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BMJ Clinical Evidence logoLink to BMJ Clinical Evidence
. 2015 Sep 28;2015:1101.

Chronic fatigue syndrome

Anthony J Cleare 1,#, Steven Reid 2,#, Trudie Chalder 3,#, Matthew Hotopf 4,#, Simon Wessely 5,#
PMCID: PMC4585442  PMID: 26415100

Abstract

Introduction

Chronic fatigue syndrome affects between 0.006% and 3% of the population depending on the criteria of definition used, with women being at higher risk than men.

Methods and outcomes

We conducted a systematic overview, aiming to answer the following clinical question: What are the effects of selected treatments for chronic fatigue syndrome? We searched: Medline, Embase, The Cochrane Library, and other important databases up to November 2013 (BMJ Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review).

Results

At this update, searching of electronic databases retrieved 169 studies. After deduplication and removal of conference abstracts, 86 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 71 studies and the further review of 15 full publications. Of the 15 full articles evaluated, two systematic reviews, one RCT, and one further follow-up report of an RCT were added at this update. We performed a GRADE evaluation for 23 PICO combinations.

Conclusions

In this systematic overview, we categorised the effectiveness of four interventions based on information relating to the effectiveness and safety of antidepressants, cognitive behavioural therapy, corticosteroids, and graded exercise therapy.

Key Points

Chronic fatigue syndrome (CFS) is characterised by severe, disabling fatigue, and other symptoms, including musculoskeletal pain, sleep disturbance, impaired concentration, and headaches.

  • CFS affects between 0.006% and 3% of the population depending on the criteria used, with women being at higher risk than men.

Previous editions of BMJ Clinical Evidence have covered a wide range of interventions, but many have retained an evaluation of 'likely to be ineffective' or 'unknown effectiveness' for several editions with no new published research available. In the current edition, we decided to focus on describing those interventions with the best evidence of effectiveness, in widespread clinical use or with recent trial data.

  • Other treatments previously considered include dietary supplements, evening primrose oil, galantamine, homeopathy, immunotherapy, intramuscular magnesium, oral nicotinamine adenine dinucleotide, and prolonged rest.

Graded exercise therapy has been shown to effectively improve measures of fatigue and physical functioning.

  • Educational interventions with encouragement of graded exercise (treatment sessions, telephone follow-ups, and an educational package explaining symptoms and encouraging home-based exercise) improve symptoms more effectively than written information alone.

Cognitive behavioural therapy (CBT) is effective in treating chronic fatigue syndrome in adults.

  • CBT may also be beneficial when administered by therapists with no specific experience of chronic fatigue syndrome, but who are adequately supervised.

  • In adolescents, CBT can reduce fatigue severity and improve school attendance compared with no treatment.

We don't know how effective antidepressants and corticosteroids are in treating chronic fatigue syndrome.

  • Antidepressants should be considered in people with depressive disorders. Tricyclics, in particular, have potential therapeutic value because of their analgesic properties and the high prevalence of muscle and joint pain in CFS.

Clinical context

General background

Chronic fatigue syndrome (CFS) is characterised by severe, disabling fatigue and other symptoms, including musculoskeletal pain, sleep disturbance, impaired concentration, and headaches. The two most widely used definitions of CFS are from the Centers for Disease Control and Prevention (CDC) and the Oxford criteria. The principal difference between these definitions is the number and severity of symptoms, other than fatigue, that must be present.

Focus of the review

There are a wide range of treatments that have been proposed for CFS, most of which have little or poor evidence base and which have been extensively considered in the previous version of this BMJ Clinical Evidence systematic overview. For this update, the focus was on treatments that had the best evidential support in previous editions, that are in widespread clinical use, and/or have recent trial data.

Comments on evidence

There is good-quality evidence that both cognitive behavioural therapy (CBT) and graded exercise therapy are effective treatments for reducing fatigue and increasing functional capacity in people with CFS. There is less evidence for the drug treatments considered in this overview (antidepressants and corticosteroids); in particular, the evidence for corticosteroid use in people with CFS is limited. Several different instruments were used across studies to measure our outcomes of interest. Some of these involved self-rating by the person with CFS, whereas others report clinician-rated outcomes (in which case the assessor should be blinded). We have not reported school attendance as a main outcome in this overview, however, if available, we have added this data to the relevant Further information on studies section. Most studies were quite short-term; we only found one study with follow-up beyond 12 months.

Search and appraisal summary

The update literature search for this overview was carried out from the date of the last search, March 2010, to November 2013. For more information on the electronic databases searched and criteria applied during assessment of studies for potential relevance to the overview, please see the Methods section. Searching of electronic databases retrieved 169 studies. After deduplication and removal of conference abstracts, 86 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 71 studies and the further review of 15 full publications. Of the 15 full articles evaluated, two systematic reviews, one RCT, and one further follow-up report of an RCT were added at this update.

Additional information

The largest RCT to date found that CBT and graded exercise therapy are more effective than adaptive pacing therapy or specialised medical care. While antidepressants may not be effective for CFS per se, they should be considered for patients with depressive disorders. Tricyclic antidepressants, in particular, should be considered in patients with chronic joint and/or muscle pain given their additional analgesic properties.

About this condition

Definition

Chronic fatigue syndrome (CFS) is characterised by severe, disabling fatigue, and other symptoms, including musculoskeletal pain, sleep disturbance, impaired concentration, and headaches. The two most widely used definitions of CFS, from the US Centers for Disease Control and Prevention (CDC) (the current criteria were issued in 1994, which superseded the 1988 CDC criteria) and from Oxford, UK, were developed as operational criteria for research (see table 1 ). The principal difference between these definitions is the number and severity of symptoms, other than fatigue, that must be present. A third operational definition, the Australian criteria, is similar to the CDC diagnostic criteria and has also been used in treatment trials. The 1994 CDC criteria were reviewed with the aim of improving case ascertainment for research. The exclusion criteria were clarified, and the use of specific instruments for the assessment of symptoms was recommended. Another suggested definition from Canada includes a large number of non-specific features, potentially includes medical disorders that could be excluded under other definitions, and mixes signs, symptoms, and presumed aetiology. The authors of the Canadian guidelines state that they are based on a lesser level of evidence and are intended more as clinical practice guidelines; this definition is not widely used.

Table 1.

Diagnostic criteria for chronic fatigue syndrome (see text).

CDC 1994 Oxford, UK
Clinically evaluated, medically unexplained fatigue of at least 6 months’ duration that is: Severe, disabling fatigue of at least 6 months’ duration that:
– of new onset – affects both physical and mental functioning
– not a result of ongoing exertion – was present for more than 50% of the time
– not substantially alleviated by rest  
– a substantial reduction in previous levels of activity  
   
The occurrence of 4 or more of the following symptoms: Other symptoms, particularly myalgia, sleep and mood disturbance, may be present
– subjective memory impairment  
– tender lymph nodes  
– muscle pain  
– joint pain  
– headache  
– unrefreshing sleep  
– postexertional malaise (greater than 24 hours)  
   
Exclusion criteria
– active, unresolved, or suspected disease likely to cause fatigue – active, unresolved, or suspected disease likely to cause fatigue
– psychotic, melancholic, or bipolar depression (but not uncomplicated major depression) – psychotic, melancholic, or bipolar depression (but not uncomplicated major depression)
– psychotic disorders – psychotic disorders
– dementia – dementia
– anorexia or bulimia nervosa – anorexia or bulimia nervosa
– alcohol or other substance misuse  
– severe obesity  
   
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CDC, US Centers for Disease Control and Prevention.

Incidence/ Prevalence

Community-based and primary-care-based studies have reported the prevalence of CFS to be from 0.007% to 2.8% in the general adult population, and from 0.006% to 3.0% in primary care, depending on the criteria used.

Aetiology/ Risk factors

Despite considerable research effort and several hypotheses, the cause of CFS remains poorly understood. Endocrine and immunological abnormalities have been found in many people, although it is unclear whether these changes are causal or are part of the course of the syndrome. Certain infectious illnesses, such as Epstein-Barr virus, Q fever, and viral meningitis, are associated with a greater risk of developing CFS, but many people have no evidence of viral infection, and there is no evidence of persistent infection. Family and twin studies suggest a significant genetic component to the tendency to develop chronic fatigue. People with prior psychiatric disorders are more likely to report CFS later in life (OR 2.7, 95% CI 1.3 to 5.6). A history of childhood trauma/abuse increases the later risk of developing CFS (OR 3.4, 95% CI 1.4 to 7.9). There is also a likely role for psychological factors such as perfectionism, attributions, perceptions, and coping. While some prospective cohort studies have suggested that a pre-morbid tendency to undertake high levels of exercise is a risk factor, others have not replicated this. Women are at higher risk than men (RR 1.3–1.7, depending on diagnostic criteria used; CIs not reported). Population surveys in the US have found that Caucasians have a lower risk of CFS compared with Latin Americans, African-Americans, and Native Americans. Contrary to popular misconceptions of the illness, there is no link with higher social class and rates may be higher in those with lower socioeconomic status.

Prognosis

Studies have focused on people attending specialist clinics. A systematic review of studies of prognosis (search date 1996) found that children with CFS had better outcomes than adults: 54% to 94% of children showed definite improvement in symptoms (after up to 6 years' follow-up), whereas 20% to 50% of adults showed some improvement in the medium term (12–39 months) and only 6% returned to premorbid levels of functioning. Nevertheless, one prospective follow-up study suggests that, even after long illness periods, around 50% of patients can return to part- or full-time work. Despite the considerable burden of morbidity associated with CFS, we found no evidence of increased mortality. The systematic review found that a longer duration of illness, fatigue severity, comorbid depression and anxiety, and a physical attribution for CFS are factors associated with a poorer prognosis. Another review found a median full recovery rate of 5% (range 0–31%), and the median proportion of patients who improved during follow-up to be 39.5% (range 8–63%). Good outcome was associated with less fatigue severity at baseline, a sense of control over symptoms, and not attributing the illness to a physical cause.

Aims of intervention

To reduce levels of fatigue and associated symptoms, to increase levels of activity, and to improve quality of life.

