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Psychosomatics 49:185-190, May-June
doi: 10.1176/appi.psy.49.3.185
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Perspective

Understanding Fatigue in Major Depressive Disorder and Other Medical Disorders

Lesley M. Arnold, M.D.

Received July 25, 2007; revised August 24, 2007; accepted September 6, 2007. From the University of Cincinnati, Cincinnati, OH. Send correspondence and reprint requests to Lesley M. Arnold, M.D., Medical Arts Building, 222 Piedmont Ave., Suite 8200, Cincinnati, OH 45219. e-mail: Lesley.Arnold{at}uc.edu
© 2008 The Academy of Psychosomatic Medicine


  ABSTRACT

 
TOP
 ABSTRACT
INTRODUCTION
 CONCLUSION
 REFERENCES
 
BACKGROUND: Although fatigue is a common symptom that occurs in many psychiatric and other medical disorders, the pathophysiological mechanisms of fatigue are still unclear. OBJECTIVE: The goal of this review is to assess the state of knowledge about fatigue in depression and other disorders and identify new avenues for research in the study of fatigue. METHOD: The author reviewed some 50 articles in the field. CONCLUSION: An approach that emphasizes the similarities between fatigue and depression may improve the understanding of these complex syndromes. As more is learned about the neuropathology of the heterogeneous syndrome of depression, the etiology of many of the symptoms domains associated with depression, including fatigue, may become clearer.

Key Words: Fatigue • Depression

  INTRODUCTION

 
TOP
 ABSTRACT
 INTRODUCTION
CONCLUSION
 REFERENCES
 
There is growing interest in fatigue associated with both psychiatric and other medical conditions. For example, recent studies of patient perspectives on important symptoms associated with rheumatological and chronic pain conditions found that fatigue is one of the most common and disabling symptoms of rheumatoid arthritis and fibromyalgia and concluded that fatigue should be included in the core set of outcome measures for clinical trials of these disorders.1,2 Also, the Centers for Disease Control recently initiated the first national public awareness campaign on chronic fatigue syndrome (CFS) in order to educate the public and healthcare professionals about the diagnosis of CFS and the impact of CFS on patients.3 Although fatigue is a common symptom that occurs in many psychiatric and other medical disorders, the cause of fatigue is still unclear. It is also unknown whether there are shared pathophysiologic mechanisms of fatigue between disorders. This review assesses the state of knowledge about fatigue in depression and other disorders and focuses on new avenues for research in fatigue.

Fatigue Associated With Major Depressive Disorder
Major depressive disorder is a complex, heterogeneous syndrome that is currently defined by symptomatic criteria established by APA’s Diagnostic and Statistical Manual of Mental Disorders (DSM–IV).4 Although the development of these criteria improved the reliability of the diagnosis of major depressive disorder, there is actually limited empirical support for the requirement for 2 weeks’ duration and the presence of at least five symptoms. Indeed, it has been suggested that the DSM–IV criteria for depression are a diagnostic convention imposed on a continuum of depressive symptoms of varying severity and length.5 Further evidence of the dimensional nature of depression comes from studies of subthreshold depression, which is common and is characterized by a cluster of depressive symptoms that do not meet full criteria for major depressive disorder. Patients with subthreshold depression have seemingly "subclinical" levels of depressive symptoms, but they experience substantial impairment in functioning and are at risk for developing future major depressive episodes.6 Furthermore, the relationship between the full syndrome of depression and individual symptoms and cluster of symptoms is largely unknown. It is possible that symptoms such as fatigue have complex etiologies that are independent of other symptoms of depression and may respond differently to treatment.7 It may therefore be important to focus research efforts on a study of symptoms rather than syndromes in order to better understand their underlying pathophysiology.8

