- Email: [email protected]
Fatigue, Depression, and Insomnia: Evidence for a Symptom Cluster in Cancer
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Seminars in Oncology Nursing, Vol 23, No 2 (May), 2007: pp 127–135
OBJECTIVES: To review the evidence for considering fatigue, depression, and insomnia as a symptom cluster in cancer.
DATA SOURCES: Empirical studies, clinical articles, and review articles.
CONCLUSION: The single- and multi-symptom measurement approaches are of limited usefulness in distinguishing fatigue, depression, and insomnia. Studies in which these symptoms have been measured concurrently in patients with cancer yield consistent evidence of high positive correlations. Results do not appear to be solely a function of overlap in measurement approaches.
IMPLICATIONS PRACTICE:
FOR
FATIGUE, DEPRESSION, AND INSOMNIA: EVIDENCE FOR A SYMPTOM CLUSTER IN CANCER
NURSING
Successful management of fatigue, depression, and insomnia in cancer patients are likely to combine pharmacologic and nonpharmacologic therapies.
KEYWORDS: Symptom cluster, cancer, fatigue, depression, insomnia
Kristine A. Donovan, PhD: Member, Health Outcomes and Behavior Program, H. Lee Moffitt Cancer Center & Research Institute; Assistant Professor, College of Medicine, University of South Florida, Tampa, FL. Paul B. Jacobsen, PhD: Program Leader, Health Outcomes and Behavior Program, H. Lee Moffitt Cancer Center & Research Institute; Professor, Department of Psychology, University of South Florida, Tampa, FL. Address correspondence to Kristine A. Donovan, PhD, Health Outcomes and Behavior Program, H. Lee Moffitt Cancer Center & Research Institute, 12902 Magnolia Dr, MRC-PSY, Tampa, FL 33612; e-mail: [email protected]
© 2007 Elsevier Inc. All rights reserved. 0749-2081/07/2302-$30.00/0 doi:10.1016/j.soncn.2007.01.004
KRISTINE A. DONOVAN
AND
PAUL B. JACOBSEN
C
ancer patients experience a multiplicity of symptoms associated with the disease and its treatment. Increasingly, oncology professionals recognize that certain symptoms occur together; thus, interest in “symptom clusters” has grown exponentially in recent years. A symptom cluster has been defined as three or more concurrent symptoms that are related to each other.1 In this article, we consider fatigue, depression, and insomnia, and whether there is evidence for their consideration as a symptom cluster in cancer.
WHAT
T
SIMILARITIES AND DIFFERENCES AMONG FATIGUE, DEPRESSION, AND INSOMNIA?
ARE THE
o understand the conceptual similarities and differences among fatigue, depression, and insomnia in cancer, it is necessary to consider how these symptoms have been operationally defined. Our approach focuses on the ways in which they have been assessed in cancer patients. Three distinct assessment approaches may be identified: the single-symptom approach, the multi-symptom approach, and the clinical syndrome approach. The single-symptom approach refers to assessment methods that focus specifically on the unidimensional nature of the symptom in question; for example, depressed mood, fatigue severity, or disturbed sleep. The symptom can be measured as a continuous variable (eg, visual analogue scales measuring severity of depressed mood, fatigue, or difficulty sleeping) or a categorical vari-
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able (eg, clinical interview items measuring presence/absence of the symptom). Measures such as the Fatigue and Depression subscales of the Profile of Mood States,2 exemplify this single-symptom approach. A measure of sleep difficulty, such as the insomnia item of the Symptom Distress Scale,3 also exemplifies the single-symptom assessment approach. The multi-symptom approach refers to assessment methods that focus on the multidimensional nature of the symptom in question. For example, a common approach to measuring depressive symptomatology in cancer patients has been to administer a multi-item self-report scale, such as the Beck Depression Inventory4 or the Center for Epidemiologic Studies Depression Scale.5 Both instruments assess a constellation of symptoms (eg, depressed mood, loss of appetite, and difficulty concentrating) that are theorized to reflect the construct of depression. Because fatigue and disturbed sleep are generally regarded as two of the core symptoms of a depressive disorder,6 it is not surprising to find that many depressive symptomatology measures include at least one item assessing fatigue-related phenomena and one item assessing changes in sleep patterns. For example, the Beck Depression Inventory asks respondents to choose among alternatives ranging from “I don’t get any more tired than usual,” to “I am too tired to do anything.” The multi-symptom approach to assessing insomnia focuses on several dimensions of sleep, including aspects such as overall sleep quality, sleep latency, sleep duration, and daytime dysfunction. Self-report measures reflecting this conceptualization include the Pittsburgh Sleep Quality Index7 and the Insomnia Severity Index.8,9 The clinical syndrome approach refers to assessment methods that focus on a diagnosable disorder or syndrome. As defined in the fourth edition of the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders (DSM-IV),6 a diagnosis of major depressive disorder requires the presence of four or more depressive symptoms during the same 2-week period in addition to depressed mood or loss of interest or pleasure in usual activities. Among the other symptoms whose presence counts toward the criterion of four or more symptoms is fatigue or loss of energy and insomnia or hypersomnia. Similarly, the International Classification System of Sleep Disorders10 and the DSM-IV6 both include diagnostic criteria for the diagnosis of an insomnia syndrome
wherein difficulty sleeping is characterized by difficulty initiating or maintaining sleep, or nonrestorative sleep, and the sleep disturbance (or associated daytime fatigue) causes significant impairment or distress. The clinical syndrome approach represents a relatively new method of assessing fatigue in cancer patients. Recognizing the need for a standard case definition, a group of investigators11 has proposed a set of criteria for the diagnosis of cancer-related fatigue (Table 1). There is overlap between the single-symptom and multi-symptom approaches to measuring fatigue and both the multi-symptom and clinical syndrome approaches to measuring depression and insomnia. As noted above, instruments used to measure depressive symptomatology and to diagnose major depressive disorder typically in-
TABLE 1. Proposed Criteria for Cancer-Related Fatigue A. Six (or more) of the following symptoms have been present every day or nearly every day during the same 2-week period in the past month and at least one of the symptoms is significant fatigue. ● Significant fatigue, diminished energy, or increased need to rest, disproportionate to any recent change in activity level ● Complaints of generalized weakness or limb heaviness ● Diminished concentration or attention ● Decreased motivation or interest to engage in usual activities ● Insomnia or hypersomnia ● Experience of sleep as unrefreshing or nonrestorative ● Perceived need to struggle to overcome inactivity ● Marked emotional reactivity (for example, sadness, frustration, or irritability) to feeling fatigued ● Difficulty completing daily tasks attributed to feeling fatigued ● Perceived problems with short-term memory ● Postexertional malaise lasting several hours B. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. C. There is evidence from the history, physical examination, or laboratory findings that the symptoms are a consequence of cancer or cancer therapy. D. The symptoms are not primarily a consequence of comorbid psychiatric disorders such as major depression, somatization disorder, somatoform disorder, or delirium. Reprinted with permission from Cella D, Peterman A, Passik S, et al: Progress toward guidelines for the management of fatigue. Oncology 1998;12:369-377.11
FATIGUE, DEPRESSION, AND INSOMNIA
