992 ^40,Cancer pain vs. opioid infusion; N = 20methylphenidate (Ritalin); placebo↑ cognition, ↓ sedationFernandez et al. 1987 ³⁷ Mixed cancer; rapid onset; N = 30 methylphenidate (Ritalin;up to 80 mg)↓ depressionBruera et al. 1986 ^41,Pain; double-blind cross-over study; N = 24mazindol (Mazanor)↓ pain, ↓ appetite, no effect on mood Joshi et al. 1982 ^42,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.⁴³ 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.^44, 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 U.S. Food and Drug Administration (FDA) has recently 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. To date, 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 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.

Tyramine-Containing Foods*

Class of Food and BeverageTyramine-Rich Foods and Beverages To AvoidAcceptable Foods Containing Little or No TyramineOTC = over-the-counter.*Adapted from the EMSAM Medication Guide.⁴⁵ 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 MAO-B enzyme in the central nervous system but also 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.^46,

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 has been much interest in the use of St. John's wort (SJW, Hypericum perforatum) as an herbal antidepressant. Its use has become widely advertised as an over-the-counter supplement for mood enhancement.

In the United States, dietary supplements are regulated as foods, not drugs. Premarket approval by the FDA is not required unless specific disease prevention or treatment claims are made, which is often not the case with SJW. Because a review for manufacturing consistency is not required for dietary supplements and no specific standards for dose or purity exist, there may be considerable variation from lot to lot for all products marketed as dietary supplements, including SJW.

Promotional statements about SJW may address mood enhancement and positive outlook. It may be found as a stand-alone supplement or in combination with other herbs, vitamin and mineral supplements, or food products such as teas. The FDA issued a warning highlighting the results from a study conducted by the National Institutes of Health that showed a significant drug interaction between SJW and indinavir, a protease inhibitor used to treat HIV infection. In this study, concomitant administration of SJW and indinavir substantially decreased indinavir plasma concentrations, potentially due to induction of the cytochrome P450 metabolic pathway.^47,

While its specific mechanisms of action are unclear, there are 3 presumed active compounds in the herb. One of these compounds is a mild MAOI (see above precautions). Historically, prescription MAOIs have been used to treat depression as well as Parkinson's disease, narcolepsy, and occasionally hypertension, but they are rarely used today. The side effects of SJW include dry mouth, dizziness, gastrointestinal (GI) distress, fatigue, and confusion.

A randomized double-blind placebo-controlled trial involving 200 adult outpatients with major depressive disorder compared the safety and efficacy of SJW with placebo. This study was designed to address the numerous methodological flaws in the existing literature ⁴⁸ that served as the basis for the meta-analysis that had concluded that SJW is significantly superior to placebo.⁴⁹ This study represents the first report of a large-scale randomized placebo-controlled trial of SJW in the United States. This study does not support significant antidepressant or antianxiety effects of SJW. Specifically, compared with placebo, there were no significant differences in response rates in the overall sample of outpatients with major depression. On the basis of these trial data indicating lack of efficacy in depressed patients in primary care settings, as well as the lack of properly designed positive trials in cancer patients, SJW should not be recommended for major depression in cancer patients.

Antidepressant effects

The following tables 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.

Physical Symptom- and Distress-Driven Approach to Choosing an Antidepressant in Adult Cancer Patients

Distressing Symptom SSRI TCA Psychostimulants OtherKey:(-) use of this medication could worsen the symptom(+) use of this medication could relieve the symptomNotes:(a) Although all SSRIs have the potential paradoxical side effect of hypersomnia, fluoxetine is particularly activating. Bupropion is also somewhat activating.(b) Sedating 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. (c) Some antidepressants are useful in treating neuropathic pain. The most studied of these are the TCAs, particularly amitriptyline. (d) Sedating antidepressants are most useful for anxious/agitated patients. These include the TCAs, trazodone, mirtazapine, and nefazodone. SSRI = Selective Serotonin Reuptake InhibitorTCA = Tricyclic AntidepressantIn 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.Fatigue + (a) + + (a)Insomnia (b) + + (b)Neuropathic pain (c) + + Opioid side effects + +Constipation + +Loss of appetite (weight loss) + +Anxiety + + + (d)Dry mouth/stomatitis + - +

Factors to Consider in Choosing an Antidepressant For Adult Cancer Patients

Comorbid Medical ConditionsSSRI TCA Psychostimulants OtherKey: (-) use of this medication may be a less appropriate choice (+) use of this medication could relieve the symptomNotes:(a) In 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.(b) The 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.(c) Clinicians should consider whether antidepressant doses and administration schedules require modification for their patients with renal or hepatic insufficiency.(d) The TCAs are contraindicated in closed-angle glaucoma. Cardiac history + - + (a) Hepatic dysfunction + (b) + - Renal dysfunction (c) 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.^50,51 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.

