To view this article in PDF form, click here.

How biological abnormalities separate CFS from depression

Chronic fatigue syndrome and depression share symptoms and may coexist—but thanks to new efforts spearheaded by the CDC, skilled clinicians can more easily tell them apart.

Katherine M. Erdman, MPAS, PA-C

Katherine Erdman is assistant professor and assistant director, Baylor College of Medicine PA program, and a PA in the Department of Emergency Medicine at Lyndon B. Johnson General Hospital, Houston, Texas. She has indicated no relationships to disclose relating to the content of this article.

Chronic fatigue syndrome (CFS), also called chronic fatigue immune dysfunction syndrome (CFIDS), is a multisystem illness characterized by a complex constellation of symptoms. CFS has long been controversial among health care providers and researchers, in part because of the difficulty of differentiating it from psychiatric illness. Much has been written about the underdiagnosis of depression,^1,2 but care must be taken as well to avoid the overdiagnosis of depression in patients who have unexplained physical symptoms. Although comorbid depression is a common emotional response to any chronic illness, some patients with CFS are not clinically depressed. These patients are poorly served when depression is the only diagnosis they are offered.

Comorbid depression in CFS has been perceived as evidence that CFS is an atypical manifestation of depression. However, the depression in CFS could be a result of multiple symptoms, an emotional response to disability, immune system changes, or alterations in brain physiology.³ Validating patients who have unexplained symptoms is often difficult. Many clinicians, unaware of the volumes of evidence pointing to a physiologic etiology to CFS, may be overdiagnosing depression by default. This article provides an overview of that evidence and offers clues to differentiating depression from physiologic illness in a patient who presents with symptoms of CFS.

The 1988 CDC case definition for CFS was revised in 1994 (see Table 1).⁴ In 2003, Reeves and colleagues pointed out ambiguities in that definition and offered an approach to guide application of the case definition so that identification of CFS cases could be more uniform for research studies.⁵ Patients with CFS defined according to the Reeves’ approach are clinically distinct from those with unexplained fatigue or depression. The criteria for CFS specifically recognize that CFS and depression can coexist. The challenge to the clinician is to decide for each patient whether the fatigue is due to primary depression, physical illness such as CFS, or a combination.

BACKGROUND

Investigators have been studying CFS from an evidence-based perspective for more than 2 decades. The CDC recently declared, “There is now abundant scientific evidence that CFS is a real physiological illness. It is not a form of depression or hypochondriasis. A number of biologic abnormalities have been identified in people with CFS.”⁶

The lack of credibility given to CFS has been a key obstacle to understanding and acceptance of it as a formal disease state. The CDC, in collaboration with the CFIDS Association of America, initiated a public health campaign to educate the medical community and the public and to advocate for awareness and effective management of CFS. The campaign includes increased dissemination of scientific findings, a CFS Toolkit for clinicians, new continuing medical education opportunities, detailed information on the CDC Web site, public service announcements, advertisements, brochures, and a traveling photo exhibit.⁷

The campaign was launched during a November 3, 2006, press conference held at the National Press Club. Identifying CFS as an “urgent reality,” Dr. Julie Gerberding, director of the CDC, commented that “we are beginning to open the shroud of mystery that has clouded this illness for a long time.” The Assistant Secretary of Health and Human Services and the CDC’s Chief of Chronic Viral Diseases discussed the emerging CFS research and the CDC’s ongoing research efforts.⁸

Dr. Anthony Komaroff, a pioneer in CFS research from Harvard Medical School, noted that “there are now more than 4,000 published studies that show underlying biological abnormalities in patients with this illness. It’s not a psychological illness. In my mind that debate, which was waged for 20 years, should now be over.”⁸

News of the press conference reached the American Medical Association (AMA), with the report immediately posted to the AMA’s Web site and published in the November 27, 2006, issue of American Medical News, the online newsletter of the AMA.⁹ It was also published in the November 27, 2006, issue of the Journal of the American Medical Association.¹⁰ The prompt attention given by the AMA highlights the changing attitudes toward the approach to CFS.

Research into CFS is ongoing at the National Institutes of Health (NIH). This includes the trans-NIH working group for CFS research, an effort to have all of the institutes in the NIH contribute. Thirteen currently participate, and seven new research grants have been awarded with the goal of better understanding how the brain functions in relation to CFS.¹¹

REVIEW OF THE LITERATURE

What does this important news and educational push by the CDC mean to physician assistants? First and foremost, care must be taken to stay informed and to consider new evidence. Because depression with somatization can initially manifest similarly to CFS, PAs must take care to keep up with ever-increasing evidence that CFS has identifiable biological underpinnings.

