DON'T ASSUME IT'S DEPRESSION

James P. Griffith, M.D., F.A.C.P., and Fahd A. Zarrouf, M.D. - From the Internal Medicine/Psychiatry Residency Program, West Virginia University, Charleston. - Corresponding author and reprints: Fahd A. Zarrouf, M.D., Medicine/ Psychiatry Residency Program, West Virginia University, 501 Morris St., 4 West, Charleston, WV 25326 fahdzarrouf@hotmail.com

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Abstract

Objective

Chronic fatigue syndrome (CFS) is characterized by profound, debilitating fatigue and a combination of several other symptoms resulting in substantial reduction in occupational, personal, social, and educational status. CFS is often misdiagnosed as depression. The objective of this study was to evaluate and discuss different etiologies, approaches, and management strategies of CFS and to present ways to differentiate it from the fatigue symptom of depression.

Study Selection and Data Extraction

CFS definitions, etiologies, differential diagnoses (especially depression) and management strategies were extracted, reviewed, and summarized to meet the objectives of this article.

Data Synthesis

CFS is underdiagnosed in more than 80% of the people who have it; at the same time, it is often misdiagnosed as depression. Genetic, immunologic, infectious, metabolic, and neurologic etiologies were suggested to explain CFS. A biopsychosocial model was suggested for evaluating, managing, and differentiating CFS from depression.

Conclusions

Evaluating and managing chronic fatigue is a challenging situation for physicians, as it is a challenging and difficult condition for patients. A biopsychosocial approach in the evaluation and management is recommended. More studies about CFS manifestations, evaluation, and management are needed.

"She is depressed," her physician wrote when referring Ms. A, a 65-year-old married woman, for a psychiatric consult. "She has been feeling tired for more than a year and described being exhausted most of the time, with headaches, joint pain, and problems with her concentration and memory. Her fatigue is frustrating for her and for her family; she cannot function well even in the morning. She denied being depressed, and does not have any previous mental or medical illnesses. Every lab I checked was normal. I still think that she is hiding her depression and manifesting it with all these somatic complaints."

Prolonged fatigue is defined as self-reported, persistent fatigue of 1 month or longer.1 Chronic fatigue syndrome (previously known as myalgic encephalomyelitis2 or neurasthenia3) is characterized by profound, debilitating fatigue and a combination of symptoms resulting in substantial reduction in occupational, personal, social, and educational status1,2,4-7 (see Table 1). Diagnosis of the chronic fatigue syndrome (CFS) can be made only after alternate medical and psychiatric causes of chronic fatiguing illness have been excluded.

At least 1 million Americans have CFS,1,8 more than have lung cancer or multiple sclerosis; yet more than 80% go undiagnosed. In the primary care setting, the prevalence of CFS ranges from 3% to 20% and from 80% to 90% at the end of life.9,10 There are no ethnic or racial differences. Previous reports have mentioned a female:male ratio of 1.3:1,6 but a recent report by the U.S. Centers for Disease Control and Prevention (CDC) showed a female:male ratio of 4:1. It occurs most often in the 40- to 59-year age group and in the geriatric population.1,9,10

Although the concept of neurasthenia was introduced in 1869 by George Miller Beard,3 CFS was defined in 1988 by the CDC, and while more than 3000 research studies have been done in this field, there is still some debate about the existence of this syndrome.1,11,12 The uncertainty about its existence and the lack of a specific laboratory test or marker to identify it, associated with hesitancy about making a diagnosis without knowing exactly how to treat it, all act as barriers to the diagnosis and treatment of CFS by primary care practitioners and psychiatrists.

Unlike the uncertainty about its existence, there is strong certainty about the impact of CFS. CFS patients, by definition, are functionally impaired and as disabled as patients with multiple sclerosis, heart disease, end-stage renal disease, and similar chronic conditions. The annual economic impact of CFS in the United States is estimated to be $9.1 billion in lost productivity.1

DATA SOURCES

A MEDLINE search was conducted to identify existing information about CFS and depression using the headings chronic fatigue syndrome AND depression. The alternative terms major depressive disorder and mood disorder were also searched in conjunction with the term chronic fatigue syndrome. Additionally, MEDLINE was searched using the term chronic fatigue. All searches were limited to articles published within the last 10 years, in English. A total of 302 articles were identified by these searches. Also, the term chronic fatigue syndrome was searched by itself. This search was limited to articles published within the last 5 years, in English, and resulted in an additional 460 articles. Additional publications were identified by manually searching the reference lists of the articles from both searches.