Outcomes

Severity of symptoms (including fatigue and overall improvement) and their effects on functional status (includes physical function, physical health, and functional impairment); quality of life; and adverse effects. There are several different instruments used to measure these outcomes, including: the medical outcomes survey short-form general health survey (SF-36, a rating scale measuring quality of life, including limitation of physical functioning caused by ill health [score range 0–100, where 0 = limited in all activities and 100 = able to carry out vigorous activities], pain, energy levels, and mood); the Karnofsky scale, a modified questionnaire originally developed for the rating of quality of life in people having chemotherapy for malignancy (where 0 = death and 100 = no evidence of disease); the Beck Depression Inventory, a self-rated checklist for quantifying depressive symptoms (score range 0–63, where a score of 20 or more is usually considered clinically significant depression); the Hospital Anxiety and Depression scale (HADS, which consists of 2 self-rated subscales, each with score range 0–21, where a score of 11 or more is considered clinically significant); the Sickness Impact Profile, a measure of the influence of symptoms on social and physical functioning; the Chalder Fatigue Scale, a rating scale measuring subjective fatigue (score range 0–11, where scores 4 or more = excessive fatigue); the Abbreviated Fatigue Questionnaire, a rating scale of subjective bodily fatigue (score range 4–28, where a lower score indicates a higher degree of fatigue); the Clinical Global Impression scale, a validated clinician-rated measure of overall change compared with baseline at study onset (7 possible scores from 'very much worse' [score 7] to 'very much better' [score 1]); the Checklist Individual Strength fatigue subscale (score range 8 [no fatigue at all] to 56 [maximally fatigued]); the Nottingham Health Profile, with questions in 6 self-report categories: energy, pain perception, sleep patterns, sense of social isolation, emotional reactions, and physical mobility (maximum weighted score 100 [all listed complaints present], and minimum 0 [none of listed complaints present]); the Multidimensional Fatigue Inventory (MFI), with 5 subscales: general fatigue, physical fatigue, mental fatigue, reduced activity, and reduced motivation (each with a score range of 4–20, higher scores indicate higher degree of fatigue); and self-reported severity of symptoms and levels of activity; and the Fatigue Severity Scale, with nine self-rated 7-point subscales assessing behavioural consequences of fatigue.

Methods

Search strategy Clinical Evidence search and appraisal November 2013. Databases used to identify studies for this systematic review include: Medline 1966 to November 2013, Embase 1980 to November 2013, The Cochrane Database of Systematic Reviews 2013, Issue 10 (1966 to date of issue), the Database of Abstracts of Reviews of Effects (DARE), and Health Technology Assessment (HTA) database. Inclusion criteria Study design criteria for inclusion in this review were systematic reviews and RCTs published in English. RCTs had to be at least single blinded for drug interventions, but non-blinded studies were included for non-drug interventions. For drug interventions we excluded all studies described as 'open', 'open label', or not blinded. RCTs had to contain 20 or more individuals, of whom 80% or more were followed up. There was no minimum length of follow-up required to include studies. BMJ Clinical Evidence does not necessarily report every study found (e.g., every systematic review). Rather, we report the most recent, relevant and comprehensive studies identified through an agreed process involving our evidence team, editorial team, and expert contributors. Evidence evaluation A systematic literature search was conducted by our evidence team, who then assessed titles and abstracts, and finally selected articles for full text appraisal against inclusion and exclusion criteria agreed a priori with our expert contributors. In consultation with the expert contributors, studies were selected for inclusion and all data relevant to this overview extracted into the benefits and harms section of the overview. In addition, information that did not meet our predefined criteria for inclusion in the benefits and harms section, may have been reported in the 'Further information on studies' or 'Comment' section. Adverse effects All serious adverse effects, or those adverse effects reported as statistically significant, were included in the harms section of the overview. Pre-specified adverse effects identified as being clinically important were also reported, even if the results were not statistically significant. Although BMJ Clinical Evidence presents data on selected adverse effects reported in included studies, it is not meant to be, and cannot be, a comprehensive list of all adverse effects, contraindications, or interactions of included drugs or interventions. A reliable national or local drug database must be consulted for this information. Comment and Clinical guide sections In the Comment section of each intervention, our expert contributors may have provided additional comment and analysis of the evidence, which may include additional studies (over and above those identified via our systematic search) by way of background data or supporting information. As BMJ Clinical Evidence does not systematically search for studies reported in the Comment section, we cannot guarantee the completeness of the studies listed there or the robustness of methods. Our expert contributors add clinical context and interpretation to the Clinical guide sections where appropriate. Structural changes this update At this update, we have removed the following interventions: immunotherapy, dietary supplements, evening primrose oil, magnesium (intramuscular), oral nicotinamide adenine dinucleotide (NADH), homeopathy, prolonged rest, and galantamine. Data and quality To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). BMJ Clinical Evidence does not report all methodological details of included studies. Rather, it reports by exception any methodological issue or more general issue which may affect the weight a reader may put on an individual study, or the generalisability of the result. These issues may be reflected in the overall GRADE analysis. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).

Table.

GRADE Evaluation of interventions for Chronic fatigue syndrome.

Important outcomes Fatigue, Functional status, Overall improvement, Quality of life
Studies (Participants) Outcome Comparison Type of evidence Quality Consistency Directness Effect size GRADE Comment
What are the effects of selected treatments for chronic fatigue syndrome?
8 (1279) Fatigue CBT versus control interventions 4 –2 0 0 0 Low Quality points deducted for flaws in analysis and incomplete reporting of results
4 (561) Overall improvement CBT versus control interventions 4 –1 –1 0 0 Low Quality point deducted for incomplete reporting of results; consistency point deducted for conflicting results
8 (991) Functional status CBT versus control interventions 4 –2 0 0 0 Low Quality points deducted for incomplete reporting of results and for inclusion of multiple comparisons with no statistical adjustment
5 (680) Quality of life CBT versus control interventions 4 –1 –1 0 0 Low Quality point deducted for incomplete reporting of results. Consistency point deducted for conflicting results
5 (599) Fatigue Graded exercise therapy versus control interventions 4 0 –1 0 0 Moderate Consistency point deducted for conflicting results
4 (496) Overall improvement Graded exercise therapy versus control interventions 4 –1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
3 (408) Functional status Graded exercise therapy versus control interventions 4 –1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
3 (403) Quality of life Graded exercise therapy versus control interventions 4 –1 0 –1 0 Low Quality point deducted for incomplete reporting of results; directness point deducted for control including active relaxation
1 (148) Fatigue Graded exercise therapy plus education versus written information alone 4 –1 0 0 0 Moderate Quality point deducted for sparse data
1 (148) Functional status Graded exercise therapy plus education versus written information alone 4 –1 0 0 0 Moderate Quality point deducted for sparse data
2 (243) Fatigue Fluoxetine versus placebo 4 –1 0 –1 0 Low Quality point deducted for incomplete reporting of results; directness point deducted for combined analysis
2 (243) Quality of life Fluoxetine versus placebo 4 –1 0 –2 0 Very low Quality point deducted for incomplete reporting of results; directness points deducted for uncertainty of clinical importance of result in 1 RCT and for combined analysis (includes an active intervention; graded aerobic exercise) in 1 RCT
1 (30) Overall improvement Phenelzine versus placebo 4 –3 0 0 0 Very low Quality points deducted for sparse data, incomplete reporting of results, and unclear statistical analysis
1 (90) Overall improvement Moclobemide versus placebo 4 –1 0 0 0 Moderate Quality point deducted for sparse data
1 (40) Overall improvement Sertraline versus clomipramine 4 –2 0 0 0 Low Quality points deducted for sparse data and incomplete reporting of results
1 (25) Fatigue Fludrocortisone versus placebo 4 –2 0 0 0 Low Quality points deducted for sparse data and possible crossover effect
1 (100) Overall improvement Fludrocortisone versus placebo 4 –2 0 0 0 Low Quality points deducted for sparse data and incomplete reporting of results
1 (25) Functional status Fludrocortisone versus placebo 4 –2 0 0 0 Low Quality points deducted for sparse data and possible crossover effects
1 (32) Fatigue Hydrocortisone versus placebo 4 –2 0 –1 0 Very low Quality points deducted for sparse data and incomplete reporting of results; directness point deducted for no statistical analysis between groups
1 (65) Overall improvement Hydrocortisone versus placebo 4 –2 0 0 0 Low Quality points deducted for sparse data and incomplete reporting of results
1 (65) Functional status Hydrocortisone versus placebo 4 –1 0 0 0 Moderate Quality point deducted for sparse data
1 (65) Quality of life Hydrocortisone versus placebo 4 –1 0 0 0 Moderate Quality point deducted for sparse data
1 (100) Fatigue Hydrocortisone plus fludrocortisone versus placebo 4 –3 0 0 0 Very low Quality points deducted for sparse data, methodological flaws, and incomplete reporting of results
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We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.

Glossary

Beck Depression Inventory

Standardised scale to assess depression. This instrument consists of 21 items to assess the intensity of depression. Each item is a list of 4 statements (rated 0, 1, 2, or 3), arranged in increasing severity, about a particular symptom of depression. The range of scores possible are 0 = least severe depression to 63 = most severe depression. It is recommended for people aged 13 to 80 years. Scores of more than 12 or 13 indicate the presence of depression.

Chronic fatigue syndrome, Australian definition

(1) Chronic persisting or relapsing fatigue of a generalised nature, exacerbated by minor exercise, causing significant disruption of usual daily activities, and present for more than 6 months; (2) Neuropsychiatric dysfunction including impairment of concentration evidenced by difficulty in completing mental tasks that were easily accomplished before the onset of the syndrome; new onset of short-term memory impairment; (3) No alternative diagnosis reached by history, physical examination, or investigations over a 6-month period.

Clinical Global Impression Scale

A one-item, observer-rated scale for measuring the severity of a condition. It has been investigated for validity and reliability. The scale is scored from 0 (not ill at all) to 7 (severely ill).

Karnofsky score

Is a measure of performance status based on physical ability (scale 0–100). 100: normal, no complaints or evidence of disease; 90: able to perform normal activity, minor signs and symptoms of disease; 80: able to perform normal activity with effort, some signs and symptoms of disease; 70: cares for self, unable to perform normal activity or to do active work; 60: requires occasional assistance but is able to care for most of own needs; 50: requires considerable assistance and frequent medical care; 40: requires special care and assistance, disabled; 30: hospital admission indicated, although death not imminent, severely disabled; 20: hospital admission necessary, active supportive treatment required, very sick; 10: fatal processes progressing rapidly, moribund; 0: death.

Low-quality evidence

Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Moderate-quality evidence

Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

Very low-quality evidence

Any estimate of effect is very uncertain.

Disclaimer

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.

Contributor Information

Anthony J. Cleare, King’s College London, Institute of Psychiatry, Psychology and Neuroscience, Centre for Affective Disorders, Department of Psychological Medicine, London, UK.

Steven Reid, Imperial College, St Mary's Hospital, London, UK.

Trudie Chalder, King’s College London, Institute of Psychiatry, Psychology and Neuroscience, Department of Psychological Medicine, Weston Education Centre, London, UK.

Matthew Hotopf, King’s College London, Institute of Psychiatry, Psychology and Neuroscience, Department of Psychological Medicine, Weston Education Centre, London, UK.

Simon Wessely, King’s College London, Institute of Psychiatry, Psychology and Neuroscience, Department of Psychological Medicine, Weston Education Centre, London, UK.

