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Randomised Controlled Trial of Cognitive Behaviour Therapy Delivered in Groups of Patients with Chronic Fatigue Syndrome

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Background: Meta-analyses have been inconclusive about the efficacy of cognitive behaviour therapies (CBTs) delivered in groups of patients with chronic fatigue syndrome (CFS) due to a lack of adequate studies. Methods: We conducted a pragmatic randomised controlled trial with 204 adult CFS patients from our routine clinical practice who were willing to receive group therapy. Patients were equally allocated to therapy groups of 8 patients and 2 therapists, 4 patients and 1 therapist or a waiting list control condition. Primary analysis was based on the intention-to-treat principle and compared the intervention group (n = 136) with the waiting list condition (n = 68). The study was open label. Results: Thirty-four (17%) patients were lost to follow-up during the course of the trial. Missing data were imputed using mean proportions of improvement based on the outcome scores of similar patients with a second assessment. Large and significant improvement in favour of the intervention group was found on fatigue severity (effect size = 1.1) and overall impairment (effect size = 0.9) at the second assessment. Physical functioning and psychological distress improved moderately (effect size = 0.5). Treatment effects remained significant in sensitivity and per-protocol analyses. Subgroup analysis revealed that the effects of the intervention also remained significant when both group sizes (i.e. 4 and 8 patients) were compared separately with the waiting list condition. Conclusions: CBT can be effectively delivered in groups of CFS patients. Group size does not seem to affect the general efficacy of the intervention which is of importance for settings in which large treatment groups are not feasible due to limited referral.
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Regular Article
Psychother Psychosom 2015;84:368–376
DOI: 10.1159/000438867
Randomised Controlled Trial of Cognitive
Behaviour Therapy Delivered in Groups of
Patients with Chronic Fatigue Syndrome
JanF.Wiborg JosevanBussel AgaatvanDijk GijsBleijenberg HansKnoop
Expert Centre for Chronic Fatigue, Radboud University Medical Center, Nijmegen , The Netherlands
tion also remained significant when both group sizes (i.e. 4
and 8 patients) were compared separately with the waiting
list condition. Conclusions: CBT can be effectively delivered
in groups of CFS patients. Group size does not seem to affect
the general efficacy of the intervention which is of impor-
tance for settings in which large treatment groups are not
feasible due to limited referral. © 2015 S. Karger AG, Basel
Introduction
According to recent meta-analyses [1–3] , cognitive be-
haviour therapy (CBT) is an evidence-based intervention
for the treatment of individual patients with chronic fa-
tigue syndrome (CFS) that leads to moderate improve-
ment of fatigue and disabilities. There are also approach-
es for the delivery of CBT in groups of CFS patients
[4, 5] ,
but randomised controlled trials (RCTs) which examined
the efficacy of group CBT for CFS in the past were either
based on unpublished trials with small sample size
[1, 3] ,
combined CBT with graded exercise therapy for CFS
[6]
or produced inconsistent results
[5] .
This ambiguity is also reflected by current meta-anal-
yses. While Malouff et al.
[2] concluded that there are not
enough adequate studies to evaluate the efficacy of group
therapy for CFS patients, Price et al.
[1] found in their
meta-analysis that group CBT for CFS was less effective
than individual therapy. More recently, Castell et al.
[3]
Key Words
Chronic fatigue syndrome · Cognitive behaviour therapy ·
Group therapy · Randomised controlled trial
Abstract
Background: Meta-analyses have been inconclusive about
the efficacy of cognitive behaviour therapies (CBTs) deliv-
ered in groups of patients with chronic fatigue syndrome
(CFS) due to a lack of adequate studies. Methods: We con-
ducted a pragmatic randomised controlled trial with 204
adult CFS patients from our routine clinical practice who
were willing to receive group therapy. Patients were equally
allocated to therapy groups of 8 patients and 2 therapists, 4
patients and 1 therapist or a waiting list control condition.
Primary analysis was based on the intention-to-treat princi-
ple and compared the intervention group (n= 136) with the
waiting list condition (n= 68). The study was open label. Re-
sults: Thirty-four (17%) patients were lost to follow-up dur-
ing the course of the trial. Missing data were imputed using
mean proportions of improvement based on the outcome
scores of similar patients with a second assessment. Large
and significant improvement in favour of the intervention
group was found on fatigue severity (effect size= 1.1) and
overall impairment (effect size= 0.9) at the second assess-
ment. Physical functioning and psychological distress im-
proved moderately (effect size= 0.5). Treatment effects re-
mained significant in sensitivity and per-protocol analyses.