clude one or more items assessing fatigue-related phenomena. Likewise, daytime fatigue is generally associated with disruptions in sleep patterns that are the primary symptom of insomnia. Multidimensional fatigue measures such as the Multidimensional Fatigue Inventory12 and the Multidimensional Fatigue Symptom Inventory13 assess a general symptom of fatigue (such as tiredness) and a mental symptom of fatigue (such as difficulty concentrating) that are also included in instruments used to measure depressive symptomatology and diagnose major depressive disorder. There is overlap between the proposed criteria for a clinical syndrome of fatigue11 and the multisymptom and clinical syndrome approaches to measuring depression and insomnia. A diagnosis of cancer-related fatigue requires the presence of six or more symptoms listed under criterion A (see Table 1). Several of the symptoms (eg, diminished concentration and decreased interest in usual activities) are also present in measures of depressive symptomatology, and included in the diagnostic criteria for major depressive disorder.6 Finally, overlap between insomnia and fatigue and depression is evidenced by the fact that the diagnostic criteria for insomnia include associated daytime fatigue and significant fatigue-related distress.6,10 Although similarities are present in approaches to measuring fatigue, depression, and insomnia, important differences also may be identified. Multi-symptom and clinical syndrome conceptualizations of depression generally include a number of symptoms that are not consistent with multi-symptom and clinical syndrome conceptualizations of fatigue and insomnia. These include changes in appetite or weight, recurrent thoughts of death, and feelings of worthlessness or excessive guilt. Likewise, multi-symptom and clinical syndrome conceptualizations of fatigue include a number of symptoms that are not consistent with multi-symptom and clinical syndrome conceptualizations of depression and insomnia. These include generalized feelings of weakness or heaviness, post-exertional malaise, and difficulty completing daily tasks because of fatigue. Similarly, multi-symptom and clinical syndrome conceptualizations of insomnia focus almost exclusively on sleep disturbance. Clinical syndrome approaches to measuring fatigue, depression, and insomnia also include criteria that seek to differentiate each from the other. For example, crite-
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rion D for cancer-related fatigue (in Table 1) states that this syndrome is not diagnosed if symptoms of fatigue are considered to be the primary consequence of a co-morbid psychiatric disorder. Likewise, the DSM-IV criteria for an insomnia disorder6 specify that insomnia is not diagnosed if the sleep disturbance occurs during the course of a mental disorder such as major depressive disorder. In summary, a review of measurement approaches indicates that overlap is present among all three approaches to measuring fatigue, both the multi-symptom and clinical syndrome approaches to measuring depression, and, to a limited degree, the multi-symptom and clinical syndrome approaches to measuring insomnia. This overlap is consistent with the fact that the symptoms of fatigue and insomnia are encompassed within current conceptualizations of depressive symptomatology as well as major depressive disorder. Overlap also reflects the fact that symptoms commonly associated with depression, including sleep disturbance, nonrestorative sleep, and daytime fatigue, are encompassed within multi-symptom and clinical syndrome approaches to measuring insomnia in cancer patients. Based on these considerations, one would expect empirical studies to show that these symptoms frequently co-occur in cancer patients.
TO WHAT EXTENT DO THESE SYMPTOMS OCCUR, ALONE AND IN COMBINATION, AMONG CANCER PATIENTS, AND HOW MIGHT THEY BE DISTINGUISHED?
P
revalence rates of fatigue, depression, and insomnia among cancer patients vary widely across studies. Factors accounting for this variability include the use of different assessment methods and whether studies distinguish between depression, for example, as a symptom and as a disorder. Similarly, differences may be attributable to cancer types, treatment modalities, stage of disease, and where patients are in the treatment process. Nevertheless, there is general agreement that fatigue is the most commonly reported symptom among cancer patients.14,15 Research indicates that between 70% and 100% of patients experience fatigue associated with cancer or cancer treatment, including radiation therapy, chemotherapy, and biological response modifiers.15 Prev-
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TABLE 2. Studies Assessing Fatigue, Depression, and Insomnia Concurrently in Patients With Cancer
Cancer Diagnoses
N
Andrykowski, 199821
Breast
88 Mixed
Broeckel, 199822
Breast
61 Chemotherapy
Carpenter, 199823
BMT
Study
Breast
Carpenter, Breast 200424 Fillion, 200325 Prostate
Hann, 199726
Breast
Hwang, 200327
Mixed
Mock, 199728 Okuyama, 200029
Redeker, 200030 Smets, 199831 Smets, 199832 Stone, 199933
Breast Mixed
Treatment Modality
155 Transplantation
102 Mixed
15 Mixed 327 Mixed
43 Transplantation
180 Mixed
46 Radiotherapy 134 Unknown
Mixed
263 Chemotherapy
Mixed
250 Radiotherapy
Mixed
154 Radiotherapy
Mixed
Stone, 200034 Prostate
95 Unknown 60 Hormone therapy
Fatigue Measure ChFS Total PFS Total SER Weak SER Tiredness POMS Fatigue POMS Fatigue POMS Fatigue POMS Fatigue POMS Fatigue POMS Depression POMS Fatigue POMS Depression CES-D POMS Fatigue POMS Fatigue MFI General MFI Activity MFI Motivation MFI Mental MFI Total POMS Fatigue POMS Fatigue POMS Fatigue
Depression Measure CES-D CES-D CES-D CES-D SCID-I-RV
Insomnia Measure PSQI Global PSQI Global
PSQI Quality PSQI Latency PSQI Efficiency PSQI Sleeping during day PSQI Global
Fatigue – Fatigue – Depression – Depression Insomnia Insomnia r r r .68 .68 .47 .63 .32
.45 .44
.27 .07 .15 .68 .58
PSQI Global
.48 PSQI Global
.48
PSQI Global PSQI Global CES-D CES-D HADS-D HADS-D HADS-D HADS-D HADS-D CES-D
POMS Fatigue BFI Global ZSDS-F (minus items 5,7,10) BFI Worst ZSDS-F (minus items 5,7,10) BFI Usual ZSDS-F (minus items 5,7,10) FACT-F ZSDS-F (minus Fatigue items 5,7,10) MSAS-SF ZSDS-F (minus Lack of items 5,7,10) energy VAS Fatigue VAS Depression CFS Total HADS-D
.49
PSQI Global PSQI Duration ISI ISI ISI ISI ISI PSQI Quality PSQI Latency PSQI Daytime drowsiness PSQI Efficiency MSAS-SF Sleep MSAS-SF Sleep MSAS-SF Sleep MSAS-SF Sleep MSAS-SF Sleep VAS Sleep 5-point Likert scale
.58 .56 .48 .45 .65 .80
.43 .21 .39 .35 .18 .24 .38 .40 .30 .26
⫺.70
.16 .27
.54
.25
.60
.31
⫺.68
⫺.33
.61
.39
.61 .58
.54 .26
.45 .35
.45
CFS Physical CFS Affective
HADS-D HADS-D
CFS Cognitive SDS Fatigue
HADS-D POMS Depression CES-D
SDS Insomnia
.41 .43
.26
GSQS Quality
.43
.41
CES-D
GSQS Quality
.49
.26
HADS-D (minus item 8) HADS-D
EORTC QLQ C30 Sleep EORTC QLQ C30 Sleep
.16
.41
.55
.31
MFI-20 General MFI-20 General FSS FSS FSS
HADS-D (minus item 8)
.48
5-point Likert scale
.46
.50 .47 .37
.51
.30
FATIGUE, DEPRESSION, AND INSOMNIA
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TABLE 2. Continued
Study
Cancer Diagnoses
Stone, 200035 Mixed
Stone, 200136 Breast, prostate
N
Treatment Modality
227 Mixed
69 Mixed
Fatigue Measure
Depression Measure
FSS
HADS-D
FSS
HADS-D (minus item 8) HADS-D
FSS FSS
HADS-D (minus item 8)
Insomnia Measure EORTC QLQ C30 Sleep
Fatigue – Fatigue – Depression – Depression Insomnia Insomnia r r r .67
.38
.60 EORTC QLQ C30 Sleep
.75
.36
.63
Abbreviations: r, Pearson or Spearman correlation coefficient; BDI, Beck Depression Inventory; BFI, Brief Fatigue Inventory; BMT, Bone Marrow Transplant; CES-D, Center for Epidemiologic Studies Depression Scale; CFS, Cancer Fatigue Scale; ChFS, Chalder Fatigue Scale; EORTC, European Organization for Research and Treatment QLQ-C 30; FACT-F, Functional Assessment of Cancer Therapy-Fatigue Subscale; FSS, Fatigue Severity Scale; GSQS, Groningen Sleep Quality Scale; HADS-D, Hospital Anxiety and Depression Scale-Depression Subscale; ISI, Insomnia Severity Index; MFI, Multidimensional Fatigue Inventory; MSAS-SF, Memorial Symptom Assessment Scale-Short Form; PFS, Piper Fatigue Scale; POMS, Profile of Mood States; PSQI, Pittsburgh Sleep Quality Index; SCID-I-RV, Structured Clinical Interview for Depression; SDS, Symptom Distress Scale; SER, Symptom Experience Report; VAS, Visual Analog Scale; ZSDS, Zung Self-Rating Depression Scale.