References

  • 1.Fukuda K, Straus S, 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;121:953–959. [DOI] [PubMed] [Google Scholar]
  • 2.Sharpe M, Archard LC, Banatvala JE, et al. A report – chronic fatigue syndrome: guidelines for research. J R Soc Med 1991;84:118–121. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Lloyd AR, Hickie I, Boughton CR, et al. Prevalence of chronic fatigue syndrome in an Australian population. Med J Aust 1990;153:522–528. [DOI] [PubMed] [Google Scholar]
  • 4.Reeves WC, Lloyd A, Vernon S D, et al. Identification of ambiguities in the 1994 chronic fatigue syndrome research case definition and recommendations for resolution. BMC Health Services Research 2003;3:25. Available online at: http://www.biomedcentral.com/1472-6963/3/25 (last accessed 17 July 2015). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Carruthers BM, Jain AK, De Meirleir KL, et al. Myalgic encephalomyelitis/chronic fatigue syndrome: clinical working case definition, diagnostic and treatment protocols. J Chronic Fatigue Syndrome 2003;11:7–116. [Google Scholar]
  • 6.De Meirlier K, McGregor N. Chronic fatigue syndrome guidelines. J Chronic Fatigue Syndrome 2003;11:1–6. [Google Scholar]
  • 7.Afari N, Buchwald D. Chronic fatigue syndrome: a review. Am J Psychiatry 2003;160:221–236. [DOI] [PubMed] [Google Scholar]
  • 8.Papadopoulos AS, Cleare AJ. Hypothalamo-pituitary-adrenal axis dysfunction in chronic fatigue syndrome. Nat Rev Endocrinol 2011;8:22–32. [DOI] [PubMed] [Google Scholar]
  • 9.White P, Thomas J, Kangro H, et al. Predictions and associations of fatigue syndromes and mood disorders that occur after infectious mononucleosis. Lancet 2001;358:1946–1954. [DOI] [PubMed] [Google Scholar]
  • 10.Harvey SB, Wadsworth M, Wessely S, et al. The relationship between prior psychiatric disorder and chronic fatigue: evidence from a national birth cohort study. Psychol Med 2008;38:933–940. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Heim C, Wagner D, Maloney E, et al. Early adverse experience and risk for chronic fatigue syndrome: results from a population-based study. Arch Gen Psychiatry 2006;63:1258–1266. [DOI] [PubMed] [Google Scholar]
  • 12.Harvey S, Wadsworth M, Wessely S, et al. Etiology of chronic fatigue syndrome: testing popular hypotheses using a national birth cohort study. Psychosom Med 2008;70:488–495. [DOI] [PubMed] [Google Scholar]
  • 13.Goodwin L, White PD, Hotopf M, et al. Psychopathology and physical activity as predictors of chronic fatigue syndrome in the 1958 british birth cohort: a replication study of the 1946 and 1970 birth cohorts. Ann Epidemiol 2011;21:343–350. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Steele L, Dobbins JG, Fukuda K, et al. The epidemiology of chronic fatigue in San Francisco. Am J Med 1998;105(suppl 3A):83S–90S. [DOI] [PubMed] [Google Scholar]
  • 15.Jason LA, Richman JA, Rademaker AW, et al. A community-based study of chronic fatigue syndrome. Arch Intern Med 1999;159:2129–2137. [DOI] [PubMed] [Google Scholar]
  • 16.Wessely S. The epidemiology of chronic fatigue syndrome. Epidemiol Rev 1995;17:139–151. [DOI] [PubMed] [Google Scholar]
  • 17.Wessely S, Chalder T, Hirsch S, et al. The prevalence and morbidity of chronic fatigue and chronic fatigue syndrome: a prospective primary care study. Am J Public Health 1997;87:1449–1455. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Joyce J, Hotopf M, Wessely S. The prognosis of chronic fatigue and chronic fatigue syndrome: a systematic review. QJM 1997;90:223–233. [DOI] [PubMed] [Google Scholar]
  • 19.Nyland M, Naess H, Birkeland JS, et al. Longitudinal follow-up of employment status in patients with chronic fatigue syndrome after mononucleosis. BMJ Open 2014;4:e005798. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Cairns R, Hotopf M. A systematic review describing the prognosis of chronic fatigue syndrome. Occup Med (Lond) 2005;55:20–31. [DOI] [PubMed] [Google Scholar]
  • 21.Stewart AL, Hays RD, Ware JE Jr. The MOS short-form general health survey. Reliability and validity in a patient population. Med Care 1988;26:724–735. [DOI] [PubMed] [Google Scholar]
  • 22.Karnofsky DA, Burchenal JH, MacLeod CM. The clinical evaluation of chemotherapeutic agents in cancer. New York, NY: Columbia University Press, 1949:191–206. [Google Scholar]
  • 23.Beck AT, Ward CH, Mendelson M, et al. An inventory for measuring depression. Arch Gen Psychiatry 1961;4:561–571. [DOI] [PubMed] [Google Scholar]
  • 24.Zigmond AS, Snaith RP. The Hospital Anxiety and Depression Scale (HAD). Acta Psychiatr Scand 1983;67:361–370. [DOI] [PubMed] [Google Scholar]
  • 25.Bergner M, Bobbit RA, Carter WB, et al. The Sickness Impact Profile: development and final revision of a health status measure. Med Care 1981;19:787–805. [DOI] [PubMed] [Google Scholar]
  • 26.Chalder T, Berelowitz C, Pawlikowska T, et al. Development of a fatigue scale. J Psychosom Res 1993;37:147–153. [DOI] [PubMed] [Google Scholar]
  • 27.Alberts M, Smets EM, Vercoulen JH, et al. Abbreviated fatigue questionnaire: a practical tool in the classification of fatigue. Ned Tijdschr Geneeskd 1997;141:1526–1530. [In Dutch] [PubMed] [Google Scholar]
  • 28.Guy W. ECDEU assessment manual for psychopharmacology. Rockville, MD: National Institute of Mental Health, 1976:218–222. [Google Scholar]
  • 29.Vercoulen JH, Swanink CM, Fennis JF, et al. Dimensional assessment of chronic fatigue syndrome. J Psychosom Res 1994;38:383–392. [DOI] [PubMed] [Google Scholar]
  • 30.Hunt SM, McEwen J, McKenna SP. Measuring health status: a new tool for clinicians and epidemiologists. J R Coll Gen Prac 1985,35:185–188. [PMC free article] [PubMed] [Google Scholar]
  • 31.Smets EMA, Garssen B, Bonke B, et al. The Multidimensional Fatigue Inventory (MFI) psychometric qualities of an instrument to assess fatigue. J Psychosom Res 1995;39:315–325. [DOI] [PubMed] [Google Scholar]
  • 32.Krupp LB, LaRocca NG, Muir-Nash J, et al. The fatigue severity scale. Application to patients with multiple sclerosis and systemic lupus erythematosus. Arch Neurol 1989;46:1121–1123. [DOI] [PubMed] [Google Scholar]
  • 33.Price J, Mitchell E, Tidy E, et al. Cognitive behaviour therapy for chronic fatigue syndrome in adults. In: The Cochrane Library: Issue 10, 2013. Chichester, UK: John Wiley & Sons, Ltd. Search date 2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Knight SJ, Scheinberg A, Harvey AR. Interventions in pediatric chronic fatigue syndrome/myalgic encephalomyelitis: a systematic review. J Adolesc Health 2013;53:154–165. [DOI] [PubMed] [Google Scholar]
  • 35.Van Cauwenbergh D, De Kooning M, Ickmans K, et al. How to exercise people with chronic fatigue syndrome: evidence-based practice guidelines. Eur J Clin Invest 2012;42:1136–1144. [DOI] [PubMed] [Google Scholar]
  • 36.Lloyd A, Hickie I, Brockman A, et al. Immunologic and psychologic therapy for patients with chronic fatigue syndrome: a double-blind, placebo-controlled trial. Am J Med 1993;94:197–203. [DOI] [PubMed] [Google Scholar]
  • 37.Sharpe M, Hawton K, Simkin S, et al. Cognitive behaviour therapy for the chronic fatigue syndrome: a randomized controlled trial. BMJ 1996;312:22–26. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Deale A, Chalder T, Marks I, et al. Cognitive behaviour therapy for chronic fatigue syndrome: a randomized controlled trial. Am J Psychiatry 1997;154:408–414. [DOI] [PubMed] [Google Scholar]
  • 39.Prins JB, Bleijenberg G, Bazelmans E, et al. Cognitive behaviour therapy for chronic fatigue syndrome: a multicentre randomised controlled trial. Lancet 2001;357:841–847. [DOI] [PubMed] [Google Scholar]
  • 40.O'Dowd H, Gladwell P, Rogers CA, et al. Cognitive behavioural therapy in chronic fatigue syndrome: A randomised controlled trial of an outpatient group programme. Health Technol Assess 2006;10:iii–iv, ix–x, 1–121. [DOI] [PubMed] [Google Scholar]
  • 41.Jason LAT. Non-pharmacologic interventions for CFS: a randomized trial. J Clin Psychol Med Settings 2007;14:275–296. [Google Scholar]
  • 42.Stulemeijer M, de Jong LWAM, Fiselier TJW, et al. Cognitive behaviour therapy for adolescents with chronic fatigue syndrome: randomised controlled trial. BMJ 2005;330:14. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Chalder T, Deary V, Husain K, et al. Family-focused cognitive behaviour therapy versus psycho-education for chronic fatigue syndrome in 11- to 18-year-olds: a randomized controlled treatment trial. Psychol Med 2010;40:1269–1279. [DOI] [PubMed] [Google Scholar]
  • 44.Nijhof SL, Bleijenberg G, Uiterwaal CS, et al. Effectiveness of internet-based cognitive behavioural treatment for adolescents with chronic fatigue syndrome (FITNET): a randomised controlled trial. Lancet 2012;379:1412–1418. [DOI] [PubMed] [Google Scholar]
  • 45.Nijhof SL, Priesterback LP, Uiterwaal CSPM, et al. Internet-based therapy for adolescents with chronic fatigue syndrome: long-term follow-up. Pediatrics 2013;131:e1788–e1795. [DOI] [PubMed] [Google Scholar]
  • 46.White PD, Goldsmith KA, Johnson AL, et al. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet 2011;377:823–836. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Deale A, Husain K, Chalder T, et al. Long-term outcome of cognitive behaviour therapy versus relaxation therapy for chronic fatigue syndrome: a 5-year follow-up study. Am J Psychiatry 2001;158:2038–2042. [DOI] [PubMed] [Google Scholar]
  • 48.Knoop H, Stulemeijer M, de Jong LW, et al. Efficacy of cognitive behavioral therapy for adolescents with chronic fatigue syndrome: long-term follow of a randomized, controlled trial. Pediatrics 2008;121:e619–e625. [DOI] [PubMed] [Google Scholar]
  • 49.Ridsdale L, Godfrey E, Chalder T, et al. Chronic fatigue in general practice: is counselling as good as cognitive behaviour therapy? A UK randomised trial. Br J Gen Pract 2001;51:19–24. [PMC free article] [PubMed] [Google Scholar]
  • 50.Knoop H, van der Meer JW, Bleijenberg G. Guided self-instructions for people with chronic fatigue syndrome: randomised controlled trial. Br J Psychiatry 2008;193:340–341. [DOI] [PubMed] [Google Scholar]
  • 51.Larun L, McGuire H, Edmonds M, et al. Exercise therapy for chronic fatigue syndrome. In: The Cochrane Library: Issue 10, 2013. Chichester, UK: John Wiley & Sons, Ltd. Search date 2004. 25674924 [Google Scholar]
  • 52.Chambers D, Bagnall AM, Hempel S, et al. Interventions for the treatment, management and rehabilitation of patients with chronic fatigue syndrome/myalgic encephalomyelitis: An updated systematic review. J R Soc Med 2006;99:506–520. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Fulcher KY, White PD. Randomised controlled trial of graded exercise in patients with the chronic fatigue syndrome. BMJ 1997;314:1647–1652. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54.Wearden AJ, Morriss RK, Mullis R, et al. Randomised, double-blind, placebo controlled treatment trial of fluoxetine and a graded exercise programme for chronic fatigue syndrome. Br J Psychiatry 1998;172:485–490. [DOI] [PubMed] [Google Scholar]
  • 55.Wallman KE, Morton AR, Goodman C, et al. Randomised controlled trial of graded exercise in chronic fatigue syndrome. Med J Aust 2004;180:444–448. [DOI] [PubMed] [Google Scholar]
  • 56.Moss-Morris R, Sharon C, Tobin R, et al. A randomized controlled graded exercise trial for chronic fatigue syndrome: outcomes and mechanisms of change. J Health Psychol 2005;10:245–259. [DOI] [PubMed] [Google Scholar]
  • 57.Gordon BA, Knapman LM, Lubitz L. Graduated exercise training and progressive resistance training in adolescents with chronic fatigue syndrome: a randomized controlled pilot study. Clin Rehabil 2010;24:1072–1079. [DOI] [PubMed] [Google Scholar]
  • 58.Powell P, Bentall RP, Nye FJ, et al. Randomised controlled trial of patient education to encourage graded exercise in chronic fatigue syndrome. BMJ 2001;322:387–390. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59.Vercoulen J, Swanink C, Zitman F. Randomised, double-blind, placebo-controlled study of fluoxetine in chronic fatigue syndrome. Lancet 1996;347:858–861. [DOI] [PubMed] [Google Scholar]
  • 60.Natelson BH, Cheu J, Pareja J, et al. Randomised, double blind, controlled placebo-phase in trial of low dose phenelzine in the chronic fatigue syndrome. Psychopharmacology 1996;124:226–230. [DOI] [PubMed] [Google Scholar]
  • 61.Hickie IB, Wilson AJ, Murray Wright J, et al. A randomized, double-blind, placebo-controlled trial of moclobemide in patients with chronic fatigue syndrome. J Clin Psychiatry 2000;61:643–648. [DOI] [PubMed] [Google Scholar]
  • 62.Behan PO, Hannifah H. 5-HT reuptake inhibitors in CFS. J Immunol Immunopharmacol 1995;15:66–69. [Google Scholar]
  • 63.Food and Drug Administration. MedWatch. http://www.fda.gov/medwatch/ (last accessed 17 July 2015). [Google Scholar]
  • 64.Rowe PC, Calkins H, DeBusk K, et al. Fludrocortisone acetate to treat neurally mediated hypotension in chronic fatigue syndrome: a randomized controlled trial. JAMA 2001;285:52–59. [DOI] [PubMed] [Google Scholar]
  • 65.Peterson PK, Pheley A, Schroeppel J, et al. A preliminary placebo-controlled crossover trial of fludrocortisone for chronic fatigue syndrome. Arch Intern Med 1998;158:908–914. [DOI] [PubMed] [Google Scholar]
  • 66.McKenzie R, O'Fallon A, Dale J, et al. Low-dose hydrocortisone for treatment of chronic fatigue syndrome: a randomized controlled trial. JAMA 1998;280:1061–1066. [DOI] [PubMed] [Google Scholar]
  • 67.Cleare AJ, Heap E, Malhi G, et al. Low-dose hydrocortisone in chronic fatigue syndrome: a randomised crossover trial. Lancet 1999;353:455–458. [DOI] [PubMed] [Google Scholar]
  • 68.Blockmans D, Persoons P, Van Houdenhove B, et al. Combination therapy with hydrocortisone and fludrocortisone does not improve symptoms in chronic fatigue syndrome: a randomized, placebo-controlled, double-blind, crossover study. Am J Med 2003;114:736–741. [DOI] [PubMed] [Google Scholar]
  • 69.Bou-Holaigah I, Rowe P, Kan J, et al. The relationship between neurally mediated hypotension and the chronic fatigue syndrome. JAMA 1995;274:961–967. [PubMed] [Google Scholar]
  • 70.Demitrack MA, Dale JK, Straus SE, et al. Evidence for impaired activation of the hypothalamic-pituitary-adrenal axis in patients with chronic fatigue syndrome. J Clin Endocrinol Metab 1991;73:1224–1234. [DOI] [PubMed] [Google Scholar]
BMJ Clin Evid. 2015 Sep 28;2015:1101.