CFS and depression share certain symptoms, but many others, such as sore throat, lymphadenopathy, arthralgias, myalgias, and postexertional fatigue, are not typical of psychiatric illness. In addition, patients with CFS generally do not have the usual depressive symptoms of anhedonia, guilt, and lack of motivation.^12-14 The fatigue of depression seems to be motivation-related and milder than in CFS. When tested, depressed persons score highest on feelings of low self-esteem manifested as self-criticism and feelings of worthlessness and guilt, but CFS patients score highest on physical symptom-related points such as pain, sleep disruption, and lack of energy.¹⁵ People with depression tend to be withdrawn and without a sense of hope, whereas people with CFS are typically more proactive about seeking treatment, are hopeful for recovery, and often join support groups and lobby for research funding.¹⁶ Striving for improved quality of life is uncommon in depressed persons.

The CDC’s CFS Research Group has contributed approximately 80 publications to peer-reviewed journals since 2000. Much of this information has come from the Wichita CFS Surveillance Study, launched by CDC researchers in 1997, which collected data from 90,000 subjects and performed extensive clinical assessments of approximately 7,000.^17,18 Observing the data, Reyes and colleagues posited that CFS may be associated with genetic and environmental determinants.¹⁷ Fourteen papers resulting from the Wichita study speaking to these very issues appeared in a special April 2006 issue of Pharmacogenomics.

In the Witchita study, data were collected over 2 days on hospitalized patients from the general population, including 227 patients with CFS, patients who had other unexplained illnesses causing fatigue, and nonfatigued controls. The CFS patients’ psychiatric status, sleep physiology, and cognitive function were evaluated, and neuroendocrine status, autonomic nervous system function, systemic cytokines, and peripheral blood gene expression were measured.¹⁸

Then, in a unique public health effort, a multidisciplinary and international group of 20 investigators was formed to offer new insight and algorithms for interpretation and integration of the Wichita data. It was also hoped that the group might be able to identify molecular markers and discover the pathophysiology of CFS. The group was divided into teams with representation from the disciplines of medicine, mathematics, biology, engineering, and computer science.

One of the most significant observations was that CFS patients have certain markers that are related to brain activity that mediates the stress response. They also have different gene activity levels, which affect the body’s ability to adapt to significant stressors, such as infection, injury, and trauma. The Wichita investigators noted that CFS has at least four distinct clinical profiles that implicate different sets of subtle alterations in the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system.¹⁸

Other research findings revolve around abnormalities of the brain, immune system, endocrine function, and energy metabolism. Studies of abnormalities in HPA axis function and hormonal stress responses have given rise to the most reproducible findings, showing that the hormone system in the hypothalamus and pituitary functions differently in CFS patients than in healthy controls, depressed persons, and persons with other illnesses.

HPA axis abnormalities, including hypercortisolemia, elevated urinary free cortisol, and exaggerated cortical response to corticotrophin, appear in persons with depression.¹⁹ In patients with CFS, however, the opposite appears to be true. CFS patients have lower plasma cortisol than do controls and have a reduced response to corticotrophin. In a direct comparison study, depressed patients had the highest levels of circulating cortisol, normal controls had lower levels, and CFS patients had the lowest levels.²⁰ Urinary free cortisol (UFC) excretion was significantly higher in patients with depression than in healthy comparison subjects, and UFC excretion was significantly lower in patients with CFS than in the comparison group in a 1998 study. The CFS patients who had comorbid depressive illness retained the profile of UFC excretion of those with CFS alone, which suggests a different pathophysiologic basis for depressive symptoms in CFS.²¹

A comprehensive review of neuroendocrine studies in 2001 also confirmed HPA abnormalities in CFS patients.²² Another study showed low cortisol levels in CFS patients compared to controls and determined that depression in CFS may be different from classic depression.²³ More recently, in 2006, reduced basal HPA axis function in CFS patients was confirmed, showing lower free cortisol and cortisone levels.²⁴ Others have found that dehydroepiandrosterone was lower in patients with CFS than in depressed persons or controls.²⁵