There are conceptual similarities between depression and fatigue. Fatigue, like depression, can be assessed as a single symptom (a unidimensional approach), a cluster of symptoms (a multidimensional approach), or as a clinical syndrome (a set of criteria for the diagnosis of fatigue such as chronic fatigue syndrome or cancer-related fatigue).9 Symptoms of fatigue include physical (e.g., reduced activity, low energy, tiredness, decreased physical endurance, increased effort with physical tasks and with overcoming inactivity, general weakness, heaviness, slowness or sluggishness, nonrestorative sleep, and sleepiness); cognitive (e.g., decreased concentration, decreased attention, decreased mental endurance, and slowed thinking); and emotional dimensions (e.g., decreased motivation or initiative, decreased interest, feeling overwhelmed, feeling bored, aversion to effort, and feeling low). Physical fatigue or loss of energy is included as a single item in the DSM–IV criteria for major depressive disorder. However, all of the dimensions of fatigue can be found in other criteria for major depressive disorder. For example, mental fatigue (e.g., difficulty concentrating) and emotional fatigue (e.g., anhedonia) are also associated with depression.10 The overlap in symptomatology makes it difficult to disentangle the complex comorbidities between depressive syndromes and fatigue syndromes. Further complicating the assessment of fatigue is the presence of different subtypes of depression.

Two of the most common clinical subtypes of major depressive disorder are melancholic and atypical depression. Characteristic features of melancholic depression are insomnia; early morning awakening; anorexia; and rumination of guilt, personal unworthiness, and pessimism. By contrast, atypical depression is associated with hypersomnia, weight gain or increase in appetite, inertia, and leaden paralysis (i.e., severe lethargy and fatigue; heavy, weighted-down feeling in arms and legs).11 In a population-based study of female twins, members of the twin pairs concordant for depression had the same depressive subtype (e.g., atypical depression) more often than expected by chance, and this resemblance was greater in monozygotic than dizygotic pairs, suggesting that familial and possibly genetic factors are involved in the etiology of some subtypes of depression. Therefore, depression is not only clinically heterogeneous, but may also be etiologically heterogeneous.12

Atypical depression is of particular interest in a consideration of fatigue because patients with this subtype are significantly more likely than patients with other forms of depression to report fatigue.13 Both community-based studies and studies of psychiatric outpatients have shown that approximately one-fifth to one-fourth of depressed individuals exhibit the atypical subtype.14,15 Compared with other depressed groups, the atypical-depressed group has a significantly higher percentage of women, an earlier age at onset of depression, often more severe depression and poorer functioning, and significantly greater association with childhood neglect and sexual abuse.13,15 A recent twin study showed that fatigue during a severe major depressive episode is more likely to be reported by women than men.16 This evidence, along with the preponderance of women with the atypical subtype of depression, suggests that women are at greater risk for developing fatigue in depression. However, the reasons for the sex difference are unknown. There is emerging evidence that atypical depression is associated with endocrine abnormalities that differ from the classic melancholic depression. In many studies of the hypothalamic-pituitary-adrenal (HPA) axis, melancholic depression is associated with hypercortisolism, which is thought to be a result of elevation in hypothalamic corticotropin-releasing hormone (CRH). In contrast to a centrally activated HPA axis in melancholic depression, atypical depression may be associated with a pathologic reduction of stress-system mediators and a deficiency in hypothalamic CRH.

Hypoactivity of the core stress system components that promote arousal could contribute to the fatigue that is characteristic of atypical depression.17 Although fatigue is common in major depressive disorder,18 especially in the atypical subtype, and is the depressive symptom that correlates most strongly with diminished functioning,19 it is a common prodromal symptom in patients with their first major depressive episode,20 and it strongly predicts progression to a chronic course of depression,21 there has only recently been an increased interest in the psychopharmacology of energy and fatigue. To discover potential targets for the pharmacological treatment of fatigue, efforts are underway to identify specific neuronal circuits involved in fatigue associated with depression.10