Cognitive behavioural therapy

Summary

Cognitive behavioural therapy (CBT) is effective in treating chronic fatigue syndrome in adults.

CBT may also be beneficial when administered by therapists with no specific experience of chronic fatigue syndrome, but who are adequately supervised.

In children and adolescents, CBT can reduce fatigue severity and improve school attendance compared with no treatment.

Benefits and harms

CBT versus control interventions:

We found three systematic reviews (search dates 2008; 1987 to 2012; and search date not specified). The first systematic review included 15 RCTs in adults. The review included results from unpublished RCTs and studies that did not meet BMJ Clinical Evidence quality criteria in its meta-analyses, and so we have reported the results of each of the six published RCTs identified by the review that did meet BMJ Clinical Evidence inclusion criteria individually. We found one additional RCT in children and adolescents that reported on the effects of CBT on school attendance; see Further information on studies for full details. The second systematic review, a narrative review of interventions in children and adolescents, found one additional RCT and one subsequent RCT. The subsequent RCT used an internet-based CBT intervention in adolescents and also reported on school attendance (see Further information on studies). Long-term follow-up of this study was reported separately. The third systematic review was also a narrative review and all the relevant RCTs were already reported individually here. We also found one additional RCT.

Fatigue

CBT compared with control interventions CBT may be more effective at improving fatigue than control interventions (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Fatigue severity

RCT
3-armed trial 		278 adults with CFS (CDC criteria)
In review 		Improvement in fatigue severity (Checklist Individual Strength [CIS-fatigue]) 8 months
27/83 (33%) with CBT
10/80 (13%) with guided support
RR 2.6 for CBT v guided support
95% CI 1.3 to 5.0
RCT had high withdrawal rate; see Further information on studies for full details 		Moderate effect size CBT

RCT
3-armed trial 		278 adults with CFS (CDC criteria)
In review 		Improvement in fatigue severity (self-reported) 8 months
42/74 (57%) with CBT
12/71 (17%) with guided support
RR 3.4 for CBT v guided support
95% 1.9 to 5.8
RCT had high withdrawal rate; see Further information on studies for full details 		Moderate effect size CBT

RCT
3-armed trial 		278 adults with CFS (CDC criteria)
In review 		Improvement in fatigue severity (CIS-fatigue) 8 months
27/83 (33%) with CBT
8/62 (13%) with no intervention
RR 2.5 for CBT v no intervention
95% CI 1.2 to 5.2
RCT had high withdrawal rate; see Further information on studies for full details 		Moderate effect size CBT

RCT
3-armed trial 		278 adults with CFS (CDC criteria)
In review 		Improvement in fatigue severity (self-reported) 8 months
42/74 (57%) with CBT
23/78 (30%) with no intervention
RR 1.9 for CBT v no intervention
95% CI 1.3 to 2.9
RCT had high withdrawal rate; see Further information on studies for full details 		Small effect size CBT

RCT
3-armed trial 		153 adults with CFS (CDC criteria)
In review 		Change in fatigue severity (Chalder Fatigue Score)
with group CBT
with usual care
Absolute results not reported
Difference –2.61 for group CBT v usual care
95% CI –4.92 to –0.30
P = 0.03 		Effect size not calculated CBT

RCT
3-armed trial 		153 adults with CFS, CDC criteria
In review 		Change in fatigue severity (Chalder Fatigue Score)
with group CBT
with education and support
Absolute results not reported
Difference –3.16 for group CBT v education and support
95% CI –5.59 to –0.74
P = 0.011 		Effect size not calculated CBT

RCT
4-armed trial 		90 adults with a mean age of 39.6 years who fulfilled diagnostic criteria for CFS (not further defined)
In review 		Mean fatigue score (profile of mood states subscale) 7 months (3 months after completion of treatment)
16.8 with CBT plus placebo
17.3 with usual care plus placebo
Significance not assessed

RCT
4-armed trial 		114 adults with CFS (as defined by CDC criteria); baseline fatigue severity scale (FSS) scores 6.05 in people having CBT, 5.82 in people having relaxation therapy
In review 		Mean score on FSS 12 months
5.37 with CBT
5.62 with relaxation therapy
Significance not assessed

RCT		 69 children and adolescents aged 10 to 17 years with CFS (CDC criteria) Change in fatigue severity score (Checklist Individual Strength [CIS-fatigue]) 5 months
–22.3 with CBT
–7.6 with no intervention
Absolute difference 14.5
95% CI 7.4 to 21.6 		Effect size not calculated CBT

RCT		 63 adolescents aged 11–18 years with CFS (CDC or Oxford criteria)
In review 		Mean fatigue score (Chalder Fatigue Scale) 6 months post treatment
13.3 with family-focused CBT
14.2 with psycho-education
Treatment effect +0.24
95% CI –3.61 to +4.10
P = 0.9 		Not significant

RCT		 131 adolescents aged 12–18 years with CFS (CDC criteria)
In review 		Fatigue severity (CIS-20) 6 months
24.0 with internet CBT
42.3 with usual care
Mean difference –18.3
95% CI –22.9 to –13.7
P <0.0001 		Effect size not calculated CBT

RCT
4-armed trial 		641 adults with CFS (Oxford criteria) Chalder Fatigue Questionnaire 24 weeks
21.5 with CBT
24.0 with specialist medical care
Significance not assessed

RCT
4-armed trial 		641 adults with CFS (Oxford criteria) Chalder Fatigue Questionnaire 52 weeks
20.3 with CBT
23.8 with specialist medical care
Mean difference –3.4
95% CI –5.0 to –1.8
P = 0.0001 		Effect size not calculated CBT
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No data from the following reference on this outcome.

Overall improvement

CBT compared with control interventions CBT seems more effective than control interventions at increasing recovery at 6 months to 5 years (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Recovery

RCT		 53 adults with CFS (CDC criteria)
Further report of reference 		Complete recovery 5 years
17/31 (55%) with CBT
7/22 (32%) with relaxation therapy
RR 1.7
95% CI 0.9 to 3.4 		Not significant

RCT		 53 adults with CFS (CDC criteria)
Further report of reference 		Proportion of people rating themselves as 'much improved' or 'very much improved' 5 years
17/25 (68%) with CBT
10/28 (36%) with relaxation therapy
RR 1.9
95% CI 1.1 to 3.4 		Small effect size CBT

RCT		 63 adolescents aged 11–18 years with CFS (CDC or Oxford criteria)
In review 		Child-reported Global Improvement 6 months post treatment
24/27 (89%) with family-focused CBT
26/29 (90%) with psycho-education
OR 1.08
95% CI 0.20 to 5.89
P = 0.93 		Not significant

RCT		 131 adolescents aged 12–18 years with CFS (CDC criteria)
In review 		Proportion of people rating themselves as 'completely recovered' or 'much better' 6 months
52/67 (78%) with internet CBT
17/64 (27%) with usual care
RR 2.9
95% CI 1.9 to 4.5
P <0.0001 		Effect size not calculated CBT

RCT		 131 adolescents aged 12–18 years with CFS (CDC criteria) Complete recovery 2.7 years
64% with internet CBT
53% with usual care
Absolute numbers not reported
P = 0.251 		Not significant

RCT
4-armed trial 		641 adults with CFS (Oxford criteria) Proportion of people rating themselves as 'much better' or 'very much better' 52 weeks
61/161 (41%) with CBT
38/160 (25%) with specialist medical care
OR 2.2
95% CI 1.2 to 3.9
P = 0.011 		Moderate effect size CBT
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No data from the following reference on this outcome.