Imaging studies, including MRI, CT, and various nuclear scans, have shown inflammation, reduced blood flow, and impaired cellular function in the brains of patients with CFS.^26,27 There is objective evidence that CFS patients who underwent blood oxygen level dependent functional MRI studies had significant auditory information processing difficulties.²⁸ In many with CFS, cognitive function is impaired.^29-31 Positron emission tomography and single-photon emission tomography of the brain have shown frontal hypoperfusion in both depressive disorders and CFS,³² but the patterns are different, with additional differences in perfusion of various parts of the brain and brain stem.^33,34

Many immune system studies have demonstrated abnormal immune system cells in patients with CFS and shown that the system is in a state of chronic activation, as if responding to a foreign invader.^35-37 Nijs and De Meirleir provided an overview of studies showing impairments of the 2-5A synthetase/RNase L pathway in CFS, with associated decreased natural killer cell function and deregulation of apoptotic pathways.³⁸ A panel of experts determined that changes in immune responses found in CFS patients fall outside normal ranges, but they were not able to determine whether these abnormalities were a cause or a result of the illness.³⁹ Gene expression studies show genes that control the activation of the immune system are abnormally expressed in patients with CFS.^40-42

Biological distinctions between CFS and depression have been found by measuring electrodermal activity and skin temperature in nondepressed subjects with CFS, subjects with depression, and healthy controls. Skin temperature differed significantly among all three groups, with the CFS group averaging 3 to 4°C higher than the depressed and healthy controls, respectively. The levels of skin conductance were significantly lower in the CFS group than in the other two groups.⁴³

Depressed patients typically have reduced rapid eye movement (REM) latency and increased REM density on sleep studies, but this is not usually present in CFS; instead, patients with CFS often have a lack of slow-wave deep sleep, sleep cycle disturbance, and frequent awakenings.⁴⁴ As primary sleep disorders cause fatigue, sleep studies may be indicated to rule out sleep apnea, periodic leg movement disorder, and other sleep-related illnesses.

RESOURCES AND DIAGNOSIS

With the new focus from the CDC and research that points to biological markers for CFS, clinicians can be more objective in their approach to patients with symptoms of this disease. Many conditions need to be ruled out, and the CDC’s Toolkit offers guidelines for the workup of a patient with CFS symptoms. The toolkit can be accessed at www.cdc.gov/cfs/toolkit.htm. Elements of the initiative that are available via the CDC Web site are a quick reference brochure, free continuing medical education courses, and a 65-page manual on CFS science and research. CDC researchers and collaborators present programs about CFS at conferences, academic institutions, and health care centers. Details can be found at www.cfids.org/sparkcfs/health-professionals.asp.

The differences between CFS and depression suggest that someday people with CFS might be identified by various physiologic measures. In an outpatient setting, differentiating CFS from depression should be focused on the history and on physical signs and symptoms. Focusing on diagnostic criteria should help to reach an accurate diagnosis. The Toolkit instructs on the appropriate laboratory tests. In addition, if appropriate, sleep studies and cortisol testing may be helpful. The Hospital Anxiety and Depression Scale can be used to assess level of depression and may be a good starting point for discussing the patient’s experience and determining if anhedonia is the result of a generalized sense of hopelessness or caused by pain and exhaustion.

CONCLUSION

Having knowledge and experience with CFS, remaining objective, and assuring that the patient meets the accepted diagnostic criteria will aid the astute clinician in making an accurate diagnosis. Using the Toolkit and having the CDC’s other resources easily accessible in the clinical setting can make for more productive encounters with patients presenting with unexplained symptoms of fatigue. Ongoing research into specific brain, hormonal, and immunologic abnormalities consistent with CFS will undoubtedly continue to shed new light onto the etiology of this frustrating illness, with possibilities for finding diagnostic markers that can be used to more easily identify CFS. Although the debate about CFS as a medical or psychiatric condition will likely continue, it is not likely that depression will be proven to be the primary cause. JAAPA