alence rates of depressive symptoms and major depressive disorder in cancer are purported to range from 10% to 25%.16 Among those patients referred for psychiatric consultation, rates of depression range as high as 59%.17 Prevalence rates of insomnia also vary widely, with most studies estimating that approximately 30% to 50% of cancer patients report sleep difficulties.18 Although prevalence rates of patients meeting diagnostic criteria for an insomnia disorder are less well known, researchers have reported estimates of nearly 20%.19,20 One way to determine the extent to which these three symptoms co-occur is to examine the magnitude of correlations between measures of fatigue, depression, and insomnia administered concurrently to patients. Although the research on symptoms clusters is limited to date, a number of studies have reported associations between these symptoms among cancer patients.21-36 As shown in Table 2, only three studies reported correlations between all possible pairings of fatigue, depression, and insomnia.21,28,30 These correlations were positive and ranged from .43 to .68 for fatigue and depression, from .26 to .54 for fatigue and insomnia, and from .30 to .51 for depression and insomnia. When all of the 16 studies measuring fatigue, depression, and insomnia were considered concurrently, the average correlations were .55 for fatigue and depression, .34 for
fatigue and insomnia, and .45 for depression and insomnia. Thus, on average, measures of fatigue and depression administered concurrently to cancer patients shared approximately 30% of their variance, measures of fatigue and insomnia shared approximately 12%, and measures of depression and insomnia shared approximately 20%. Three of the studies listed in Table 2 included analyses designed specifically to examine the effects of overlap on correlations between measures of fatigue and depression. In these studies,34-36 the Fatigue Severity Scale (FSS) and the depression subscale of the Hospital Anxiety and Depression Scare (HADS) were administered concurrently to cancer patients. The latter measure includes one item (“I feel as if I am slowed down”) that would appear to overlap with fatigue. Correlations were computed between the FSS and both the original version of the HADS depression subscale and a version that excluded this item. Across studies, the average correlation between the FSS and the HADS depression subscale was .66 before exclusion of the item and .56 after exclusion of the item. In summary, empirical studies yield consistent evidence of a relatively high degree of correspondence between levels of fatigue, depression, and insomnia among patients with cancer. This state of affairs is not particularly surprising considering the overlap present in many current approaches
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to assessing these constructs. In comparative studies using the multi-symptom approach to assessing fatigue, depression, and insomnia, researchers have shown that more fatigued breast cancer patients report significantly more sleep problems and depressive symptoms compared with patients who are not as fatigued.30,37 However, there is evidence to suggest that the degree of correspondence is not solely a function of overlap in assessment approaches. First, as shown in Table 2, correlations between fatigue and depression remained relatively high, even when items reflecting phenomena associated with fatigue were removed from measures of depressive symptomatology.34-36 Second, relatively high correlations have been observed between measures focusing specifically on depressed mood and multi-symptom approaches to sleep,34 between measures of general, unidimensional fatigue and multi-symptom approaches to sleep,24,34 and between multisymptom approaches to fatigue and selected unidimensional measures of sleep difficulty.27,29,32-36
WHAT ARE THE IMPLICATIONS OF THIS SYMPTOM CLUSTER FOR PATIENT ASSESSMENT AND MANAGEMENT?
T
he research findings provide considerable evidence that fatigue, depression, and insomnia cluster together in cancer. The next logical step is to consider the evidence for treatment of this symptom cluster. Considered individually, each symptom has generally accepted pharmacologic and non-pharmacologic management approaches in patients. Pharmacologic Approaches Fatigue. Efforts to manage fatigue are typically focused on correcting potential etiologies as well as relieving symptoms. Potentially correctable etiologies include depression, anemia, infection, and other symptoms such as pain or insomnia. There is evidence that psychostimulants (such as methylphenidate, dextroamphetamine, and pemoline) may be useful in relieving fatigue related to opioid-induced somnolence,38 neurobehavioral slowing,39,40 and depression41 in patients with cancer. Preliminary research suggests that these agents are also useful in relieving disease- or treatment-related fatigue in cancer patients.42-46 The mechanisms by which psychostimulants relieve disease- or treatment-related fatigue have yet
to be identified. In particular, it is unclear whether the effects of psychostimulants on fatigue are related to, or distinct from, their mood-enhancing properties. Recommendations regarding the use of antidepressant medications to relieve fatigue in cancer patients are based largely on clinical observations that these agents, in particular velafaxine and bupropion, have energizing effects.47 Both agents appear to function similarly to psychostimulants; their use is associated with increased synaptic levels of norepinephrine.48 These findings are consistent with animal and human studies suggesting that increased levels of norepinephrine and/or dopamine are associated with increased levels of cortical arousal.49 Randomized controlled trials are needed to identify the specific antidepressant agents that are effective at relieving fatigue. As with the psychostimulants, it is not clear whether the observed effects of these agents on fatigue are related to, or distinct from, their mood-enhancing effects. Depression. Randomized controlled trials of pharmacologic interventions for depressive symptoms in cancer patients are limited in number, but in general indicate that antidepressant medications are beneficial.16 The selection of a specific antidepressant is guided by the constellation of presenting symptoms. By and large, research indicates that serotonin-selective reuptake inhibitors and medications that inhibit primarily norepinephrine reuptake are equally efficacious in the treatment of major depressive disorder.50-52 As depressed mood improves, the associated fatigue or sleep disturbance can also be expected to resolve. Insomnia. Treatment of insomnia, like fatigue, may involve treating the underlying etiologies such as pain, delirium, menopausal symptoms, gastrointestinal distress, and anxiety and depression.18,53 When insomnia is the primary presenting complaint, hypnotics medications are most commonly used. Benzodiazepines such as lorazepam, clonazepam, and oxazepam, which are specifically marketed as anxiolytics, are often the first choice for sleep initiation problems or shortterm insomnia because of their sedating effects. However, these long-acting medications may cause daytime sedation, dizziness, light-headedness, or cognitive and psychomotor impairments.54,55 Psychostimulants may be used to counter daytime sleepiness and sedation, but can cause insomnia. Non-benzodiazepines such as zol-
FATIGUE, DEPRESSION, AND INSOMNIA
pidem, zaleplon, and escopiclone for sleep initiation and maintenance are believed to have more specific and selective mechanisms of action, resulting in fewer side effects and residual effects the next day.18,53 Additional non-benzodiazepine medications include neuroleptics such as olanzapine and quetiapine and sedating antidepressants such as amitriptyline, trazodone, and mirtazapine. Nonpharmacologic Approaches Nonpharmacologic approaches to the management of fatigue, depression, and insomnia in cancer patients can be divided into activity-based therapies and psychological therapies. Activitybased therapies generally involve supervised or unsupervised exercise programs while psychological therapies may include relaxation training, coping skills training, and education. Fatigue. Systematic reviews of randomized and controlled clinical trials of exercise in cancer patients have documented positive results for a variety of psychological and physiological outcomes, including fatigue.56-58 Aerobic exercise in the form of home-based walking programs or supervised laboratory treadmill or exercise bicycle programs has consistently resulted in significant reductions in selfreported fatigue during and after active cancer treatment compared with control conditions. Although most of the studies have involved women with a diagnosis of breast cancer, beneficial effects of exercise have also been shown among prostate cancer patients, melanoma, leukemia, multiple myeloma, and lymphoma patients. A diverse array of psychological interventions has been evaluated in cancer patients; several have included fatigue as an endpoint. Interventions tested include relaxation training, psychoeducation, energy conservation programs, coping skills training, problem-solving therapy, and supportive and expressive therapy. In general, the effects of these interventions on fatigue have been positive (see for example, Jacobsen et al59). The number of randomized controlled clinical trials of psychological interventions that include fatigue as a primary outcome has begun to increase in recent years.60 Thus, we can anticipate more evidence-based management approaches to fatigue in the future. Depression. Despite the fact that exercise intervention studies in cancer have more often focused on psychological distress or mood distur-