Functional status

CBT compared with control interventions CBT may be more effective than control interventions at improving physical functioning (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Physical functioning

RCT		 60 adults with CFS (CDC criteria) attending a secondary-care centre
In review 		Predefined increase in functional score (assessed by SF-36 questionnaire) 13 weeks
19/30 (63%) with CBT
5/30 (17%) with relaxation
RR 3.70
95% CI 2.37 to 6.31
NNT 3
95% CI 1 to 7 		Moderate effect size CBT

RCT
3-armed trial 		153 adults with CFS (CDC criteria)
In review 		Change in functional score (assessed by SF-36 questionnaire)
with group CBT
with usual care
Absolute results not reported
Absolute difference –1.63 for group CBT v usual care
95% CI –4.05 to +0.78 		Not significant

RCT
3-armed trial 		153 people with CFS (CDC criteria)
In review 		Change in functional score (assessed by SF-36 questionnaire)
with group CBT
with education and support
Absolute results not reported
Absolute difference –1.23 for group CBT v education and support
95% CI –3.52 to +1.05 		Not significant

RCT
4-armed trial 		90 adults with a mean age of 39.6 years who fulfilled diagnostic criteria for CFS (not further defined)
In review 		Mean number of non-sedentary hours 7 months (3 months after completion of treatment)
5.2 with CBT plus placebo
5.2 with usual care plus placebo
Significance not assessed

RCT
4-armed trial 		90 adults with a mean age of 39.6 years who fulfilled diagnostic criteria for CFS (not further defined)
In review 		Mean score for ability to participate in daily activities (Karnofsky performance score) 7 months (3 months after completion of treatment)
72.1 with CBT plus placebo
73.4 with usual care plus placebo
Significance not assessed

RCT
4-armed trial 		114 adults with CFS (defined by CDC criteria); baseline physical functioning scores 46.36 in people receiving CBT, 53.77 in people receiving relaxation
In review 		Mean score on SF-36 for physical functioning 12 months
58.64 with CBT
61.20 with relaxation therapy
Significance not assessed

RCT		 69 children and adolescents aged 10 to 17 years with CFS (CDC criteria) Change in functional score (assessed by short-form [SF]-36 questionnaire) 5 months
27.3 with CBT
10.0 with no treatment
Absolute difference 17.3
95% CI 6.2 to 28.4 		Effect size not calculated CBT

RCT		 63 adolescents aged 11–18 years with CFS (CDC or Oxford criteria)
In review 		Mean score on SF-36 for physical functioning 6 months post treatment
80.4 with family-focused CBT
64.0 with psycho-education
Adjusted mean difference +13.42
95% CI –2.14 to +29.00
P = 0.09
Mean difference adjusted for associated baseline values 		Not significant

RCT		 131 adolescents aged 12–18 years with CFS (CDC criteria)
In review 		Physical functioning (assessed by CHQ-CF87) 6 months
88.5 with internet CBT
70.1 with usual care
Mean difference 18.4
95% CI 12.9 to 23.9
P <0.0001 		Effect size not calculated CBT

RCT
4-armed trial 		641 adults with CFS (Oxford criteria) Mean score on SF-36 for physical functioning 52 weeks
58.2 with CBT
50.8 with specialist medical care
Mean difference 7.1
95% CI 2.0 to 12.1
P = 0.0068 		Effect size not calculated CBT
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No data from the following reference on this outcome.

Quality of life

CBT compared with control interventions CBT may be more effective than usual care at improving measures of mental health; however, we don't know about overall quality of life, as results are inconsistent (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Quality of life

RCT		 60 adults with CFS (Oxford criteria)
In review 		Proportion of people with a final score on Karnofsky quality-of-life scale of >80 12 months
22/30 (73%) with CBT
8/30 (27%) with usual care
RR 2.75
95% CI 1.54 to 5.32
NNT 3
95% CI 2 to 5 		Moderate effect size CBT

RCT
3-armed trial 		153 adults with CFS (CDC criteria)
In review 		Change in quality-of-life score (assessed by short-form [SF]-36 questionnaire) 12 months
with group CBT
with usual care
Absolute results not reported
Absolute difference 4.36 for group CBT v usual care
95% CI 0.72 to 7.97
P = 0.019 		Effect size not calculated CBT

RCT
3-armed trial 		153 adults with CFS (CDC criteria)
In review 		Change in quality-of-life score (assessed by SF-36 questionnaire) 12 months
with group CBT
with education and support
Absolute results not reported
Absolute difference +3.16 for group CBT v education and support
95% CI –0.05 to +6.38
P = 0.5 		Not significant

RCT
4-armed trial 		90 adults with a mean age of 39.6 years who fulfilled diagnostic criteria for CFS (not further defined)
In review 		Mean visual analogue score 7 months (3 months after completion of treatment)
469 with CBT plus placebo
477 with usual care plus placebo
Significance not assessed

RCT		 63 adolescents aged 11–18 years with CFS (CDC or Oxford criteria)
In review 		Mean work and social adjustment score 6 months post treatment
2.5 with family-focused CBT
3.3 with psycho-education
Adjusted mean difference –0.48
95% CI –1.55 to +0.59
P = 0.37
Mean difference adjusted for associated baseline values 		Not significant
Mental health

RCT
3-armed trial 		153 adults with CFS (CDC criteria)
In review 		Change in mental health score (assessed by SF-36 questionnaire)
with group CBT
with usual care
Absolute results not reported
Absolute difference 4.35 for group CBT v usual care
95% CI 0.72 to 7.97
P = 0.019 		Effect size not calculated CBT

RCT
3-armed trial 		153 adults with CFS (CDC criteria)
In review 		Change in mental health score (assessed by SF-36 questionnaire)
with group CBT
with education and support
Absolute results not reported
Absolute difference +3.16 for group CBT v education and support
95% CI –0.05 to +6.38
P = 0.5 		Not significant

RCT
3-armed trial 		153 adults with CFS (CDC criteria)
In review 		Anxiety (assessed by Hospital Anxiety and Depression scale [HADS] score)
with group CBT
with usual care
Absolute results not reported
Absolute difference –1.27 for group CBT v usual care
95% CI –2.52 to –0.02
P = 0.045
Result is of borderline significance 		Effect size not calculated CBT

RCT
3-armed trial 		153 adults with CFS (CDC criteria)
In review 		Anxiety (assessed by HADS score)
with group CBT
with education and support
Absolute results not reported
Absolute difference –0.51 for group CBT v education and support
95% CI –1.70 to +0.68 		Not significant

RCT
3-armed trial 		153 adults with CFS (CDC criteria)
In review 		Depression (assessed by HADS score)
with group CBT
with usual care
Absolute results not reported
Absolute difference –0.56 for group CBT v usual care
95% CI –1.69 to +0.58 		Not significant

RCT
3-armed trial 		153 adults with CFS (CDC criteria)
In review 		Depression (assessed by HADS score)
with group CBT
with education and support
Absolute results not reported
Absolute difference –0.13 for group CBT v education and support
95% CI –1.13 to +0.87 		Not significant

RCT
4-armed trial 		641 adults with CFS (Oxford criteria) Depression (assessed by HADS score) 52 weeks
6.2 with CBT
7.2 with specialist medical care
P = 0.0003 		Effect size not calculated CBT

RCT
4-armed trial 		641 adults with CFS (Oxford criteria) Anxiety (assessed by HADS score) 52 weeks
6.8 with CBT
8.0 with specialist medical care
P = 0.0003 		Effect size not calculated CBT
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No data from the following reference on this outcome.

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects

RCT		 63 adolescents aged 11–18 years with CFS (CDC or Oxford criteria)
In review 		Serious adverse events
with family-focused CBT
with psycho-education

RCT
4-armed trial 		641 adults with CFS (Oxford criteria) Serious adverse events
7/161 (4%) with CBT
7/160 (4%) with specialist medical care
Significance not assessed
Open in a new tab

No data from the following reference on this outcome.

Further information on studies

The active treatment consisted of a cognitive behavioural assessment, followed by 16 weekly sessions of behavioural experiments, problem-solving activity, and re-evaluation of thoughts and beliefs that inhibited a return to normal functioning. The control was usual general practice care in people attending a secondary-care centre.

Interventions CBT consisted of 16 sessions over 8 months administered by 13 therapists with no previous experience of treating CFS. The guided-support groups were similar to CBT in terms of treatment schedule, with people receiving non-directive support from a social worker. Loss to follow-up This multicentre RCT had a high withdrawal rate (25% after 8 months), especially in the CBT and guided-support groups. Although the presented confidence intervals are not adjusted for multiple comparisons, the results would remain significant after any reasonable adjustment. The authors commented that the results were similar after intention-to-treat analysis, but these results were not presented.

CBT (52 people) consisted of eight sessions over 16 weeks administered by experienced therapists. The education and support group (50 people) met the same therapists as those with CBT, in the same setting, for the same duration, and were taught a different relaxation exercise each week. The usual-care group (51 people) was managed in primary care and only attended the hospital for assessment at baseline and at 6 and 12 months. No adjustments were made for the multiple number of statistical tests carried out.

CBT (29 people) consisted of 13 45-minute sessions over 26 weeks administered by experienced therapists. Relaxation treatment (28 people) comprised a combination of progressive muscle relaxation, stretching, autogenic training, and breathing focus techniques over 26 weeks and each biweekly session also lasted 45 minutes. Both of the interventions were individualised for different participants (not further defined). The RCT also reported that the study population at baseline was less physically impaired, more likely to be employed, and less likely to have psychiatric co-morbidities than some of the previous similar RCTs in this area, and this may explain the difference in the results between RCTs.

The RCT found that CBT significantly improved school attendance at 5 months (% change in school attendance: 28% with CBT v 10% with no treatment; difference 18%, 95% CI 0.8% to 35.5%). A follow-up study (mean duration 2.1 years) of the RCT assessed 66/69 (96%) of the original trial participants. At the end of the trial, all participants were offered CBT: of the 34 people originally assigned waiting-list control, 18 received CBT. The analysis, therefore, compared outcomes in 50 people treated with CBT (32 people initially randomised to CBT plus 18 people initially randomised to waiting-list control who subsequently received CBT) with outcomes in the 16 people who refused CBT and thus received no treatment. The follow-up study found that, irrespective of the group to which they were randomised in the initial RCT, people receiving CBT were significantly less fatigued (P = 0.009), had significantly higher physical functioning as measured on the short-form (SF)-36 physical functioning subscale (P = 0.07), and had significantly improved school/work attendance (P = 0.002) at a mean 2 years than people given no intervention.