Subgroup analysis revealed that the effects of the interven-
Received: March 21, 2015
Accepted after revision: July 20, 2015
Published online: September 25, 2015
Dr. Hans Knoop
Expert Centre for Chronic Fatigue
Radboud University Medical Center, PO Box 9101
NL–6500 HB Nijmegen (The Netherlands)
E-Mail Hans.knoop @ radboudumc.nl
© 2015 S. Karger AG, Basel
0033–3190/15/0846–0368$39.50/0
www.karger.com/pps
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CBT in Patients with Chronic Fatigue
Syndrome
Psychother Psychosom 2015;84:368–376
DOI: 10.1159/000438867
369
concluded that both treatments should be considered
equally effective based on a moderator analysis of the
treatment effects. None of these reviews used data from
group therapy studies conducted after 2006 so that a dif-
ference in available studies cannot explain these contrast-
ing conclusions.
More research with sufficiently powered samples is
thus strongly needed to enhance the evaluation of group
CBT for patients who suffer from CFS. We conducted a
pragmatic RCT with CFS patients from our routine clin-
ical practice who were willing to receive group therapy
and tested whether our group intervention would be
more effective in reducing fatigue and disabilities than a
waiting list control condition. We did not test the group
intervention against individual CBT for CFS to avoid that
a potential efficacy of the group intervention would re-
main undetected in case that the group intervention was
less effective than individual therapy.
While we normally deliver group therapy in groups of
8 patients and 2 therapists, implementation of CBT for
CFS has shown that the number of patients who are re-
ferred for treatment in community-based settings can be
substantially lower than in academic settings
[7] . To in-
crease the flexibility of the group size for an implementa-
tion of the group intervention outside academic settings,
we decided to also deliver treatment in groups of 4 pa-
tients and 1 therapist and tested the efficacy of the differ-
ent group sizes against the control condition in subgroup
analyses.
Methods
Design
Patients were randomly assigned in a 1:
1:1 ratio to one of the
following three conditions: (I) CBT in groups of 8 patients and 2
therapists, (II) CBT in groups of 4 patients and 1 therapist, (III) a
waiting list for individual CBT for CFS at our clinic. Baseline as-
sessment took place prior to randomisation as part of our routine
assessment. Any patient’s eligibility for the trial was evaluated
based on this assessment. Eligible patients who were willing to re-
ceive group therapy were introduced to a research assistant who
performed randomisation after informed consent had been signed.
We also asked patients if they were able to function well in groups,
but this item proved to be difficult to answer and was dropped as
criterion for participation.
The random allocation sequence was computer generated with
a block size of 6 prepared by the Department of Biostatistics at the
Radboud University Medical Center. Sequentially numbered,
opaque and sealed envelopes with the condition enclosed were
opened in the presence of the patient. Reassessment was scheduled
at least 6 months after baseline assessment following the interven-
tion or waiting period. Primary outcomes of the study were fatigue
and disabilities (i.e. physical functioning and overall impairment).
The secondary outcome was psychological distress. The study was
open label. The study protocol
[8] was approved by the local ethics
committee of the Radboud University Medical Center. No funding
was obtained for the study. This trial is registered at http://isrctn.
org, No. ISRCTN15823716.
Participants
All patients were referred to our outpatient clinic for the man-
agement of chronic fatigue. Inclusion took place between January
2008 and April 2011 among patients with CFS who were at least 18
years of age and who were able to speak and read Dutch. In accor-
dance with the US Centers for Disease Control
[9] , CFS was de-
fined as severe and unexplained fatigue which lasts for at least
6months and which is accompanied by substantial impairment in
functioning and 4 or more additional complaints such as pain or
concentration problems. We operationalised severe fatigue as a
score of 35 or higher on the fatigue severity subscale of the Check-
list Individual Strength (CIS)
[10, 11] and substantial impairment
as a weighted total score of 700 or higher on the Sickness Impact
Profile (SIP)
[11, 12] . Patients who were in dispute over a disabil-
ity pension were temporarily excluded from the trial
[4] .