133
bance than depression,56,61 there is evidence for the effectiveness of exercise in relieving depression in cancer (see for example, Segar et al62). A number of different psychological interventions also have been tested for their effect on depression in cancer. The most commonly evaluated interventions appear to be relaxation training and education.63 In general, comprehensive reviews of existing studies provide considerable support for these interventions in managing depression in cancer patients.63,64 Insomnia. Sleep hygiene, stimulus control, sleep restriction, and relaxation training have each been shown to be effective treatments for insomnia.65 However, few studies have evaluated their effectiveness in cancer patients. Although pilot studies evaluating the efficacy of relaxation training for insomnia in cancer have reported mixed results,66,67 more recent nonrandomized studies of interventions combining relaxation training with education about sleep hygiene, the use of stimulus control, and sleep restriction, have yielded positive results.68-70
CONCLUSION
A
s noted previously, fatigue, depression, and insomnia can each be assessed using a singlesymptom, a multi-symptom, or a clinical syndrome approach. A review of measurement approaches indicates that there is overlap among all three approaches, although research has been limited primarily to the use of either single- or multisymptom approaches. Existing research also indicates that fatigue, depression, and insomnia commonly co-occur in cancer. However, there is evidence that this clustering is not solely a function of overlap in measurement approaches. Our findings suggest that the single- and multi-symptom measurement approaches are of limited usefulness in attempting to distinguish each symptom from the others. There is a growing evidence base for the effective treatment of fatigue, depression, and insomnia in cancer patients. Successful management approaches are likely to combine pharmacologic and nonpharmacologic therapies. Given that the presentation as well as the assessment of symptoms in this cluster shows significant overlap, we can expect that treatments for each symptom will overlap as well, and that a modality used to treat one symptom may also be effective in treating one or both of the others.
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22. Broeckel JA, Jacobsen PB, Horton J, et al. Characteristics and correlates of fatigue after adjuvant chemotherapy for breast cancer. J Clin Oncol 1998;16:1689-1696. 23. Carpenter JS, Andrykowski MA. Psychometric evaluation of the Pittsburgh Sleep Quality Index. J Psychosom Res 1998;45:5-13. 24. Carpenter JR, Elam JL, Ridner SH, et al. Sleep, fatigue, and depressive symptoms in breast cancer survivors and matched healthy women experiencing hot flashes. Oncol Nurs Forum 2004;31:591-598. 25. Fillion L, Gelinas C, Simard S, et al. Validation evidence for the French Canadian adaptation of the Multidimensional Fatigue Inventory as a measure of cancer-related fatigue. Cancer Nurs 2003;26:143-153. 26. Hann DM, Jacobsen PB, Martin SC, et al. Fatigue in women treated with bone marrow transplantation for breast cancer: a comparison with women with no history of cancer. Support Care Cancer 1997;5:44-52. 27. Hwang SS, Chang VT, Kasimis BS. A comparison of three fatigue measures in veterans with cancer. Cancer Invest 2003;21:363-373. 28. Mock V, Dow KH, Meares CJ, et al. Effects of exercise on fatigue, physical functioning, and emotional distress during radiation therapy for breast cancer. Oncol Nurs Forum 1997;24:991-1000. 29. Okuyama T, Akechi T, Kugaya A, et al. Factors correlated with fatigue in disease-free breast cancer patients: application of the Cancer Fatigue Scale. Support Care Cancer 2000;8:215-222. 30. Redeker NS, Lev EL, Ruggiero J. Insomnia, fatigue, anxiety, depression, and quality of life of cancer patients undergoing chemotherapy. Sch Inq Nurs Pract 2000;14: 275-290. 31. Smets EMA, Visser M, Willems-Groot AF, et al. Fatigue and radiotherapy: (A) experience in patients undergoing treatment. Br J Cancer 1998;78:899-906. 32. Smets EMA, Visser M, Willems-Groot AF, et al. Fatigue and radiotherapy: (B) experience in patients 9 months following treatment. Br J Cancer 1998;78:907-912. 33. Stone P, Hardy J, Broadley K, et al. Fatigue in advanced cancer: a prospective controlled cross-sectional study. Br J Cancer 1999;79:1479-1486. 34. Stone P, Hardy J, Huddart R, et al. Fatigue in patients with prostate cancer receiving hormone therapy. Eur J Cancer 2000;36:1134-1141. 35. Stone P, Richards M, A’Hern R, et al. A study to investigate the prevalence, severity and correlates of fatigue among patients with cancer in comparison with a control group of volunteers without cancer. Ann Oncol 2000;11:561-567. 36. Stone P, Richards M, A’Hern R, et al. Fatigue in patients with cancers of the breast or prostate undergoing radical radiotherapy. J Pain Symptom Manage 2001;22:1007-1015. 37. Servaes P, Prins S, Verhagen S, et al. Fatigue after breast cancer and in chronic fatigue syndrome: similarities and differences. J Psychosom Res 2002;52:453-459. 38. 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 1989;4:3-6. 39. Weitzner MA, Meyers CA, Valentine AD. Methylphenidate in the treatment of neurobehavioral slowing associated
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with cancer and cancer treatment. Clin Neurosci 1995;7: 347-350. 40. Meyers CA, Weitzner MA, Valentine AD, et al. Methylphenidate therapy improves cognition, mood, and function in brain tumor patients. J Clin Oncol 1998;16:2522-2527. 41. Breitbart W, Mermelstein H. An alternative psychostimulant for the management of depressive disorders in cancer patients. Psychosomatics 1992;33:352-356. 42. Schwartz AL, Thompson J, Massood N. Interferon-induced fatigue in patients with melanoma: a pilot study of exercise and methylphenidate. Oncol Nurs Forum 2002;29: E85-E90. 43. Homsi J, Nelson KA, Sarhill N, et al. A phase II study of methylphenidate for depression in advanced cancer. Am J Hospice Palliative Care 2001;18:403-407. 44. Sugawara Y, Akechi T, Shima Y, et al. Efficacy of methylphenidate for fatigue in advanced cancer patients: a preliminary study. Palliat Med 2002;16:261-263. 45. Hanna A, Sledge G, Mayer ML, et al. A phase II study of methylphenidate for the treatment of fatigue. Support Care Cancer 2006;14:210-215. 46. Bruera E, Driver L, Barnes EA, et al. Patient-controlled methylphenidate for the management of fatigue in patients with advanced cancer: a preliminary report. J Clin Oncol 2003;21:4439-4443. 47. Marin R. Apathy: concept, syndrome, neural mechanisms, and treatment. Semin Neuropsych 1996;1:304-314. 48. Popper CW. Pharmacologic alternatives to psychostimulants for the treatment of attention-deficit/hyperactivity disorder. Child Adolesc Psychiatr Clin North Am 2000;9:605-646. 49. Duffy JD. The neural substrates of motivation. Psychiatric Ann 1997;27:24-29. 50. Moller H, Berzewski H, Eckmann F, et al. Double-blind multicenter study of paroxetine and amitriptyline in depressed inpatients. Pharmacopsychiatry 1993;26:75-78. 51. Stuppaeck CH, Geretsegger C, Whitwirth AB, et al. A multicenter double-blind trial of paroxetine versus amitriptyline in depressed inpatients. J Clin Psychopharmacol 1994;14: 241-246. 52. Feighner J, Cohn J, Fabre L, et al. A study comparing paroxetine, placebo, and imipramine in depressed patients. J Affect Disord 1993;28:71-79. 53. Graci G. Pathogenesis and management of cancer-related insomnia. J Support Oncol 2005;3:349-359. 54. O’Donnell JF. Insomnia in cancer patients. Clin Cornerstone 2004;6:S6-S14. 55. Holbrook AM, Crowther R, Lotter A, et al. Meta-analysis of benzodiazepine use in the treatment of insomnia. CMAJ 2000;162:225-233.