Family-focused CBT (32 people) consisted of 13 1-hour sessions offered every 2 weeks. The psycho-education consisted of four sessions over 6 months, the content was similar to that for the CBT, however, the delivery was didactic. Both interventions were provided by the same two experienced therapists with independent assessors for subjective outcomes. The RCT found that school attendance improved faster in the CBT group (dichotomised school attendance of at least 70%: 7/32 [22%] with family-focused CBT v 3/31 [10%] with psycho-education, P value not reported). However, this improvement was not maintained over time, and by the 6-month follow-up there was no significant difference between the groups (dichotomised school attendance of at least 70%: 21/32 [66%] with family-focused CBT v 18/31 [67%] with psycho-education, OR 0.95 [95% CI 0.32 to 2.82], P = 0.93). This was one of the few studies that found CBT may be no better than a control, though it is worth noting that the control, psycho-education, had some active ingredients.

The internet-based programme consisted of a psycho-educational section and a CBT section with 21 interactive modules. Support was also given by trained cognitive behavioural psychotherapists through e-consults alone. People could email therapists at anytime; emails were answered on a set day, once per week, unless it was an emergency email. Parents participated in a parallel program on a separate account with the same frequency of email contact to offer support and encouragement to their child as required. Usual multidisciplinary care consisted of individual or group-based rehabilitation, face-to-face CBT, or graded exercise treatment with a physical therapist; however, it was unclear how many got what treatment or how long for in the control arm. The authors state it was pragmatic, and that they were unable to state what was given, as treatments varied by region. The RCT (131 adolescents, aged 12–18 years) found that CBT significantly improved school attendance at 6 months (84% with internet CBT v 52% with usual care; mean difference 36%, 95% CI 21.5 to 43.6, P <0.0001) and full school attendance (defined as absence of 10% or less) at 6 months (50/67 [75%] with internet CBT v 10/64 [16%] with usual care; RR 4.8, 95% CI 2.7 to 8.9, P <0.0001). After 6 months, people could switch groups: 32/67 (48%) went from usual care to the internet intervention and 11/68 (16%) of the internet group changed to usual care.

The RCT reported that 112/135 (83%) adolescents completed long-term follow-up (mean 2.7 years, range 1.7–3.8 years). Only recovery was reported based on original randomisation. Other outcomes, such as fatigue and school attendance, were reported as recovered versus not recovered and are, therefore, not reported here.

CBT included planned gradual increases in both physical and mental activity and problem-solving to help address social and emotional obstacles. It was delivered by clinical psychologists and nurse therapists with up to 14 sessions in the first 23 weeks (initially once-weekly, decreasing to once every 2 weeks after the first four sessions). An additional booster session was offered at 36 weeks. The control group received specialist medical care delivered by doctors with specialist experience in CFS. Treatment consisted of an explanation of CFS, generic advice (e.g., to avoid extremes of activity and rest), specific self-help advice, and drug therapy if required (especially for insomnia, pain, and mood). At least three sessions were offered during the 12 months, increasing in number if clinically indicated.

Comment

A randomised trial comparing CBT and non-directive counselling found that both interventions were of benefit in the management of people who consulted their family doctor because of fatigue symptoms. In this study, 28% of the sample conformed to CDC criteria for CFS.

We found one RCT (171 people, CDC criteria) comparing a minimal intervention based on CBT (comprising a self-instruction booklet with information about CFS and weekly assignments) with a waiting-list control. The intervention lasted at least 16 weeks and included email or phone contact with an experienced therapist every 2 weeks. The RCT found that guided self-instructions significantly reduced fatigue as measured by the Checklist Individual Strength (CIS) fatigue severity subscale compared with waiting list control at 6 to 12 months. The RCT also found that a greater proportion of those receiving self-instructions had a clinically significant improvement (CIS fatigue severity <35) compared with waiting list controls and the self-instruction group also scored significantly higher on the SF-36 physical function subscale compared with the control group at 6 to 12 months.

Clinical guide

There is moderate evidence of benefit of CBT in CFS. The effectiveness of CBT for CFS outside specialist settings has been questioned. The results of the multicentre RCT suggest that CBT may be effective when administered by less-experienced therapists with adequate supervision. The largest trial to date (PACE) found that CBT is more effective than adaptive pacing and equally effective to graded exercise.

Substantive changes

Cognitive behavioural therapy Two systematic reviews, one RCT, and a further longer term follow-up report added. Categorisation unchanged (beneficial).

BMJ Clin Evid. 2015 Sep 28;2015:1101.

Graded exercise therapy

Summary

Graded exercise therapy has been shown to effectively improve measures of fatigue and physical functioning.

Educational interventions with encouragement of graded exercise (treatment sessions, telephone follow-ups, and an educational package explaining symptoms and encouraging home-based exercise) improve symptoms more effectively than written information alone.

Benefits and harms

Graded exercise therapy versus control interventions:

We found four systematic reviews (search dates 2004; 2005; 1987 to 2012; and search date not specified). The first systematic review included the results of an unpublished RCT in its meta-analyses, and so we have reported the results of the three published RCTs identified by the review individually. The second systematic review did not perform a meta-analysis or report quantified results from each study, and identified one additional RCT not included in the first systematic review. The third systematic review, a narrative review of interventions in children and adolescents, included one RCT that met BMJ Clinical Evidence inclusion criteria. The fourth systematic review was a narrative review, and all the relevant RCTs were already reported individually here. We also found one additional RCT.

Fatigue

Graded exercise therapy compared with control intervention Graded aerobic exercise programmes seem more effective at improving measures of fatigue compared with control interventions (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Fatigue

RCT		 66 people with CFS (Oxford criteria)
In review 		Mean change in Chalder Fatigue Score 12 weeks
–8.4 with graded exercise therapy
–3.1 with control intervention (flexibility and relaxation training)
P = 0.004 		Effect size not calculated graded exercise therapy

RCT
4-armed trial 		136 people with CFS (Oxford criteria)
In review 		Proportion of people with Chalder Fatigue Score <4 26 weeks
12/67 (18%) with graded exercise therapy, with or without fluoxetine
4/69 (6%) with general advice, with or without fluoxetine
RR 3.10
95% CI 1.05 to 9.10
NNT 9
95% CI 5 to 91 		Moderate effect size graded exercise therapy

RCT		 61 people with CFS (CDC criteria)
In review 		Mean change in Chalder Fatigue Score for physical fatigue (8 items for physical fatigue [0–8]) 12 weeks
3.5 with graded exercise therapy
1.8 with control intervention (flexibility and relaxation training)
P = 0.07 		Not significant

RCT		 22 adolescents with CFS (Fuduka critera)
In review 		Fatigue severity (on Fatigue Severity Scale [FSS]) change from baseline to 4 weeks
–0.42 with graded exercise therapy
–0.12 with control intervention (progressive resistance training)
P = 0.16 		Not significant

RCT
4-armed trial 		641 adults with CFS (Oxford criteria) Chalder Fatigue Questionnaire 52 weeks
20.6 with graded exercise therapy
23.8 with specialist medical care
Mean difference –3.2
95% CI –4.8 to –1.7
P = 0.0003 		Effect size not calculated graded exercise therapy
Mental fatigue

RCT		 61 people with CFS (CDC criteria)
In review 		Mean change in Chalder Fatigue Score for mental fatigue (6 items for mental fatigue [0–6]) 12 weeks
1.8 with graded exercise therapy
0.8 with control intervention (flexibility and relaxation training)
P = 0.02 		Effect size not calculated graded exercise therapy
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No data from the following reference on this outcome.

Overall improvement

Graded exercise therapy compared with control interventions Graded exercise therapy seems to lead to greater overall improvement in symptoms compared with control interventions (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Overall improvement

RCT		 66 people with CFS (Oxford criteria)
In review 		Proportion of people who reported feeling 'much better' or 'very much better' on Clinical Global Impression Scale 12 weeks
52% with graded aerobic exercise therapy
27% with control intervention (flexibility and relaxation training)
Absolute numbers not reported
P = 0.04 		Effect size not calculated graded exercise therapy

RCT		 61 people with CFS (CDC criteria)
In review 		Proportion of people with self-rated improvement with Clinical Global Impression Scale 12 weeks
29/32 (91%) with graded exercise therapy
22/29 (76%) with control intervention (flexibility and relaxation training)
P = 0.23 		Not significant

RCT		 49 people with CFS (CDC criteria)
In review 		Proportion of people who reported feeling 'much better' or 'very much better' in a self-reported rating of improvement 12 weeks
48% with graded exercise therapy
21% with standard medical care
Absolute numbers not reported
P = 0.05 		Effect size not calculated graded exercise therapy

RCT
4-armed trial 		641 adults with CFS (Oxford criteria) Proportion of people rating themselves as 'much better' or 'very much better' 52 weeks
62/160 (41%) with graded exercise therapy
38/160 (25%) with specialist medical care
OR 2.0
95% CI 1.2 to 3.5
P = 0.013 		Effect size not calculated graded exercise therapy
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No data from the following reference on this outcome.

Functional status

Graded exercise therapy compared with control intervention Graded aerobic exercise programmes seem to be more effective at improving measures of physical functioning compared with control interventions (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Physical functioning

RCT		 66 people with CFS (Oxford criteria)
In review 		Mean change in short-form (SF)-36 physical function score 12 weeks
20.5 with graded exercise therapy
8.0 with control intervention (flexibility and relaxation training)
P = 0.01 		Effect size not calculated graded exercise therapy

RCT		 22 adolescents wit CFS (Fuduka critera)
In review 		Physical function (SF-36 physical function score) change from baseline to 4 weeks
5.7 with graded exercise therapy
6.4 with control intervention (progressive resistance training)
P = 0.83 		Not significant

RCT
4-armed trial 		641 adults with CFS (Oxford criteria) Physical function (SF-36 physical) 52 weeks
57.7 with graded exercise therapy
50.8 with specialist medical care
Mean difference 9.4
95% CI 4.4 to 14.4
P = 0.0005 		Effect size not calculated graded exercise therapy
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No data from the following reference on this outcome.

Quality of life

Graded exercise therapy compared with control interventions Graded exercise therapy may be more effective than control interventions at improving depressive symptoms and anxiety symptoms at up to 1 year (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Mental health

RCT		 61 people with CFS (CDC criteria)
In review 		Self-reported anxiety symptoms (mean change in Hospital Anxiety and Depression scale [HADS] anxiety score) 12 weeks
1.6 with graded exercise therapy
0.9 with control intervention (flexibility and relaxation training)
P = 0.2 		Not significant

RCT		 61 people with CFS (CDC criteria)
In review 		Self-reported depressive symptoms (mean change in HADS depression score) 12 weeks
1.7 with graded exercise therapy
0.6 with control intervention (flexibility and relaxation training)
P = 0.04 		Effect size not calculated graded exercise therapy

RCT		 22 adolescents wit CFS (Fuduka critera)
In review 		Depression (assessed by Becks Depression Index) change from baseline to 4 weeks
–4.2 with graded exercise therapy
–6.7 with control intervention (progressive resistance training)
P = 0.40 		Not significant

RCT
4-armed trial 		641 adults with CFS (Oxford criteria) Depression (assessed by HADS score) 52 weeks
6.1 with graded exercise therapy
7.2 with specialist medical care
P = 0.0035 		Effect size not calculated graded exercise therapy

RCT
4-armed trial 		641 adults with CFS (Oxford criteria) Anxiety (assessed by HADS score) 52 weeks
7.1 with graded exercise therapy
8.0 with specialist medical care
P = 0.0142 		Effect size not calculated graded exercise therapy
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No data from the following reference on this outcome.