Different mechanisms might be involved in the physical, mental, and emotional dimensions of fatigue. Possible circuits contributing to the development of physical fatigue include serotonin and dopamine projections to the striatum and the norepinephrine projections to the cerebellum, two areas that regulate motor function. Descending serotonergic and noradrenergic fibers in the spinal cord may also regulate the perception of physical fatigue. Diffuse cortical projections of norepinephrine, dopamine, acetylcholine, and histamine may play a role in mental fatigue at the cortical level. Finally, reduced prefrontal activity could also contribute to mental fatigue.10

Studies of antidepressants in major depressive disorder have only recently begun to examine the impact of these treatments on fatigue. Unfortunately, information about the response of atypical depressive symptoms to treatment has been limited by the use of symptom measures in clinical trials of antidepressants, such as the Hamilton Rating Scale for Depression (Ham–D) and the Montgomery-Asberg Depression Rating Scale (MDRS), which focus primarily on the melancholic symptoms of depression.22,23 However, several findings have recently emerged about the treatment of fatigue in depression. First, although full remission of major depressive disorder symptoms is the goal of treatment, only 25%–50% of patients in monotherapy clinical trials achieve it.24

One of the symptoms that appears to be less responsive to antidepressant treatment is fatigue.25 Even among those patients who fully respond to antidepressants, fewer than 20% report being symptom-free after treatment, and fatigue is one of the most common residual symptoms.26 After remission of major depressive disorder, approximately 10%–35% of patients continue to experience fatigue.27 Second, fatigue may emerge or worsen as a side effect of some antidepressants, complicating the evaluation and management of those subgroups of depressed patients with fatigue.28 Finally, pharmacological augmentation of antidepressant therapy has shown promise in the treatment of residual fatigue. Bupropion or atomoxetine, which enhance dopamine and norepinephrine in cortical and subcortical areas of the brain, have been added to selective serotonergic antidepressants to improve residual fatigue.29 Studies suggest that modafinil, which activates orexin-containing and histaminergic neurons in the hypothalamus and releases histamine in the hypothalamus, as well as dopamine, norepinephrine, and serotonin in the cortex, may relieve residual fatigue after treatment with antidepressants.30 Modafinil, unlike central nervous stimulants, does not release dopamine and norepinephrine in the nucleus accumbens, which reduces its abuse potential.

From the results of antidepressant treatment studies of depression, it appears that the etiology of fatigue may involve several neuronal circuits that may be distinct from those that influence depressed mood. More studies of the treatment of fatigue in major depressive disorder are clearly needed. Perhaps the results of such studies will guide the treatment of fatigue associated with other medical disorders.

Fatigue Associated With Other Medical Disorders
Studies of fatigue associated with medical disorders have shown a high degree of correspondence between fatigue and depression. For example, "vital exhaustion," defined as unusual fatigue, demoralization, and increased irritability, and associated with the pathogenesis of cardiovascular disease,31,32 shares many features with depression and is highly correlated with depression in patients with cardiovascular disorders.31 Results of studies that have attempted to identify possible differences between depression and vital exhaustion have been conflicting, and questions remain about whether depression and vital exhaustion are independent risk factors for cardiovascular disorders and morbidity.32 Fatigue has also been highly correlated with depression in patients with rheumatological disorders, such as rheumatoid arthritis and systemic lupus erythematosus33,34 and other medical disorders, such as multiple sclerosis,35 cancer,36 heart failure,37 and HIV/AIDS.38

The symptomatic overlap between fatigue and depression might have confounded the findings of high correspondence between fatigue and depression in medical disorders. To address this problem, studies of cancer-related fatigue limited the assessment of depression to its mood components, but still showed a high correlation between depression and fatigue. Furthermore, the association between fatigue and depression remained high even after items reflecting symptoms of fatigue were removed from measures of depression. These results suggest that the strong association between fatigue and depression in cancer patients is not simply a function of overlap in their assessment.36 There is limited evidence that depression is a secondary response to the experience of fatigue produced by cancer and indirect evidence to support the possibility that fatigue associated with cancer occurs as a consequence of depression. However, the most compelling data suggest that fatigue and depression share etiologic factors. For example, pancreatic tumors may secrete neuropeptides and neurohormones that contribute to the development of both depression and fatigue.36