Psychotherapy

Overview

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.^52,

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.^{53,54,55,56,57} 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.^58,59 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.^60,61,62 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.⁶³ Recent reviews have also concluded that psychotherapy is an effective intervention for cancer patients experiencing depression.^52,64 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).⁵² However, in those studies in which patients were intentionally selected because they exhibited depressive symptoms, intervention effects were strong (effect size, 0.94).⁶⁴ 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.⁶⁵ 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.

¹ Whooley MA, Simon GE: Managing depression in medical outpatients. N Engl J Med 343 (26): 1942-50, 2000.

² Derogatis LR, Morrow GR, Fetting J, et al.: The prevalence of psychiatric disorders among cancer patients. JAMA 249 (6): 751-7, 1983.

³ Endicott J: Measurement of depression in patients with cancer. Cancer 53 (10 Suppl): 2243-9, 1984.

⁴ Massie MJ, Holland JC: Consultation and liaison issues in cancer care. Psychiatr Med 5 (4): 343-59, 1987.

⁵ Fisch M: Treatment of depression in cancer. J Natl Cancer Inst Monogr (32): 105-11, 2004.

⁶ Ashbury FD, Madlensky L, Raich P, et al.: Antidepressant prescribing in community cancer care. Support Care Cancer 11 (5): 278-85, 2003.

⁷ Williams JW Jr, Mulrow CD, Chiquette E, et al.: A systematic review of newer pharmacotherapies for depression in adults: evidence report summary. Ann Intern Med 132 (9): 743-56, 2000.

⁸ Fisch MJ, Callahan CM, Kesterson JG, et al.: The use of an electronic patient record system to identify advanced cancer patients and antidepressant drug use. J Palliat Med 2 (4): 403-9, 1999.

⁹ Holland JC, Romano SJ, Heiligenstein JH, et al.: A controlled trial of fluoxetine and desipramine in depressed women with advanced cancer. Psychooncology 7 (4): 291-300, 1998 Jul-Aug.

¹⁰ Pezzella G, Moslinger-Gehmayr R, Contu A: Treatment of depression in patients with breast cancer: a comparison between paroxetine and amitriptyline. Breast Cancer Res Treat 70 (1): 1-10, 2001.

¹¹ Fisch MJ, Loehrer PJ, Kristeller J, et al.: Fluoxetine versus placebo in advanced cancer outpatients: a double-blinded trial of the Hoosier Oncology Group. J Clin Oncol 21 (10): 1937-43, 2003.

¹² Musselman DL, Lawson DH, Gumnick JF, et al.: Paroxetine for the prevention of depression induced by high-dose interferon alfa. N Engl J Med 344 (13): 961-6, 2001.

¹³ Preskorn SH: Clinically relevant pharmacology of selective serotonin reuptake inhibitors. An overview with emphasis on pharmacokinetics and effects on oxidative drug metabolism. Clin Pharmacokinet 32 (Suppl 1): 1-21, 1997.

¹⁴ U.S. Food and Drug Administration.: FDA Public Health Advisory (March 22, 2004): Worsening Depression and Suicidality in Patients Being Treated With Antidepressant Medications. Rockville, Md: Food and Drug Administration, Center for Drug Evaluation and Research, 2004. Available online. Last accessed April 24, 2007.

¹⁵ Passik SD, Kirsh KL, Theobald D, et al.: Use of a depression screening tool and a fluoxetine-based algorithm to improve the recognition and treatment of depression in cancer patients. A demonstration project. J Pain Symptom Manage 24 (3): 318-27, 2002.

¹⁶ Emslie GJ, Rush AJ, Weinberg WA, et al.: A double-blind, randomized, placebo-controlled trial of fluoxetine in children and adolescents with depression. Arch Gen Psychiatry 54 (11): 1031-7, 1997.

¹⁷ Emslie GJ, Heiligenstein JH, Wagner KD, et al.: Fluoxetine for acute treatment of depression in children and adolescents: a placebo-controlled, randomized clinical trial. J Am Acad Child Adolesc Psychiatry 41 (10): 1205-15, 2002.

¹⁸ Keller MB, Ryan ND, Strober M, et al.: Efficacy of paroxetine in the treatment of adolescent major depression: a randomized, controlled trial. J Am Acad Child Adolesc Psychiatry 40 (7): 762-72, 2001.