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Withdrawal rates

RCT
4-armed trial 		136 people with CFS, Oxford criteria
In review 		Withdrawal rates
25/68 (37%) with graded exercise therapy, with or without fluoxetine
15/69 (22%) with general advice, with or without fluoxetine
RR 1.70
95% CI 0.98 to 2.90 		Not significant

RCT
4-armed trial 		641 adults with CFS (Oxford criteria) Serious adverse events
13/160 (8%) with graded exercise therapy
7/160 (4%) with specialist medical care
P = 0.0142 		Effect size not calculated specialist medical care
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No data from the following reference on this outcome.

Graded exercise therapy plus education versus written information alone:

We found one systematic review (search date 2004). The review identified one RCT comparing three types of educational intervention plus encouragement of graded exercise with only written information (control group).

Fatigue

Graded exercise therapy plus education compared with written information alone An educational package to encourage graded exercise is more effective at improving measures of fatigue at 1 year than written information alone (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Fatigue

RCT
4-armed trial 		148 people with CFS, Oxford criteria
In review 		Mean Chalder Fatigue Score (scale range: 0–11; a score >3 indicates excessive fatigue) 1 year
3.2 with minimum intervention graded exercise
10.6 with written information
P <0.001 for minimum intervention graded exercise v control 		Effect size not calculated graded exercise therapy plus education

RCT
4-armed trial 		148 people with CFS, Oxford criteria
In review 		Mean Chalder Fatigue Score (scale range: 0–11; a score >3 indicates excessive fatigue) 1 year
3.5 with telephone intervention graded exercise
10.6 with written information
P <0.001 for telephone intervention graded exercise v control 		Effect size not calculated graded exercise therapy plus education

RCT
4-armed trial 		148 people with CFS, Oxford criteria
In review 		Mean Chalder Fatigue Score (scale range: 0–11; a score >3 indicates excessive fatigue) 1 year
3.1 with maximum intervention graded exercise
10.6 with written information
P <0.001 for maximum intervention graded exercise v control 		Effect size not calculated graded exercise therapy plus education
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Overall improvement

No data from the following reference on this outcome.

Functional status

Graded exercise therapy plus education compared with written information alone An educational package to encourage graded exercise is more effective at improving measures of physical functioning at 1 year than written information alone (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Physical functioning

RCT
4-armed trial 		148 people with CFS, Oxford criteria
In review 		Mean short-form (SF)-36 physical functioning score (score range: 10–30, where 10 = maximum impairment and 30 = no impairment) 1 year
25.1 with minimum intervention graded exercise
16.9 with written information
P <0.001 for minimum intervention graded exercise v control 		Effect size not calculated graded exercise therapy plus education

RCT
4-armed trial 		148 people with CFS, Oxford criteria
In review 		Mean SF-36 physical functioning score (score range: 10–30, where 10 = maximum impairment and 30 = no impairment) 1 year
24.3 with telephone intervention graded exercise
16.9 with written information
P <0.001 for telephone intervention graded exercise v control 		Effect size not calculated graded exercise therapy plus education

RCT
4-armed trial 		148 people with CFS, Oxford criteria
In review 		Mean SF-36 physical functioning score (score range: 10–30, where 10 = maximum impairment and 30 = no impairment) 1 year
24.9 with maximum intervention graded exercise
16.9 with written information
P <0.001 for maximum intervention graded exercise v control 		Effect size not calculated graded exercise therapy plus education
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Quality of life

No data from the following reference on this outcome.

Adverse effects

No data from the following reference on this outcome.

Further information on studies

Everyone had individual weekly sessions supervised by an exercise physiologist. People in the aerobic-exercise group built up their level of activity to 30 minutes of exercise a day (walking, cycling, swimming up to a maximum oxygen consumption of 60% of VO2 max). People in the flexibility and relaxation training group were taught stretching and relaxation techniques (maximum 30 minutes daily, 5 days/week) and were specifically told to avoid any extra physical activities.

The graded-exercise groups were given specific advice to do preferred aerobic exercise (such as walking, jogging, swimming, or cycling) for 20 minutes three times a week up to an energy expenditure of 75% of VO2 max. People in the general-advice groups were not given any specific advice on frequency, intensity, or duration of aerobic activity.

Graded activity consisted of aerobic exercise (walking, swimming, or cycling) for up to 15 minutes every second day. Intensity of activity was determined by mean heart rate during exercise. If there was a worsening of symptoms, the next exercise session was shortened or cancelled, and subsequent sessions reduced to a length considered by the participant to be manageable. People in the relaxation and flexibility group listened to a relaxation tape and performed stretching exercises every second day.

People in the three educational-intervention groups received a minimum intervention consisting of two treatment sessions, two telephone follow-ups, and an educational package that provided an explanation of symptoms and encouraged home-based exercise. One group received the minimum intervention; one group received seven additional follow-up telephone calls (telephone intervention); and another received seven additional face-to-face sessions over 4 months (maximum intervention). People in the written-information group received advice and an information booklet that encouraged graded activity, but gave no explanation for the symptoms.

Graded aerobic exercise training consisted of 20 to 40 minutes of stationary cycling and treadmill at 40% to 60% of heart rate reserve. The progressive resistance training involved 16 exercises combining upper and lower body strength and core stability performed with single set, light to moderate load, and high (10-15) repetitions. In addition, exercise programmes (aerobic or resistance-based, according to group) were set for weekends and bank holidays. Both were for 5 days per week for a total of 4 weeks. All exercise was supervised by an experienced physiologist. The outcomes assessor was blinded.

Graded exercise therapy was aimed at 30 minutes of light exercise, five times per week. The intensity and aerobic nature of the exercise was gradually increased as target heart rates were reached. The most commonly chosen exercise was walking. The therapy delivered by physiotherapists and an exercise physiologist with up to 14 sessions in the first 23 weeks (initially once-weekly, decreasing to once every 2 weeks after the first four sessions). An additional booster session was offered at 36 weeks. The control group received specialist medical care delivered by doctors with specialist experience in CFS. Treatment consisted of an explanation of CFS, generic advice (e.g., to avoid extremes of activity and rest), specific self-help advice, and drug therapy if required (especially for insomnia, pain, and mood). At least three sessions were offered during the 12 months, increasing in number if clinically indicated.

Comment

Clinical guide

There is good evidence of benefit for graded exercise therapy in CFS. However, experience suggests that CFS symptoms may be exacerbated by overly ambitious or overly hasty attempts at exercise. The largest RCT to date (PACE) suggested that graded exercise therapy is more effective than adaptive pacing, and equally effective to CBT.

Substantive changes

Graded exercise therapy Two systematic reviews and one RCT added. Categorisation unchanged (beneficial).

BMJ Clin Evid. 2015 Sep 28;2015:1101.

Antidepressants

Summary

We don't know how effective antidepressants are in treating chronic fatigue syndrome (CFS).

Antidepressants should be considered in people with depressive disorders. Tricyclics, in particular, have potential therapeutic value because of their analgesic properties, given the high prevalence of muscle and joint pain in CFS.

Benefits and harms

Fluoxetine versus placebo:

We found one systematic review (search date 2005), which did not conduct a meta-analysis or report quantified results from each study. The systematic review identified two RCTs.

Fatigue

Fluoxetine compared with placebo Fluoxetine may be no more effective at improving fatigue than placebo at 8 to 12 weeks (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Fatigue

RCT		 107 depressed and non-depressed people with CFS (Oxford criteria)
In review 		Mean scores on subscale of Checklist Individual Strength 8 weeks
with fluoxetine
with placebo
Absolute results not reported
Mean difference –0.16
95% CI –0.64 to +0.31 		Not significant

4-armed trial 		136 people with CFS (Oxford criteria)
In review 		Fatigue severity 12 weeks
with fluoxetine
with placebo
Absolute results not reported
Reported as not significant
P value not reported 		Not significant
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Overall improvement

No data from the following reference on this outcome.

Functional status

No data from the following reference on this outcome.

Quality of life

Fluoxetine compared with placebo Fluoxetine may be more effective than placebo at improving symptoms of anxiety and depression (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Depression

RCT		 107 depressed and non-depressed people with CFS (Oxford criteria)
In review 		Improvement in the Beck Depression Inventory 8 weeks
with fluoxetine
with placebo
Absolute results not reported
Mean difference –0.19
95% CI –0.35 to –0.02
The difference is small, and possibly not clinically important 		Effect size not calculated fluoxetine

4-armed trial 		136 people with CFS (Oxford criteria)
In review 		Mean change in Hospital Anxiety and Depression scale (HADS) score 12 weeks
with fluoxetine
with placebo
Absolute results not reported
Mean difference 1.10
95% CI 0.03 to 2.20 		Effect size not calculated fluoxetine
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Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Withdrawal

RCT		 107 depressed and non-depressed people with CFS (Oxford criteria)
In review 		Withdrawal rates owing to adverse effects
9/54 (17%) with fluoxetine
2/53 (4%) with placebo
Reported as not significant
P value not reported 		Not significant

RCT
4-armed trial 		136 people with CFS (Oxford criteria)
In review 		Withdrawal rates
24/68 (36%) with fluoxetine
16/69 (24%) with placebo
Significance not assessed
Adverse effects

RCT		 107 depressed and non-depressed people with CFS (Oxford criteria)
In review 		Tremor 8 weeks
with fluoxetine
with placebo
P = 0.006 		Effect size not calculated placebo

RCT		 107 depressed and non-depressed people with CFS (Oxford criteria)
In review 		Perspiration 8 weeks
with fluoxetine
with placebo
P = 0.008 		Effect size not calculated placebo
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Phenelzine versus placebo:

We found one systematic review (search date 2005), which identified one RCT.

Fatigue

No data from the following reference on this outcome.

Overall improvement

Phenelzine compared with placebo Phenelzine may be more effective than placebo at improving symptoms of chronic fatigue syndrome at 6 weeks. However, evidence was very weak and limited to one small RCT of 30 people (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Overall improvement

RCT		 30 people with CFS (CDC 1988 criteria)
In review 		Overall improvement 6 weeks
with phenelzine
with placebo
Absolute results not reported
Significance not assessed for individual measures reported
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Functional status

No data from the following reference on this outcome.

Quality of life

No data from the following reference on this outcome.

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Withdrawal because of adverse effects

RCT		 30 people with CFS (CDC 1988 criteria)
In review 		Withdrawal because of adverse effects 6 weeks
3/15 (20%) with phenelzine
0/15 (0%) with placebo
Significance not assessed
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Moclobemide versus placebo:

We found one systematic review (search date 2005), which identified one RCT.

Fatigue

No data from the following reference on this outcome.