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56. Schmitz KH, Holtzman J, Courneya KS, et al. Controlled physical activity trials in cancer survivors: a systematic review and meta-analysis. Cancer Epidemiol Biomarkers Prev 2005;14:1588-1595. 57. Knols R, Aaronson NK, Uebelhart D, et al. Physical exercise in cancer patients during and after medical treatment: a systematic review of randomized and controlled clinical trials. J Clin Oncol 2005;23:3830-3842. 58. Conn VS, Hafdahl A, Porock DC, et al. A meta-analysis of exercise interventions among people treated for cancer. Support Care Cancer 2006;14:699-712. 59. Jacobsen PB, Meade CD, Stein KD, et al. Efficacy and costs of two forms of stress management training for cancer patients undergoing chemotherapy. J Clin Oncol 2002;20:2851-2862. 60. Mock V. Evidence-based treatment for cancer-related fatigue. J Natl Cancer Inst Monogr 2004;32:112-118. 61. Galvao DA, Newton RU. Review of exercise interventions studies in cancer patients. J Clin Oncol 2005;23:899-909. 62. Segar M L, Katch VL, Roth RS, et al. The effect of aerobic exercise on self-esteem and depressive and anxious symptoms among breast cancer survivors. Oncol Nurs Forum 1998;25: 107-113. 63. Jacobsen PB, Donovan KA, Swaine ZN, et al. Management of Anxiety and Depression in Adult Cancer Patients: Toward an Evidence-Based Approach. New York, NY: Springer-Verlag: 2005. 64. Barsevick AM, Sweeney C, Haney E, et al. A systematic qualitative analysis of psychoeducational interventions for depression in patients with cancer. Oncol Nurs Forum 2002;29: 73-84. 65. Murtagh DRR, Greenwood KM. Identifying effective psychological treatments for insomnia: a meta-analysis. J Consult Clin Psychol 1995;63:79-89. 66. Cannici J, Malcolm R, Peek LA. Treatment of insomnia in cancer patients using muscle relaxation training. J Behav Ther Exp Psychiatry 1983;14:251-256. 67. Stam HJ, Bultz BD. The treatment of severe insomnia in a cancer patient. J Behav Ther Exp Psychiatry 1986;17:33-37. 68. Simeit R, Deck R, Conta-Marx B. Sleep management training for cancer patients with insomnia. Support Care Cancer 2004;12:176-183. 69. Davidson JR, Waisberg JL, Brundage MD, et al. Nonpharmacologic group treatment of insomnia: a preliminary study with cancer survivors. Psychooncol 2001;10:389-397. 70. Quesnel C, Savard J, Simard S, et al. Efficacy of cognitive-behavioral therapy for nonmetastatic breast cancer. J Consult Clin Psychol 2003;71:189-200.
Seminars in Oncology Nursing, Vol 23, No 2 (May), 2007: pp 127–135
OBJECTIVES: To review the evidence for considering fatigue, depression, and insomnia as a symptom cluster in cancer.
DATA SOURCES: Empirical studies, clinical articles, and review articles.
CONCLUSION: The single- and multi-symptom measurement approaches are of limited usefulness in distinguishing fatigue, depression, and insomnia. Studies in which these symptoms have been measured concurrently in patients with cancer yield consistent evidence of high positive correlations. Results do not appear to be solely a function of overlap in measurement approaches.
IMPLICATIONS PRACTICE:
FOR
FATIGUE, DEPRESSION, AND INSOMNIA: EVIDENCE FOR A SYMPTOM CLUSTER IN CANCER
NURSING
Successful management of fatigue, depression, and insomnia in cancer patients are likely to combine pharmacologic and nonpharmacologic therapies.
KEYWORDS: Symptom cluster, cancer, fatigue, depression, insomnia
Kristine A. Donovan, PhD: Member, Health Outcomes and Behavior Program, H. Lee Moffitt Cancer Center & Research Institute; Assistant Professor, College of Medicine, University of South Florida, Tampa, FL. Paul B. Jacobsen, PhD: Program Leader, Health Outcomes and Behavior Program, H. Lee Moffitt Cancer Center & Research Institute; Professor, Department of Psychology, University of South Florida, Tampa, FL. Address correspondence to Kristine A. Donovan, PhD, Health Outcomes and Behavior Program, H. Lee Moffitt Cancer Center & Research Institute, 12902 Magnolia Dr, MRC-PSY, Tampa, FL 33612; e-mail: [email protected]
© 2007 Elsevier Inc. All rights reserved. 0749-2081/07/2302-$30.00/0 doi:10.1016/j.soncn.2007.01.004
KRISTINE A. DONOVAN
AND
PAUL B. JACOBSEN
C
ancer patients experience a multiplicity of symptoms associated with the disease and its treatment. Increasingly, oncology professionals recognize that certain symptoms occur together; thus, interest in “symptom clusters” has grown exponentially in recent years. A symptom cluster has been defined as three or more concurrent symptoms that are related to each other.1 In this article, we consider fatigue, depression, and insomnia, and whether there is evidence for their consideration as a symptom cluster in cancer.
WHAT
T
SIMILARITIES AND DIFFERENCES AMONG FATIGUE, DEPRESSION, AND INSOMNIA?