Chronic, disabling fatigue lasting 6 months or longer that is unexplained by current medical knowledge has been classified according to internationally agreed-upon criteria as chronic fatigue syndrome or idiopathic chronic fatigue.39 The relationship between unexplained chronic fatigue and depression is still unclear. Numerous studies in tertiary-care centers, primary-care settings, and the community have all shown a strong association of medically unexplained chronic fatigue and depression.40–45 Furthermore, a lifetime history of major depressive disorder occurs in approximately 50%–75% of individuals with chronic fatigue syndrome.46 Even after removing fatigue symptoms as criteria for depression, the majority of patients with chronic fatigue syndrome meet criteria for a lifetime history of major depressive disorder, suggesting that the comorbidity is not simply a consequence of diagnostic overlap between major depression and chronic fatigue syndrome.42,47

The strong association of chronic fatigue and depression and the high rates of lifetime major depressive disorder in persons with chronic fatigue syndrome suggest that chronic fatigue syndrome may be a manifestation of major depressive disorder. One of the main arguments against this possibility is that about one-quarter to one-half of patients with chronic fatigue do not have a history of major depressive disorder.48 It is very important to consider, however, that the presence of only one subtype of depression, melancholic major depressive disorder, excludes a patient from a diagnosis of chronic fatigue syndrome according to the Centers for Disease Control and Prevention (CDC) definition.39 It is possible that patients with chronic fatigue syndrome may have subthreshold symptoms of depression, which, as discussed above, represents an important, but understudied, clinical problem. Furthermore, other subtypes of depression, such as atypical depression, are not excluded when making a diagnosis of chronic fatigue syndrome. As reviewed above, atypical depression is characterized by prominent fatigue and, like chronic fatigue syndrome, predominately affects women and is associated with a history of abuse.49

Interestingly, unlike melancholic depression, both atypical depression and chronic fatigue syndrome are associated with reduced activation of the HPA axis.50 Proinflammatory cytokines, may also be a common factor involved in the development of fatigue and depression. Also, controlled studies with monoamine oxidase inhibitors (MAOIs) showed that there was improvement in the symptoms of CFS. In a single-blind trial, selegiline given for 6 weeks improved measures of fatigue, functional status, and mood states.51 In a more recent study, 51% of CFS patients receiving moclobemide improved in their subjective sense of vigor and energy, as compared with 33% of those receiving placebo.52 These results suggest that there may be common pathophysiological factors that contribute to the development of fatigue and some forms of depression.


  CONCLUSION

 
TOP
 ABSTRACT
 INTRODUCTION
 CONCLUSION
REFERENCES
 
The study of the etiology and treatment of fatigue associated with the spectrum of depressive disorders has the potential to improve the understanding and management of fatigue associated with other medical disorders. Perhaps there has been too much emphasis on distinguishing depressive disorders from fatigue associated with other medical disorders. Instead, an approach that emphasizes the similarities between fatigue and depression may open up new avenues for research in these complex syndromes. As we continue to learn more about the neuropathology of the heterogeneous syndrome we call depression, we may also learn about the etiology of many of the symptom domains, including fatigue, that are associated with depression.


  ACKNOWLEDGMENTS

 
Dr. Arnold receives grant/research support from Eli Lilly and Company, Pfizer, Cypress Bioscience, Wyeth, Sanofi-Aventis, Boehringer Ingelheim, Allergan, and Forest. Dr. Arnold is a consultant for Eli Lilly and Company, Pfizer, Cypress Bioscience, Wyeth, Sanofi-Aventis, Boehringer Ingelheim, Forest, Sepracor, Allergan, and Vivus, and is on the Speaker’s Bureau for Eli Lilly and Company and Pfizer.


  REFERENCES

 
TOP
 ABSTRACT
 INTRODUCTION
 CONCLUSION
 REFERENCES
 

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