Overall improvement

Moclobemide compared with placebo Moclobemide seems to be no more effective than placebo at improving symptoms of chronic fatigue at 6 weeks. However, evidence was limited to one small RCT of 90 people (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Overall improvement

RCT		 90 people with CFS (Australian criteria)
In review 		Proportion of people reporting improvement on self-reported global improvement scale 6 weeks
24/47 (51%) with moclobemide (450–600 mg/day)
14/43 (33%) with placebo
OR 2.16
95% CI 0.90 to 5.10 		Not significant

RCT		 90 people with CFS (Australian criteria)
In review 		Standardised improvement on Karnofsky scale 6 weeks
0.86 with moclobemide (450–600 mg/day)
0.58 with placebo
Mean difference +0.28
95% CI –0.2 to +0.8 		Not significant
Open in a new tab

Functional status

No data from the following reference on this outcome.

Quality of life

No data from the following reference on this outcome.

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Withdrawal because of adverse effects

RCT		 90 people with CFS (Australian criteria)
In review 		Withdrawal because of adverse effects 6 weeks
7/47 (15%) with moclobemide (450–600 mg/day)
6/43 (14%) with placebo
Significance not assessed
Adverse effects

RCT		 90 people with CFS (Australian criteria)
In review 		Adverse effects 6 weeks
with moclobemide (450–600 mg/day)
with placebo
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Sertraline versus clomipramine:

We found one RCT.

Fatigue

No data from the following reference on this outcome.

Overall improvement

Sertraline compared with clomipramine Sertraline may be no more effective than clomipramine at improving symptoms of chronic fatigue. However, evidence was limited to one small RCT of 40 people (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Overall improvement

RCT		 40 people with CFS Mean % improvement from baseline in the Clinical Global Impression scale
31.8% with sertraline
20.7% with clomipramine
P = 0.28 		Not significant
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Functional status

No data from the following reference on this outcome.

Quality of life

No data from the following reference on this outcome.

Adverse effects

No data from the following reference on this outcome.

Comment

Fluoxetine versus placebo

The first RCT used a shorter duration of treatment and studied people with a longer duration of illness compared with the second RCT.

Adverse effects

The FDA and other regulatory bodies have issued a number of alerts and revised prescribing information regarding the use of antidepressants — in particular, relating to the increased risk of self-harm and suicide.

Clinical guide

Although antidepressants have not been shown in RCTs to be of significant benefit, their use should be considered in people with depressive disorders. Tricyclic antidepressants have analgesic properties and may be of benefit to patients experiencing muscle and/or joint pain; they may also be of benefit in people complaining of persistent insomnia.

Substantive changes

No new evidence

BMJ Clin Evid. 2015 Sep 28;2015:1101.

Corticosteroids

Summary

We don’t know how effective corticosteroids are in the treatment of chronic fatigue syndrome.

Benefits and harms

Fludrocortisone versus placebo:

We found one systematic review (search date 2005), which did not conduct a meta-analysis or report quantified results from each study. The review identified two RCTs.

Fatigue

Fludrocortisone compared with placebo Fludrocortisone may be no more effective than placebo at improving measures of fatigue at 6 weeks. However, evidence was limited to one small RCT of 25 people (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Fatigue

RCT
Crossover design 		25 people with CFS, CDC criteria
In review 		Mean change in fatigue severity visual analogue scale (VAS) score 6 weeks
0.1 with fludrocortisone
0.4 with placebo
P = 0.37
Results should be interpreted with caution, as it is possible that treatment effects may persist after crossover 		Not significant
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No data from the following reference on this outcome.

Overall improvement

Fludrocortisone compared with placebo Fludrocortisone may be no more effective than placebo at improving symptoms of chronic fatigue syndrome at 9 weeks (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Overall improvement

RCT		 100 people with neurally mediated hypotension and CFS (CDC criteria)
In review 		Proportion of people with an improvement of at least 15 points on a self-reported global scale of 'wellness' (scale of 1–100) 9 weeks
14% with fludrocortisone (titrated to 0.1 mg/day)
10% with placebo
Absolute numbers not reported
P = 0.76 		Not significant
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No data from the following reference on this outcome.

Functional status

Fludrocortisone compared with placebo Fludrocortisone may be no more effective than placebo at improving measures of physical functioning at 6 weeks. However, evidence was limited to one small RCT of 25 people (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Physical functioning

RCT
Crossover design 		25 people with CFS (CDC criteria)
In review 		Mean change in short-form (SF)-36 physical functioning score 6 weeks
+6.5 with fludrocortisone
–1.6 with placebo
P = 0.15
Results should be interpreted with caution, as it is possible that treatment effects may persist after crossover 		Not significant
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No data from the following reference on this outcome.

Quality of life

No data from the following reference on this outcome.

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Withdrawal

RCT		 100 people with neurally mediated hypotension and CFS (CDC criteria)
In review 		Withdrawal because of adverse effects 9 weeks
12/50 (24%) with fludrocortisone (titrated to 0.1 mg/day)
4/50 (8%) with placebo
RR 3.00
95% CI 1.04 to 8.67
NNH 6
95% CI 3 to 8 		Moderate effect size placebo

RCT
Crossover design 		25 people with CFS (CDC criteria)
In review 		Withdrawal rate
3 people with fludrocortisone
1 person with placebo
Results should be interpreted with caution, as it is possible that treatment effects may persist after crossover
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Hydrocortisone versus placebo:

We found one systematic review (search date 2005), which did not conduct a meta-analysis or report quantified results from each study. The review identified two RCTs.

Fatigue

Hydrocortisone compared with placebo Hydrocortisone may be more effective than placebo at improving fatigue scores at 1 month. However, the RCT did not test the significance of differences between groups, and evidence was limited to one small RCT of 32 people (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Fatigue

RCT
Crossover design 		32 people with CFS
In review 		Mean change in fatigue score from baseline (patient-assessed 11-item scale, overall score 0–33, higher score indicates greater fatigue) 1 month
–6.7 with hydrocortisone (5 or 10 mg/day)
–2.4 with placebo
Absolute numbers not reported
Significance not assessed
Benefit from hydrocortisone may be short-term; see Further information on studies for full details
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No data from the following reference on this outcome.

Overall improvement

Hydrocortisone compared with placebo Hydrocortisone may be more effective than placebo at improving overall symptoms of chronic fatigue at 12 weeks. However, the clinical significance of the result was unclear (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Overall improvement

RCT		 65 people with CFS (CDC 1998 criteria)
In review 		Proportion of people with improvement of at least 5 points on self-rated 100-point scale 12 weeks
53% with hydrocortisone (25–35 mg/day)
29% with placebo
Absolute numbers not reported
P = 0.04
Clinical significance of this difference is unclear 		Effect size not calculated hydrocortisone
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No data from the following reference on this outcome.

Functional status

Hydrocortisone compared with placebo Hydrocortisone seems no more effective than placebo at improving functional status (as assessed by activity scale and Sickness Impact Profile) at 12 weeks. However, evidence was limited to one small RCT of 65 people (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Functional status

RCT		 65 people with CFS (CDC 1998 criteria)
In review 		Change in activity scale (change from baseline) 12 weeks
0.3 with hydrocortisone (25–35 mg/day)
0.7 with placebo
P = 0.32 		Not significant

RCT		 65 people with CFS (CDC 1998 criteria)
In review 		Change in Sickness Impact Profile (change from baseline) 12 weeks
–2.5 with hydrocortisone (25–35 mg/day)
–2.2 with placebo
P = 0.85 		Not significant
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No data from the following reference on this outcome.

Quality of life

Hydrocortisone compared with placebo Hydrocortisone seems no more effective than placebo at improving depressive symptoms at 12 weeks. However, evidence was limited to one small RCT of 65 people (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Depression

RCT		 65 people with CFS (CDC 1998 criteria)
In review 		Change in Beck Depression Inventory (change from baseline) 12 weeks
–2.1 with hydrocortisone (25–35 mg/day)
–0.4 with placebo
P = 0.17 		Not significant
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No data from the following reference on this outcome.

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects

RCT		 65 people with CFS (CDC 1998 criteria)
In review 		Adverse effects
with hydrocortisone (25–35 mg/day)
with placebo

RCT
Crossover design 		32 people with CFS
In review 		Adverse effects
with hydrocortisone (5 or 10 mg/day)
with placebo
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Hydrocortisone plus fludrocortisone versus placebo:

We found one systematic review (search date 2005), which identified one RCT.

Fatigue

Hydrocortisone plus fludrocortisone compared with placebo Combined treatment with hydrocortisone plus fludrocortisone may be no more effective than placebo at improving fatigue at 3 months (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Fatigue

RCT
Crossover design 		100 people with CFS (CDC criteria)
In review 		Mean visual analogue scale (VAS) fatigue score (0 = no fatigue to 10 = severe fatigue) 3 months
6.6 with hydrocortisone 5 mg daily plus fludrocortisone 50 micrograms daily
6.7 with placebo
P = 0.76
Results should be interpreted with caution, as it is possible that treatment effects may persist after crossover 		Not significant

RCT
Crossover design 		100 people with CFS (CDC criteria)
In review 		Mean score on Abbreviated Fatigue Questionnaire 3 months
8 with hydrocortisone 5 mg daily plus fludrocortisone 50 micrograms daily
7 with placebo
P = 0.69
Results should be interpreted with caution, as it is possible that treatment effects may persist after crossover 		Not significant
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Overall improvement

No data from the following reference on this outcome.

Functional status

No data from the following reference on this outcome.

Quality of life

No data from the following reference on this outcome.

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects

RCT
Crossover design 		100 people with CFS (CDC criteria)
In review 		Adverse effects
with hydrocortisone 5 mg daily plus fludrocortisone 50 micrograms daily
with placebo
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Further information on studies

The RCT found no significant difference between fludrocortisone and placebo in change in myalgia score (assessed using a visual analogue scale [VAS] from 0 [no problem] to 10 [could not be worse]: –0.3 with fludrocortisone v +1.1 with placebo; P = 0.53); concentration (change in concentration score: –0.9 with fludrocortisone v –0.3 with placebo; P = 0.4); joint pain (change in joint pain score: –0.3 with fludrocortisone v 0.8 with placebo; P = 0.15); or social functioning (change in social functioning: 6.5 with fludrocortisone v 0.0 with placebo; P = 0.3).

The crossover RCT found that, although fatigue decreased with low-dose hydrocortisone, fatigue increased within 28 days of crossover into the placebo group. Therefore, any benefit from low-dose hydrocortisone may be short-lived, whereas higher doses are associated with adverse effects.

Comment

The RCTs used different reasons for their choice of active treatment. The use of fludrocortisone, a mineralocorticoid, was based on the hypothesis that CFS is associated with neurally mediated hypotension. The use of hydrocortisone, a glucocorticoid, in the other RCTs was based on evidence of under-activity of the hypothalamic-pituitary-adrenocortical axis in some people with CFS.

Clinical guide

There is weak evidence of benefit for low-dose hydrocortisone; however, benefit may be short-lived, there are no longer-term or follow-up studies, and higher doses are associated with adverse effects.

Substantive changes

No new evidence

Articles from BMJ Clinical Evidence are provided here courtesy of BMJ Publishing Group

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