ARE THE
o understand the conceptual similarities and differences among fatigue, depression, and insomnia in cancer, it is necessary to consider how these symptoms have been operationally defined. Our approach focuses on the ways in which they have been assessed in cancer patients. Three distinct assessment approaches may be identified: the single-symptom approach, the multi-symptom approach, and the clinical syndrome approach. The single-symptom approach refers to assessment methods that focus specifically on the unidimensional nature of the symptom in question; for example, depressed mood, fatigue severity, or disturbed sleep. The symptom can be measured as a continuous variable (eg, visual analogue scales measuring severity of depressed mood, fatigue, or difficulty sleeping) or a categorical vari-
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able (eg, clinical interview items measuring presence/absence of the symptom). Measures such as the Fatigue and Depression subscales of the Profile of Mood States,2 exemplify this single-symptom approach. A measure of sleep difficulty, such as the insomnia item of the Symptom Distress Scale,3 also exemplifies the single-symptom assessment approach. The multi-symptom approach refers to assessment methods that focus on the multidimensional nature of the symptom in question. For example, a common approach to measuring depressive symptomatology in cancer patients has been to administer a multi-item self-report scale, such as the Beck Depression Inventory4 or the Center for Epidemiologic Studies Depression Scale.5 Both instruments assess a constellation of symptoms (eg, depressed mood, loss of appetite, and difficulty concentrating) that are theorized to reflect the construct of depression. Because fatigue and disturbed sleep are generally regarded as two of the core symptoms of a depressive disorder,6 it is not surprising to find that many depressive symptomatology measures include at least one item assessing fatigue-related phenomena and one item assessing changes in sleep patterns. For example, the Beck Depression Inventory asks respondents to choose among alternatives ranging from “I don’t get any more tired than usual,” to “I am too tired to do anything.” The multi-symptom approach to assessing insomnia focuses on several dimensions of sleep, including aspects such as overall sleep quality, sleep latency, sleep duration, and daytime dysfunction. Self-report measures reflecting this conceptualization include the Pittsburgh Sleep Quality Index7 and the Insomnia Severity Index.8,9 The clinical syndrome approach refers to assessment methods that focus on a diagnosable disorder or syndrome. As defined in the fourth edition of the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders (DSM-IV),6 a diagnosis of major depressive disorder requires the presence of four or more depressive symptoms during the same 2-week period in addition to depressed mood or loss of interest or pleasure in usual activities. Among the other symptoms whose presence counts toward the criterion of four or more symptoms is fatigue or loss of energy and insomnia or hypersomnia. Similarly, the International Classification System of Sleep Disorders10 and the DSM-IV6 both include diagnostic criteria for the diagnosis of an insomnia syndrome
wherein difficulty sleeping is characterized by difficulty initiating or maintaining sleep, or nonrestorative sleep, and the sleep disturbance (or associated daytime fatigue) causes significant impairment or distress. The clinical syndrome approach represents a relatively new method of assessing fatigue in cancer patients. Recognizing the need for a standard case definition, a group of investigators11 has proposed a set of criteria for the diagnosis of cancer-related fatigue (Table 1). There is overlap between the single-symptom and multi-symptom approaches to measuring fatigue and both the multi-symptom and clinical syndrome approaches to measuring depression and insomnia. As noted above, instruments used to measure depressive symptomatology and to diagnose major depressive disorder typically in-
TABLE 1. Proposed Criteria for Cancer-Related Fatigue A. Six (or more) of the following symptoms have been present every day or nearly every day during the same 2-week period in the past month and at least one of the symptoms is significant fatigue. ● Significant fatigue, diminished energy, or increased need to rest, disproportionate to any recent change in activity level ● Complaints of generalized weakness or limb heaviness ● Diminished concentration or attention ● Decreased motivation or interest to engage in usual activities ● Insomnia or hypersomnia ● Experience of sleep as unrefreshing or nonrestorative ● Perceived need to struggle to overcome inactivity ● Marked emotional reactivity (for example, sadness, frustration, or irritability) to feeling fatigued ● Difficulty completing daily tasks attributed to feeling fatigued ● Perceived problems with short-term memory ● Postexertional malaise lasting several hours B. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. C. There is evidence from the history, physical examination, or laboratory findings that the symptoms are a consequence of cancer or cancer therapy. D. The symptoms are not primarily a consequence of comorbid psychiatric disorders such as major depression, somatization disorder, somatoform disorder, or delirium. Reprinted with permission from Cella D, Peterman A, Passik S, et al: Progress toward guidelines for the management of fatigue. Oncology 1998;12:369-377.11
FATIGUE, DEPRESSION, AND INSOMNIA
clude one or more items assessing fatigue-related phenomena. Likewise, daytime fatigue is generally associated with disruptions in sleep patterns that are the primary symptom of insomnia. Multidimensional fatigue measures such as the Multidimensional Fatigue Inventory12 and the Multidimensional Fatigue Symptom Inventory13 assess a general symptom of fatigue (such as tiredness) and a mental symptom of fatigue (such as difficulty concentrating) that are also included in instruments used to measure depressive symptomatology and diagnose major depressive disorder. There is overlap between the proposed criteria for a clinical syndrome of fatigue11 and the multisymptom and clinical syndrome approaches to measuring depression and insomnia. A diagnosis of cancer-related fatigue requires the presence of six or more symptoms listed under criterion A (see Table 1). Several of the symptoms (eg, diminished concentration and decreased interest in usual activities) are also present in measures of depressive symptomatology, and included in the diagnostic criteria for major depressive disorder.6 Finally, overlap between insomnia and fatigue and depression is evidenced by the fact that the diagnostic criteria for insomnia include associated daytime fatigue and significant fatigue-related distress.6,10 Although similarities are present in approaches to measuring fatigue, depression, and insomnia, important differences also may be identified. Multi-symptom and clinical syndrome conceptualizations of depression generally include a number of symptoms that are not consistent with multi-symptom and clinical syndrome conceptualizations of fatigue and insomnia. These include changes in appetite or weight, recurrent thoughts of death, and feelings of worthlessness or excessive guilt. Likewise, multi-symptom and clinical syndrome conceptualizations of fatigue include a number of symptoms that are not consistent with multi-symptom and clinical syndrome conceptualizations of depression and insomnia. These include generalized feelings of weakness or heaviness, post-exertional malaise, and difficulty completing daily tasks because of fatigue. Similarly, multi-symptom and clinical syndrome conceptualizations of insomnia focus almost exclusively on sleep disturbance. Clinical syndrome approaches to measuring fatigue, depression, and insomnia also include criteria that seek to differentiate each from the other. For example, crite-
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rion D for cancer-related fatigue (in Table 1) states that this syndrome is not diagnosed if symptoms of fatigue are considered to be the primary consequence of a co-morbid psychiatric disorder. Likewise, the DSM-IV criteria for an insomnia disorder6 specify that insomnia is not diagnosed if the sleep disturbance occurs during the course of a mental disorder such as major depressive disorder. In summary, a review of measurement approaches indicates that overlap is present among all three approaches to measuring fatigue, both the multi-symptom and clinical syndrome approaches to measuring depression, and, to a limited degree, the multi-symptom and clinical syndrome approaches to measuring insomnia. This overlap is consistent with the fact that the symptoms of fatigue and insomnia are encompassed within current conceptualizations of depressive symptomatology as well as major depressive disorder. Overlap also reflects the fact that symptoms commonly associated with depression, including sleep disturbance, nonrestorative sleep, and daytime fatigue, are encompassed within multi-symptom and clinical syndrome approaches to measuring insomnia in cancer patients. Based on these considerations, one would expect empirical studies to show that these symptoms frequently co-occur in cancer patients.
TO WHAT EXTENT DO THESE SYMPTOMS OCCUR, ALONE AND IN COMBINATION, AMONG CANCER PATIENTS, AND HOW MIGHT THEY BE DISTINGUISHED?