REFERENCES

	1.	Tylee A, Gandhi P. The importance of somatic symptoms in depression in primary care. Prim Care Companion J Clin Psychiatry. 2005;7(4):167-176.
	2.	Nuyen J, Volkers AC, Verhaak PF, et al. Accuracy of diagnosing depression in primary care: the impact of chronic somatic and psychiatric co-morbidity. Psychol Med. 2005;35(8):1185-1195.
	3.	Johnson SK, DeLuca J, Natelson BH. Depression in fatiguing illness: comparing patients with chronic fatigue syndrome, multiple sclerosis and depression. J Affect Disord. 1996;39(1):21-30.
	4.	Fukuda K, Straus SE, Hickie I, et al. The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med. 1994;121(12):953-959.
	5.	Reeves WC, Lloyd A, Vernon SD, et al. International Chronic Fatigue Syndrome Study Group. Identification of ambiguities in the 1994 chronic fatigue syndrome research case definition and recommendations for resolution. BMC Health Serv Res. 2003;3:25. http://www.biomedcentral.com/1472-6963/3/25. Accessed February 19, 2008.
	6.	Chronic fatigue syndrome. Toolkit: facts sheets for healthcare professionals. CDC Web site. http://www.cdc.gov/cfs/toolkit.htm. Accessed February 19, 2008.
	7.	CFIDS Association of America. Spark! The Campaign to Ignite CFS Awareness. Chronic fatigue syndrome for health care professionals. http://www.cfids.org/sparkcfs/health-professionals.asp. Accessed February 19, 2008.
	8.	The Chronic Fatigue and Immune Dysfunction Syndrome Association of America and The Centers For Disease Control and Prevention Press Conference at The National Press Club to Launch a Chronic Fatigue Syndrome Awareness Campaign. November 3, 2006. CDC Web site. http://www.cdc.gov/od/oc/media/transcripts/t061103.htm?id=36410. Accessed February 19, 2008.
	9.	Landers SJ. Campaign puts a spotlight on chronic fatigue syndrome. AMNews. http://www.ama-assn.org/amednews/2006/11/27/hlsb1127.htm. Accessed February 19, 2008.
	10.	Hampton T. Chronic fatigue syndrome answers sought [Medical news & perspectives]. JAMA. 2006;296(24):2915.
	11.	National Institutes of Health. The Trans-NIH Working Group on Chronic Fatigue Syndrome. Diagnostic criteria. http://orwh.od.nih.gov/cfs/cfsWG.html. Accessed February 19, 2008.
	12.	Powell R, Dolan R, Wessely S. Attributions and self-esteem in depression and chronic fatigue syndrome. J Psychosom Res. 1990;34(6):665-673.
	13.	Wessely S, Chalder T, Hirsch S, et al. Psychological symptoms, somatic symptoms, and psychiatric disorder in chronic fatigue and chronic fatigue syndrome: a prospective study in the primary care setting. Am J Psychiatry. 1993;153(8):1050-1059.
	14.	Johnson SK, DeLuca J, Natelson BH. Chronic fatigue syndrome: reviewing the research findings. Ann Behav Med. 1999;21(3):258-271.
	15.	Moss-Morris R, Petrie KJ. Discriminating between chronic fatigue syndrome and depression: a cognitive analysis. Psychol Med. 2001;31(3):469-479.
	16.	Lapp CW. Differentiating CFS from depression. The CFS Research Review. 2006;7(1):4-7.
	17.	Reyes M, Nisenbaum R, Hoaglin DC, et al. Prevalence and incidence of chronic fatigue syndrome in Wichita, Kansas. Arch Intern Med. 2003;163(13):1530-1536.
	18.	Vernon SD, Reeves WC. The challenge of integrating disparate high-content data: epidemiological, clinical and laboratory data collected during an in-hospital study of chronic fatigue syndrome. Pharmacogenomics. 2006;7(3):345-354.
	19.	Hayes PE, Ettigi P. Dexamethasone suppression test in diagnosis of depressive illness. Clin Pharm. 1983;2(6):538-545.
	20.	Cleare AJ, Bearn J, Allain T, et al. Contrasting neuroendocrine responses in depression and chronic fatigue syndrome. J Affect Disord. 1995:34(4):283-289.
	21.	Scott LV, Dinan TG. Urinary free cortisol excretion in chronic fatigue syndrome, major depression and in healthy volunteers. J Affect Disord. 1998;47(1-3):49-54.
	22.	Parker AJR, Wessely S, Cleare AJ. The neuroendocrinology of chronic fatigue syndrome and fibromyalgia. Psychol Med. 2001:31(8):1331-1345.