FATIGUE ETIOLOGIES

CFS cannot be considered either physical or psychological but instead requires a biopsychosocial approach to the illness. Numerous studies have tried to pinpoint specific etiologies by considering the following fields.

Genetic Etiologies

CFS is sometimes seen in members of the same family,13,14 but there is no evidence that it is contagious; instead, there may be a familial predisposition or a genetic link. The concordance rate was higher in monozygotic than in dizygotic female twins for chronic fatigue.15 Hickie et al.16 evaluated genetic and environmental determinants of prolonged fatigue in a twin study and found 44% (95% CI=25% to 60%) of the genetic variance for fatigue was not shared by the other forms of psychological distress, and also found that environmental factors made negligible contributions to fatigue. On the other hand, Cho et al.17 found evidence of a partly genetic influence, but environmental effects continued to be predominant. Clearly, further research is needed to explore these possible relationships.

Immunologic Etiologies

Abnormal natural killer cell cytotoxicity,18 increase immune activation markers,19 greater numbers of CD16+/CD3- natural killer cells,20 and the presence of interferon in serum and cerebrospinal fluid in CFS patients21 have been identified. Staines22 suggested the loss of immunologic tolerance to vasoactive neuropeptides or their receptors following infection, other events, or de novo as a mechanism.

Infectious Etiologies

Possible infectious etiologies have generated the most interest among CFS researchers. It has been postulated that chronic fatigue is a continuum ranging from cases with chronic viremia on the one hand to instances of frank psychiatric illness on the other.23 Multiple infectious agents have been linked to CFS, including Borna disease virus,24,25 parvovirus B19,26,27 glandular fever,28 Enterovirus,29 human herpesviruses 4, 6, and 7,30-32 infectious mononucleosis,33 Nipah virus encephalitis,34 and Q fever.35

Infections have not only played important etiologic roles, but also have been considered predictors of better prognoses when compared to noninfectious CFS cases.36 Human herpesvirus 6 reactivation has been suggested as an objective biomarker for fatigue.30

Endocrinology/Metabolism Etiologies

Hypothalamic-pituitary-adrenal (HPA) axis abnormalities have been studied as potential biological tests to diagnose CFS. Studies have shown HPA hypoactivity and higher chronic adrenocorticotropic hormone (ACTH) autoantibody levels as significant pathologic factors in CFS.37-39 Also reduced area under the ACTH response curve in CFS patients undergoing insulin tolerance test was significantly associated with the duration of CFS symptoms (r=-0.592, p=.005) and the severity of fatigue symptomatology.40 Other studies have suggested upregulation of hypothalamic 5-hydroxytryptamine receptors in patients with postviral fatigue syndrome but not in those with primary depression.41 However, another study showed no etiologic role for deficiency in central opioids or the HPA axis in the symptoms of CFS.42 Other biological factors have been investigated and considered as biological markers in CFS, including low magnesium level,43 low arachidonic acid level, low L-carnitine level,25 serum dehydroepiandrosterone (DHEA) sulfate deficiency,44 and impairments of the 2',5'-oligoadenylate (2-5A) synthetase/RNase L pathway.45 Other studies showed no role of linoleic acid, eicosatrienoic acid (both p>.05),25 ferritin, vitamin B12, folate, or serum erythropoietin levels.46

Mental/Neurologic Etiologies

Psychosocial factors are frequently thought to contribute to fatigue. Rangel et al.13 found that CFSin childhood and adolescence is associated with higher levels of parental mental distress, emotional involvement, and family illness burden than those observed in association with juvenile rheumatoid arthritis, a chronic pediatric physical illness. Endicott14 described stressors including earlier mortality age and increased prevalence of cancer, autoimmune disorders, and CFS-like conditions in parents of psychiatric patients with CFS as compared to control groups. Thirty percent of the CFS patients and none of the controls reported dilemmas in the 3 months prior to the CFS onset in one study.47 History of abuse, particularly during childhood, may play a role in the development and perpetuation of chronic fatigue,48 and childhood trauma was associated with a 3- to 8-fold increased risk for CFS across different trauma types in one study.49 Sleep is also an interesting etiologic factor, as many patients with CFS have sleep disorders, and those with sleep disorders showed greater functional impairment independent of their psychiatric disorders.50-52