P
revalence rates of fatigue, depression, and insomnia among cancer patients vary widely across studies. Factors accounting for this variability include the use of different assessment methods and whether studies distinguish between depression, for example, as a symptom and as a disorder. Similarly, differences may be attributable to cancer types, treatment modalities, stage of disease, and where patients are in the treatment process. Nevertheless, there is general agreement that fatigue is the most commonly reported symptom among cancer patients.14,15 Research indicates that between 70% and 100% of patients experience fatigue associated with cancer or cancer treatment, including radiation therapy, chemotherapy, and biological response modifiers.15 Prev-
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TABLE 2. Studies Assessing Fatigue, Depression, and Insomnia Concurrently in Patients With Cancer
Cancer Diagnoses
N
Andrykowski, 199821
Breast
88 Mixed
Broeckel, 199822
Breast
61 Chemotherapy
Carpenter, 199823
BMT
Study
Breast
Carpenter, Breast 200424 Fillion, 200325 Prostate
Hann, 199726
Breast
Hwang, 200327
Mixed
Mock, 199728 Okuyama, 200029
Redeker, 200030 Smets, 199831 Smets, 199832 Stone, 199933
Breast Mixed
Treatment Modality
155 Transplantation
102 Mixed
15 Mixed 327 Mixed
43 Transplantation
180 Mixed
46 Radiotherapy 134 Unknown
Mixed
263 Chemotherapy
Mixed
250 Radiotherapy
Mixed
154 Radiotherapy
Mixed
Stone, 200034 Prostate
95 Unknown 60 Hormone therapy
Fatigue Measure ChFS Total PFS Total SER Weak SER Tiredness POMS Fatigue POMS Fatigue POMS Fatigue POMS Fatigue POMS Fatigue POMS Depression POMS Fatigue POMS Depression CES-D POMS Fatigue POMS Fatigue MFI General MFI Activity MFI Motivation MFI Mental MFI Total POMS Fatigue POMS Fatigue POMS Fatigue
Depression Measure CES-D CES-D CES-D CES-D SCID-I-RV
Insomnia Measure PSQI Global PSQI Global
PSQI Quality PSQI Latency PSQI Efficiency PSQI Sleeping during day PSQI Global
Fatigue – Fatigue – Depression – Depression Insomnia Insomnia r r r .68 .68 .47 .63 .32
.45 .44
.27 .07 .15 .68 .58
PSQI Global
.48 PSQI Global
.48
PSQI Global PSQI Global CES-D CES-D HADS-D HADS-D HADS-D HADS-D HADS-D CES-D
POMS Fatigue BFI Global ZSDS-F (minus items 5,7,10) BFI Worst ZSDS-F (minus items 5,7,10) BFI Usual ZSDS-F (minus items 5,7,10) FACT-F ZSDS-F (minus Fatigue items 5,7,10) MSAS-SF ZSDS-F (minus Lack of items 5,7,10) energy VAS Fatigue VAS Depression CFS Total HADS-D
.49
PSQI Global PSQI Duration ISI ISI ISI ISI ISI PSQI Quality PSQI Latency PSQI Daytime drowsiness PSQI Efficiency MSAS-SF Sleep MSAS-SF Sleep MSAS-SF Sleep MSAS-SF Sleep MSAS-SF Sleep VAS Sleep 5-point Likert scale
.58 .56 .48 .45 .65 .80
.43 .21 .39 .35 .18 .24 .38 .40 .30 .26
⫺.70
.16 .27
.54
.25
.60
.31
⫺.68
⫺.33
.61
.39
.61 .58
.54 .26
.45 .35
.45
CFS Physical CFS Affective
HADS-D HADS-D
CFS Cognitive SDS Fatigue
HADS-D POMS Depression CES-D
SDS Insomnia
.41 .43
.26
GSQS Quality
.43
.41
CES-D
GSQS Quality
.49
.26
HADS-D (minus item 8) HADS-D
EORTC QLQ C30 Sleep EORTC QLQ C30 Sleep
.16
.41
.55
.31
MFI-20 General MFI-20 General FSS FSS FSS
HADS-D (minus item 8)
.48
5-point Likert scale
.46
.50 .47 .37
.51
.30
FATIGUE, DEPRESSION, AND INSOMNIA
131
TABLE 2. Continued
Study
Cancer Diagnoses
Stone, 200035 Mixed
Stone, 200136 Breast, prostate
N
Treatment Modality
227 Mixed
69 Mixed
Fatigue Measure
Depression Measure
FSS
HADS-D
FSS
HADS-D (minus item 8) HADS-D
FSS FSS
HADS-D (minus item 8)
Insomnia Measure EORTC QLQ C30 Sleep
Fatigue – Fatigue – Depression – Depression Insomnia Insomnia r r r .67
.38
.60 EORTC QLQ C30 Sleep
.75
.36
.63
Abbreviations: r, Pearson or Spearman correlation coefficient; BDI, Beck Depression Inventory; BFI, Brief Fatigue Inventory; BMT, Bone Marrow Transplant; CES-D, Center for Epidemiologic Studies Depression Scale; CFS, Cancer Fatigue Scale; ChFS, Chalder Fatigue Scale; EORTC, European Organization for Research and Treatment QLQ-C 30; FACT-F, Functional Assessment of Cancer Therapy-Fatigue Subscale; FSS, Fatigue Severity Scale; GSQS, Groningen Sleep Quality Scale; HADS-D, Hospital Anxiety and Depression Scale-Depression Subscale; ISI, Insomnia Severity Index; MFI, Multidimensional Fatigue Inventory; MSAS-SF, Memorial Symptom Assessment Scale-Short Form; PFS, Piper Fatigue Scale; POMS, Profile of Mood States; PSQI, Pittsburgh Sleep Quality Index; SCID-I-RV, Structured Clinical Interview for Depression; SDS, Symptom Distress Scale; SER, Symptom Experience Report; VAS, Visual Analog Scale; ZSDS, Zung Self-Rating Depression Scale.
alence rates of depressive symptoms and major depressive disorder in cancer are purported to range from 10% to 25%.16 Among those patients referred for psychiatric consultation, rates of depression range as high as 59%.17 Prevalence rates of insomnia also vary widely, with most studies estimating that approximately 30% to 50% of cancer patients report sleep difficulties.18 Although prevalence rates of patients meeting diagnostic criteria for an insomnia disorder are less well known, researchers have reported estimates of nearly 20%.19,20 One way to determine the extent to which these three symptoms co-occur is to examine the magnitude of correlations between measures of fatigue, depression, and insomnia administered concurrently to patients. Although the research on symptoms clusters is limited to date, a number of studies have reported associations between these symptoms among cancer patients.21-36 As shown in Table 2, only three studies reported correlations between all possible pairings of fatigue, depression, and insomnia.21,28,30 These correlations were positive and ranged from .43 to .68 for fatigue and depression, from .26 to .54 for fatigue and insomnia, and from .30 to .51 for depression and insomnia. When all of the 16 studies measuring fatigue, depression, and insomnia were considered concurrently, the average correlations were .55 for fatigue and depression, .34 for
fatigue and insomnia, and .45 for depression and insomnia. Thus, on average, measures of fatigue and depression administered concurrently to cancer patients shared approximately 30% of their variance, measures of fatigue and insomnia shared approximately 12%, and measures of depression and insomnia shared approximately 20%. Three of the studies listed in Table 2 included analyses designed specifically to examine the effects of overlap on correlations between measures of fatigue and depression. In these studies,34-36 the Fatigue Severity Scale (FSS) and the depression subscale of the Hospital Anxiety and Depression Scare (HADS) were administered concurrently to cancer patients. The latter measure includes one item (“I feel as if I am slowed down”) that would appear to overlap with fatigue. Correlations were computed between the FSS and both the original version of the HADS depression subscale and a version that excluded this item. Across studies, the average correlation between the FSS and the HADS depression subscale was .66 before exclusion of the item and .56 after exclusion of the item. In summary, empirical studies yield consistent evidence of a relatively high degree of correspondence between levels of fatigue, depression, and insomnia among patients with cancer. This state of affairs is not particularly surprising considering the overlap present in many current approaches
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to assessing these constructs. In comparative studies using the multi-symptom approach to assessing fatigue, depression, and insomnia, researchers have shown that more fatigued breast cancer patients report significantly more sleep problems and depressive symptoms compared with patients who are not as fatigued.30,37 However, there is evidence to suggest that the degree of correspondence is not solely a function of overlap in assessment approaches. First, as shown in Table 2, correlations between fatigue and depression remained relatively high, even when items reflecting phenomena associated with fatigue were removed from measures of depressive symptomatology.34-36 Second, relatively high correlations have been observed between measures focusing specifically on depressed mood and multi-symptom approaches to sleep,34 between measures of general, unidimensional fatigue and multi-symptom approaches to sleep,24,34 and between multisymptom approaches to fatigue and selected unidimensional measures of sleep difficulty.27,29,32-36
WHAT ARE THE IMPLICATIONS OF THIS SYMPTOM CLUSTER FOR PATIENT ASSESSMENT AND MANAGEMENT?