	23.	Cevik R, Gur A, Acar S, et al. Hypothalamic-pituitary-gonadal axis hormones and cortisol in both menstrual phases of women with chronic fatigue syndrome and effect of depressive mood on these hormones. BMC Musculoskelet Disord. 2004;5:47. doi:10.1186/1471-2474-5-47.
	24.	Jerjes WK, Peters TJ, Taylor NF, et al. Diurnal excretion of urinary cortisol, cortisone, and cortisol metabolites in chronic fatigue syndrome. J Psychosom Res. 2006;60(2):145-153.
	25.	Scott LV, Salahuddin F, Cooney J, et al. Differences in adrenal steroid profile in chronic fatigue syndrome, in depression and in health. J Affect Disord. 1999;54(1-2):129-137.
	26.	Chaudhuri A, Condon BR, Gow JW, et al. Proton magnetic resonance spectroscopy of basal ganglia in chronic fatigue syndrome. Neuroreport. 2003;14(2):225-228.
	27.	Cleare AJ, Messa C, Rabiner EA, Grasby PM. Brain 5-HT1A receptor binding in chronic fatigue syndrome measured using positron emission tomography and [11C]WAY-100635. Biol Psychiatry. 2005;57(3):239-246.
	28.	Lange G, Steffener J, Cook BM, et al. Objective evidence of cognitive complaints in chronic fatigue syndrome: a BOLD fMRI study of verbal working memory. Neuroimage. 2005;26(2):513-524.
	29.	Busichio K, Tiersky LA, Deluca J, Natelson BH. Neuropsychological deficits in patients with chronic fatigue syndrome. J Int Neuropsychol Soc. 2004;10(2):278-285.
	30.	Deluca J, Johnson SK, Beldowicz D, Natelson BH. Neuropsychological impairments in chronic fatigue syndrome, multiple sclerosis, and depression. J Neurol Neurosurg Psychiatry. 1995;58(1):38-43.
	31.	Michiels V, Cluydts R. Neuropsychological functioning in chronic fatigue syndrome: a review. Acta Psychiatr Scand. 2001;103(2):84-93.
	32.	George MS, Ketter TA, Post RM. SPECT and PET imaging in mood disorders. J Clin Psychiatry. 1993;54(suppl):6-13.
	33.	Costa DC, Tannock C, Brostoff J. Brainstem perfusion is impaired in chronic fatigue syndrome. QJ Med. 1995;88(11):767-773.
	34.	MacHale SM, Lawrie SM, Cavanagh JTO, et al. Cerebral perfusion in chronic fatigue syndrome and depression. Br J Psychiatry. 2000;176:550-556.
	35.	Kennedy G, Spence V, Underwood C, Belch JJF. Increased neutrophil apoptosis in chronic fatigue syndrome. J Clin Pathol. 2004;57(8):891-893.
	36.	Maher KJ, Klimas NG, Fletcher MA. Chronic fatigue syndrome is associated with diminished intracellular perforin. Clin Exp Immunol. 2005;142(3):505-511.
	37.	Robertson MJ, Schacterie RS, Mackin GA, et al. Lymphocyte subset differences in patients with chronic fatigue syndrome, multiple sclerosis and major depression. Clin Exp Immunol. 2005;141(2):326-332.
	38.	Nijs J, De Meirleir K. Impairments of the 2-5A synthetase/RNase L pathway in chronic fatigue syndrome. Anticancer Res. 2005;25:1013-1022.
	39.	Gerrity TR, Papanicoulaou DA, Amsterdam JD, et al. Immunologic aspects of chronic fatigue syndrome. Report on a research symposium convened by the CFIDS Association of America and co-sponsored by the US Centers for Disease Control and Prevention and the National Institutes of Health. Neuroimmunomodulation. 2004;11(6):351-357.
	40.	Kaushik N, Fear D, Richards SCM, et al. Gene expression in peripheral blood mononuclear cells from patients with chronic fatigue syndrome. J Clin Pathol. 2005;58(8):826-832.
	41.	Steinau M, Unger ER, Vernon SD, et al. Differential-display PCR of peripheral blood for biomarker discovery in chronic fatigue syndrome. J Mol Med. 2004;82(11):750-755.
	42.	Whistler T, Jones JF, Unger ER, Vernon SD. Exercise responsive genes measured in peripheral blood of women with chronic fatigue syndrome and matched control subjects. BMC Physiol. 2005;5(1):5. doi:10.1186/1472-6793-5-5.
	43.	Pazderka-Robinson H, Morrison JW, Flor-Henry P. Electrodermal dissociation of chronic fatigue and depression: evidence for distinct physiological mechanisms. Int J Psychophysiol. 2004;53(3):171-182.
	44.	Morriss RK, Wearden AJ, Battersby L. The relation of sleep difficulties to fatigue, mood and disability in chronic fatigue syndrome. J Psychosom Res. 1997;42(6):597-605.