FATIGUE: DON'T ASSUME IT'S DEPRESSION

Fatigue is a part of a wide spectrum of diagnoses ranging from being a symptom in depression, anxiety, seasonal affective disorder,53 and multiple other diagnoses to being a full syndromal disorder in CFS, yet CFS goes undiagnosed in 80% of cases and is often misdiagnosed as depression. The Diagnostic and Statistical Manual of Mental Disorders doesn't list CFS as a diagnosis although the International Classification of Diseases, 10th Revision, does.12 In clinical practice, CFS presentations range from complicated cases associated with a psychotic state resulting in multiple murders in one case report54 to noncomplicated presentations with multiple psychiatric disorders, primarily depression.55 It is very important to understand the distinctive features between chronic fatigue and depressive disorder when evaluating a patient with a main complaint of fatigue. A full detailed history accompanied by questionnaire forms can be very helpful to differentiate CFS from major depressive disorder. There is still no specific test that can confidently differentiate between them. Multiple studies have tried to find distinctive factors and they are listed in Table 2.

EVALUATION OF FATIGUE

Diagnosing CFS can be challenging for health care professionals for many reasons; the most important one is finding fatiguein a large number of illnesses and disorders. We reviewed information available about evaluation of chronic fatigue and discuss it in 3 parts: history, exam, and diagnostic tests.

History and Differentials

Because CFS is a diagnosis of exclusion,1 a full detailed history is considered essential. The history should include a detailed account of the symptoms, the associated disability, the choice of coping strategies, and importantly, the patient's own understanding of his/her illness.65 Every patient should be carefully evaluated for certain medical, psychiatric, and neurologic diseases that can cause fatigue as the most prominent symptom (Table 3). Two of the important differential diagnoses are depression and fibromyalgia. Although it is difficult to differentiate CFS from fibromyalgia confidently depending on the history or other reported differences of cognitive dysfunction components or clinical pain measures,66,67 CFS and fibromyalgia commonly co-occur within the concept of central sensitivity syndromes or functional somatic syndromes.68 This co-occurring increases functional impairment when compared to CFS individuals alone.69,70 Some of the distinguishing features between CFS and fibromyalgia include evidence for triggering viral infection and lower level of serum acylcarnitine observed in CFS patients, which is lacking in the majority of patients with fibromyalgia;71 slower information-processing in CFS patients compared to impaired control of attention in fibromyalgia patients;66 and lacking of the characteristic diffuse soft tissue pain and pain on palpation in at least 11 of 18 paired tender points in CFS patients.

Exam

Every CFS evaluation should include a mental status examination to identify abnormalities in mood, intellectual function, memory, and personality. Particular attention should be directed toward current symptoms of depressive, anxious, self-destructive thoughts and observable signs such as psychomotor retardation.1 Although there is no definite physical finding, a full and thorough physical examination may be helpful in excluding other conditions. Multiple studies have suggested dysautonomia with greater increase in heart rate together with a more pronounced systolic blood pressure fall on standing in CFS patients compared to healthy individuals.46, 72 Other studies found no statistically significant differences in either heart rate or galvanic skin resistance both during a normal day and before, during, and after exercise testing.73

Tests

The CDC has recommended the following initial screening tests when evaluating patients with CFS: urinalysis, total protein, glucose, C-reactive protein, phosphorus, electrolyte, complete blood count with leukocyte differential, alkaline phosphatase, creatinine, blood urea nitrogen, albumin, antinuclear antibody and rheumatoid factor, globulin, calcium, alanine aminotransferase or aspartate transaminase serum level, and thyroid function tests (thyroid stimulating hormone and free T4).1 Further tests or referral to specialists may be indicated to confirm or exclude a diagnosis that better explains the fatigue state or to follow up on results of the initial screening tests.