T
he research findings provide considerable evidence that fatigue, depression, and insomnia cluster together in cancer. The next logical step is to consider the evidence for treatment of this symptom cluster. Considered individually, each symptom has generally accepted pharmacologic and non-pharmacologic management approaches in patients. Pharmacologic Approaches Fatigue. Efforts to manage fatigue are typically focused on correcting potential etiologies as well as relieving symptoms. Potentially correctable etiologies include depression, anemia, infection, and other symptoms such as pain or insomnia. There is evidence that psychostimulants (such as methylphenidate, dextroamphetamine, and pemoline) may be useful in relieving fatigue related to opioid-induced somnolence,38 neurobehavioral slowing,39,40 and depression41 in patients with cancer. Preliminary research suggests that these agents are also useful in relieving disease- or treatment-related fatigue in cancer patients.42-46 The mechanisms by which psychostimulants relieve disease- or treatment-related fatigue have yet
to be identified. In particular, it is unclear whether the effects of psychostimulants on fatigue are related to, or distinct from, their mood-enhancing properties. Recommendations regarding the use of antidepressant medications to relieve fatigue in cancer patients are based largely on clinical observations that these agents, in particular velafaxine and bupropion, have energizing effects.47 Both agents appear to function similarly to psychostimulants; their use is associated with increased synaptic levels of norepinephrine.48 These findings are consistent with animal and human studies suggesting that increased levels of norepinephrine and/or dopamine are associated with increased levels of cortical arousal.49 Randomized controlled trials are needed to identify the specific antidepressant agents that are effective at relieving fatigue. As with the psychostimulants, it is not clear whether the observed effects of these agents on fatigue are related to, or distinct from, their mood-enhancing effects. Depression. Randomized controlled trials of pharmacologic interventions for depressive symptoms in cancer patients are limited in number, but in general indicate that antidepressant medications are beneficial.16 The selection of a specific antidepressant is guided by the constellation of presenting symptoms. By and large, research indicates that serotonin-selective reuptake inhibitors and medications that inhibit primarily norepinephrine reuptake are equally efficacious in the treatment of major depressive disorder.50-52 As depressed mood improves, the associated fatigue or sleep disturbance can also be expected to resolve. Insomnia. Treatment of insomnia, like fatigue, may involve treating the underlying etiologies such as pain, delirium, menopausal symptoms, gastrointestinal distress, and anxiety and depression.18,53 When insomnia is the primary presenting complaint, hypnotics medications are most commonly used. Benzodiazepines such as lorazepam, clonazepam, and oxazepam, which are specifically marketed as anxiolytics, are often the first choice for sleep initiation problems or shortterm insomnia because of their sedating effects. However, these long-acting medications may cause daytime sedation, dizziness, light-headedness, or cognitive and psychomotor impairments.54,55 Psychostimulants may be used to counter daytime sleepiness and sedation, but can cause insomnia. Non-benzodiazepines such as zol-
FATIGUE, DEPRESSION, AND INSOMNIA
pidem, zaleplon, and escopiclone for sleep initiation and maintenance are believed to have more specific and selective mechanisms of action, resulting in fewer side effects and residual effects the next day.18,53 Additional non-benzodiazepine medications include neuroleptics such as olanzapine and quetiapine and sedating antidepressants such as amitriptyline, trazodone, and mirtazapine. Nonpharmacologic Approaches Nonpharmacologic approaches to the management of fatigue, depression, and insomnia in cancer patients can be divided into activity-based therapies and psychological therapies. Activitybased therapies generally involve supervised or unsupervised exercise programs while psychological therapies may include relaxation training, coping skills training, and education. Fatigue. Systematic reviews of randomized and controlled clinical trials of exercise in cancer patients have documented positive results for a variety of psychological and physiological outcomes, including fatigue.56-58 Aerobic exercise in the form of home-based walking programs or supervised laboratory treadmill or exercise bicycle programs has consistently resulted in significant reductions in selfreported fatigue during and after active cancer treatment compared with control conditions. Although most of the studies have involved women with a diagnosis of breast cancer, beneficial effects of exercise have also been shown among prostate cancer patients, melanoma, leukemia, multiple myeloma, and lymphoma patients. A diverse array of psychological interventions has been evaluated in cancer patients; several have included fatigue as an endpoint. Interventions tested include relaxation training, psychoeducation, energy conservation programs, coping skills training, problem-solving therapy, and supportive and expressive therapy. In general, the effects of these interventions on fatigue have been positive (see for example, Jacobsen et al59). The number of randomized controlled clinical trials of psychological interventions that include fatigue as a primary outcome has begun to increase in recent years.60 Thus, we can anticipate more evidence-based management approaches to fatigue in the future. Depression. Despite the fact that exercise intervention studies in cancer have more often focused on psychological distress or mood distur-
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bance than depression,56,61 there is evidence for the effectiveness of exercise in relieving depression in cancer (see for example, Segar et al62). A number of different psychological interventions also have been tested for their effect on depression in cancer. The most commonly evaluated interventions appear to be relaxation training and education.63 In general, comprehensive reviews of existing studies provide considerable support for these interventions in managing depression in cancer patients.63,64 Insomnia. Sleep hygiene, stimulus control, sleep restriction, and relaxation training have each been shown to be effective treatments for insomnia.65 However, few studies have evaluated their effectiveness in cancer patients. Although pilot studies evaluating the efficacy of relaxation training for insomnia in cancer have reported mixed results,66,67 more recent nonrandomized studies of interventions combining relaxation training with education about sleep hygiene, the use of stimulus control, and sleep restriction, have yielded positive results.68-70
CONCLUSION
A
s noted previously, fatigue, depression, and insomnia can each be assessed using a singlesymptom, a multi-symptom, or a clinical syndrome approach. A review of measurement approaches indicates that there is overlap among all three approaches, although research has been limited primarily to the use of either single- or multisymptom approaches. Existing research also indicates that fatigue, depression, and insomnia commonly co-occur in cancer. However, there is evidence that this clustering is not solely a function of overlap in measurement approaches. Our findings suggest that the single- and multi-symptom measurement approaches are of limited usefulness in attempting to distinguish each symptom from the others. There is a growing evidence base for the effective treatment of fatigue, depression, and insomnia in cancer patients. Successful management approaches are likely to combine pharmacologic and nonpharmacologic therapies. Given that the presentation as well as the assessment of symptoms in this cluster shows significant overlap, we can expect that treatments for each symptom will overlap as well, and that a modality used to treat one symptom may also be effective in treating one or both of the others.
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