¹⁹ Wagner KD, Ambrosini P, Rynn M, et al.: Efficacy of sertraline in the treatment of children and adolescents with major depressive disorder: two randomized controlled trials. JAMA 290 (8): 1033-41, 2003.

²⁰ Safety Review of Antidepressants Used by Children Completed. London, UK: Medicines and Healthcare Products Regulatory Agency, 2003. Available online. Last accessed April 24, 2007.

²¹ US Food and Drug Administration.: FDA Public Health Advisory (October 15, 2004): Suicidality in Children and Adolescents Being Treated With Antidepressant Medications. Rockville, Md: Food and Drug Administration, Center for Drug Evaluation and Research, 2004. Available online. Last accessed April 24, 2007.

²² Ramchandani P: Treatment of major depressive disorder in children and adolescents. BMJ 328 (7430): 3-4, 2004.

²³ Rosenbaum JF, Zajecka J: Clinical management of antidepressant discontinuation. J Clin Psychiatry 58 (Suppl 7): 37-40, 1997.

²⁴ Bruera E, Brenneis C, Paterson AH, et al.: Use of methylphenidate as an adjuvant to narcotic analgesics in patients with advanced cancer. J Pain Symptom Manage 4 (1): 3-6, 1989.

²⁵ Richelson E: Pharmacokinetic drug interactions of new antidepressants: a review of the effects on the metabolism of other drugs. Mayo Clin Proc 72 (9): 835-47, 1997.

²⁶ Caccia S: Metabolism of the newer antidepressants. An overview of the pharmacological and pharmacokinetic implications. Clin Pharmacokinet 34 (4): 281-302, 1998.

²⁷ Jin Y, Desta Z, Stearns V, et al.: CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst 97 (1): 30-9, 2005.

²⁸ Physician's Desk Reference. 51st ed. Montvale, NJ: Medical Economics, 1997.

²⁹ Horne RL, Ferguson JM, Pope HG Jr, et al.: Treatment of bulimia with bupropion: a multicenter controlled trial. J Clin Psychiatry 49 (7): 262-6, 1988.

³⁰ Stahl SM: Basic psychopharmacology of antidepressants, part 1: Antidepressants have seven distinct mechanisms of action. J Clin Psychiatry 59 (Suppl 4): 5-14, 1998.

³¹ Theobald DE, Kirsh KL, Holtsclaw E, et al.: An open-label, crossover trial of mirtazapine (15 and 30 mg) in cancer patients with pain and other distressing symptoms. J Pain Symptom Manage 23 (5): 442-7, 2002.

³² Montgomery SA: Safety of mirtazapine: a review. Int Clin Psychopharmacol 10 (Suppl 4): 37-45, 1995.

³³ Chaplin S: Bone marrow depression due to mianserin, phenylbutazone, oxyphenbutazone, and chloramphenicol--Part II. Adverse Drug React Acute Poisoning Rev 5 (3): 181-96, 1986 Autumn.

³⁴ Owen JR, Nemeroff CB: New antidepressants and the cytochrome P450 system: focus on venlafaxine, nefazodone, and mirtazapine. Depress Anxiety 7 (Suppl 1): 24-32, 1998.

³⁵ Homsi J, Nelson KA, Sarhill N, et al.: A phase II study of methylphenidate for depression in advanced cancer. Am J Hosp Palliat Care 18 (6): 403-7, 2001 Nov-Dec.

³⁶ Feighner JP, Boyer WF: Perspectives in Psychiatry. Volume 1. Selective Serotonin Re-uptake Inhibitors: The Clinical Use of Citalopram, Fluoxetine, Fluvoxamine, Paroxetine, and Sertraline. New York, NY: John Wiley & Sons Ltd, 1991.

³⁷ Fernandez F, Adams F, Holmes VF, et al.: Methylphenidate for depressive disorders in cancer patients. An alternative to standard antidepressants. Psychosomatics 28 (9): 455-61, 1987.

³⁸ Meyers CA, Weitzner MA, Valentine AD, et al.: Methylphenidate therapy improves cognition, mood, and function of brain tumor patients. J Clin Oncol 16 (7): 2522-7, 1998.

³⁹ Olin J, Masand P: Psychostimulants for depression in hospitalized cancer patients. Psychosomatics 37 (1): 57-62, 1996 Jan-Feb.

⁴⁰ Bruera E, Miller MJ, Macmillan K, et al.: Neuropsychological effects of methylphenidate in pati