Multiple other studies have tried to find biomarkers or radiological markers for CFS. Erythrocyte sedimentation rate was normal in all 23 CFS patients in one study.74 Another study found that concentrations of C-reactive protein, beta_2-microglobulin, and neopterin were higher in patients with CFS (p=<.01).75 On the other hand, a study by Swanink et al.76 found that complete blood cell count, serum chemistry panel, C-reactive protein, and serologic tests were not different in 88 patients with CFS when compared to a control group. A potential role for DHEA in CFS, both therapeutically and as a diagnostic tool, was suggested in one study.64

Magnetic resonance imaging studies have been inconsistent, with some of them suggesting larger ventricular volumes.77-84 Functional magnetic resonance was more promising, as it showed quantitative and qualitative differences in activation of the working memory network,85 attenuation of the responsiveness to stimuli not directly related to the fatigue-inducing tasks,86 utilization of more extensive regions of the network associated with the verbal working memory system,87 impaired functioning and reduced gray-matter volume in the bilateral prefrontal cortex,88 and inactive ventral anterior cingulate after making an error.89

Single-photon emission computed tomography (SPECT) and brain electrical activity mapping scans were promising in one study,90 and SPECT scans showed more abnormalities than did magnetic resonance scans in one study (p<.025).91 Siessmeier et al.92 detected abnormalities in 18-fluorodeoxyglucose positron emission tomography in approximately half the CFS patients examined, but found that no specific pattern for CFS could be identified. Positron emission tomography showed an alteration of the serotonergic system in the rostral anterior cingulate in one study, which was suggested as an etiology.93 Recently, Puri94 described the application of proton neurospectroscopy and 31-phosphorus neurospectroscopy in chronic fatigue syndrome. It is essential to mention that evidence to date does not support routine use of the imaging modalities discussed above in evaluating potential CFS patients.

Finally, it is important to remember that a good history is more important than any available test to diagnose CFS and differentiate it from depression. The algorithm shown in Figure 1, which is based on the CDC recommendations and the results of the studies reviewed, is suggested for evaluating chronic fatigue.

Written by kmc528 Blog about this entry

This entry has 20 comments: (Add your own)

#20 Comment from kmc528Entry Author
7/1/08 8:02 PM | Permalink

This has nothing to do with “mindset”. It’s a simple FACT that one group of researchers are looking into a post-infectious physical disease with proven immune/neurological/endocrine abnormalities, and that another group of researchers are using the same name for a psychiatric condition that has none of those telltale test results. They are obviously not the same condition despite researchers co-opting the same name and hoping most people are too stupid to tell the difference. Some of us intelligent/educated folk can.

You can tell which condition the researchers are investigating by reading their patient selection criteria. It becomes quite clear from a careful reading of that paragraph whether they’re using CFS a/k/a ME patients, or whether they’re using people with none of the physical symptoms of what I have. If they’re not studying the type of CFS that I have, then their research isn’t applicable to me.

The problem isn’t in the minds of the patients, who are quite clear – some of them with hospital records to prove it – that their condition has an infectious onset, but in the minds of the researchers who choose to blur the line between Chronic Fatigue SYNDROME and the SYMPTOM of chronic fatigue in order to get research grants that provide no useful information to those of us who have what used to be called ME because they’re researching something else entirely.

What I have is related to polio and MS, which are also viruses. Psychiatrists have continually given me a clean bill of psychiatric health, repeatedly saying “the most well-adjusted person I’ve ever met”. So, obviously, there’s no psychiatric component to what I have, and therefore, it’s not triggered by stress/trauma/abuse. Mine started with a 105 fever, not with any emotional attack, and I feel flu-ish, not depressed, because what I have is a virus. No one will convince me that I don’t have a virus, not when all the evidence
#19 Comment from marielsunata
7/1/08 5:15 PM | Permalink

My apologies for not responding sooner. After showing some of my colleagues your replies we took some time to read other writings on this site, and got a clearer idea of the mindset here. In short we wish you well and hope in time you will be able to resolve or come to terms with your present situation.
#18 Comment from kmc528Entry Author
7/1/08 1:52 AM | Permalink

Dr. Katrina Berne: “The medical profession often views depression or inability to cope productively with stress as the cause of any symptom for which a physiological cause is not evident. Psychiatry becomes a convenience dumping ground for those with unexplained illness. However, indiscriminate attribution of symptoms to psychological factors is inappropriate.

“... The notion that we cannot handle life, fabricate symptoms, or develop illnesses in order to receive special attention is ludicrous. Attribution of illness to such conscious or unconscious motivation is inaccurate, unfair and insulting. Phrases such as ‘can’t manage stress’ and ‘mind over matter’ add insult to illness. ... Some CFS/FMS patients experience little or no depression.

“Numerous chronic disorders share common features, including symptoms and abnormalities. The similarities are remarkable ... Skeptics who dismiss CFS, FMS ... imply that poorly understood conditions do not deserve the respect afforded ‘testable’ illnesses. This practice lifts a burden from disinterested physicians and blames – even traumatizes – sufferers.

“Double standards allow medical doctors to diagnose psychiatric illness ... in the absence of a known physiological cause, but do not typically allow the psychiatrist or psychologist who rules out emotional causes to rule in physiologic illness. That is, acceptable practice allows a physician to say ‘It is all in your head’ but how often does a psychiatrist or psychologist say ‘Nothing is wrong with your head, the illness is in your body’? ... Illnesses such as MS, rheumatoid arthritis, polio, HIV/AIDS, stomach ulcers and diabetes were once considered to be of psychiatric origin. When markers or diagnostic tests were developed, the diagnoses shifted to ‘real’ illnesses, those of the body. History repeats itself.”
#17 Comment from kmc528Entry Author
7/1/08 1:52 AM | Permalink

Dr. Katrina Berne: “The medical profession often views depression or inability to cope productively with stress as the cause of any symptom for which a physiological cause is not evident. Psychiatry becomes a convenience dumping ground for those with unexplained illness. However, indiscriminate attribution of symptoms to psychological factors is inappropriate.

“... The notion that we cannot handle life, fabricate symptoms, or develop illnesses in order to receive special attention is ludicrous. Attribution of illness to such conscious or unconscious motivation is inaccurate, unfair and insulting. Phrases such as ‘can’t manage stress’ and ‘mind over matter’ add insult to illness. ... Some CFS/FMS patients experience little or no depression.

“Numerous chronic disorders share common features, including symptoms and abnormalities. The similarities are remarkable ... Skeptics who dismiss CFS, FMS ... imply that poorly understood conditions do not deserve the respect afforded ‘testable’ illnesses. This practice lifts a burden from disinterested physicians and blames – even traumatizes – sufferers.

“Double standards allow medical doctors to diagnose psychiatric illness ... in the absence of a known physiological cause, but do not typically allow the psychiatrist or psychologist who rules out emotional causes to rule in physiologic illness. That is, acceptable practice allows a physician to say ‘It is all in your head’ but how often does a psychiatrist or psychologist say ‘Nothing is wrong with your head, the illness is in your body’? ... Illnesses such as MS, rheumatoid arthritis, polio, HIV/AIDS, stomach ulcers and diabetes were once considered to be of psychiatric origin. When markers or diagnostic tests were developed, the diagnoses shifted to ‘real’ illnesses, those of the body. History repeats itself.”
#16 Comment from kmc528Entry Author
7/1/08 1:51 AM | Permalink

Dr. Katrina Berne: “...The history of psychiatric disorders in the CFS/FMS population is similar to that in the general population. ... Depression does not cause these syndromes and is not present in all cases; however, many patients are given a psychiatric diagnosis when a physiological diagnosis is not apparent. Overlapping symptoms ...and simple ignorance causes confusion between CFS/FMS and depression.

“The rate of depression is not necessarily higher in patients with the most severe symptoms. ... Nonantidepressant medications common in CFS/FMS treatment are not effective in treating [depression].

“Psychological tests are frequently used to ‘rule in’ depression and other psychiatric disorders; however, they cannot distinguish between a test-taker’s medical and psychological disorders. One who endorses numerous physical complaints is likely to be labeled depressed. ‘Results in ill populations may be falsely elevated for psychological disorders’ (Jason, Richman, et al. 1997).

“...When ‘neurological’ items were removed from the test and the tests were rescored, all scores dropped to within the normal range, that is, no elevations remained. This finding provides evidence that neurological dysfunction rather than psychopathology accounts for the typical CFS profile.”

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DON'T ASSUME IT'S DEPRESSION - PART 1