The Department of Internal Medicine at the Radboud Univer-
sity Medical Center assessed the medical examination status of all
patients and decided whether patients had been sufficiently exam-
ined by a medical doctor to rule out relevant medical explanations
for the complaints. If patients had not been sufficiently examined,
they were seen for standard medical tests at the Department of In-
ternal Medicine prior to referral to our outpatient clinic. In accor-
dance with recommendations by the Centers for Disease Control,
sufficient medical examination included evaluation of somatic pa-
rameters that may provide evidence for a plausible somatic expla-
nation for prolonged fatigue [for a list, see
9] . When abnormalities
were detected in these tests, additional tests were made based on
the judgement of the clinician of the Department of Internal Med-
icine who ultimately decided about the appropriateness of referral
to our clinic. Trained therapists at our clinic ruled out psychiatric
comorbidity as potential explanation for the complaints in un-
structured clinical interviews.
Intervention
The intervention consisted of 14 group sessions of 2 h within a
period of 6 months followed by a second assessment. Before the in-
tervention started, patients were introduced to their group therapist
in an individual session. The intervention was based on previous
work of our research group
[4, 13] and included personal goal set-
ting, fixing sleep-wake cycles, reducing the focus on bodily symp-
toms, a systematic challenge of fatigue-related beliefs, regulation and
gradual increase in activities, and accomplishment of personal goals.
A formal exercise programme was not part of the intervention.
Patients received a workbook with the content of the therapy.
During sessions, patients were explicitly invited to give feedback
about fatigue-related cognitions and behaviours to fellow patients.
This aspect was introduced to facilitate a pro-active attitude and to
avoid misperceptions of the sessions as support group meetings
which have been shown to be insufficient for the treatment of CFS
[11] . Regular attendance of the sessions was emphasised by the
therapists because a missed group session could not be caught up
on by the patients. In contrast to our previous work
[4] , we com-
municated recovery in terms of fatigue and disabilities as general
goal of the intervention
[14] .
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Group therapists held degrees in psychology with the exception
of a therapist who held a degree in pedagogy and a social worker
with experience in group therapy, who also coordinated the group
programme. Twelve therapists delivered group therapy during the
trial period. All therapists were trained in manualised CBT for in-
dividual CFS patients. The therapists did not receive additional
training for group therapy but had the opportunity to join more
experienced colleagues in the large therapy groups.
Measures
The subscale of fatigue severity of the CIS was used to indicate
the level of fatigue. The sum score varies between 8, no fatigue, and
56, severe fatigue. The CIS is a reliable and valid instrument for the
assessment of fatigue which is sensitive to change and which helps
to discriminate between patients with CFS and healthy individuals
[10, 15] . The CIS is part of our routine assessment for CFS patients
and has been used in previous clinical trials conducted by our re-
search group
[4, 7, 11, 14] . Our fatigue assessment was comple-
mented by additional questions about other clinical features rele-
vant to CFS such as the number of additional symptoms and the
duration of the complaints, both aspects which are required by the
US Center for Disease Control to classify patients as CFS cases
[9] .
Physical functioning was assessed with the physical function-
ing subscale of the Short Health Survey 36 (SF-36)
[16] . Scores on
this scale range from 0 (worst possible functioning) to 100 (opti-
mal functioning). Overall impairment in functioning was assessed
with the SIP which has good reliability and content validity
[12] .
A total score was calculated by addition of the weights of items
(range 0–5,799) in eight subscales: home management, mobility,
alertness behaviour, sleep and rest, ambulation, social interactions,
work and recreation
[11] . Higher scores on this scale indicate more
disability.
The secondary outcome was psychological distress which was
assessed with the Symptom Checklist 90
[17] . Higher scores on this
scale indicate more psychological distress. Potential harms of the
intervention were not assessed. Previous research has shown that
cognitive behavioural interventions for CFS are safe and unlikely
to produce detrimental effects
[18–20] .
Statistical Analyses
Sample size was calculated for analysis of differences between
the intervention group and the control condition (2:
1 ratio) with
90% power and a one-sided α of 0.025 based on the two different
kinds of the primary outcomes fatigue and disabilities. We as-
sumed a mean difference on the CIS fatigue severity subscale of 6.5
with a standard deviation of 9.0 in the intervention group and a
total drop-out rate of 20% during the study
[11] . Based on these
assumptions, a total sample size of 204 patients was needed for
random allocation consisting of 136 patients in the intervention
group (68 patients in small and 68 patients in large therapy groups
for subgroup analysis) and 68 patients in the control group.
Effects of the intervention were tested using analysis of covari-
ance with intervention as fixed factor. We entered baseline scores
of the outcome measure as covariate instead of using change scores
to increase the statistical power of the tests
[21] . Subgroup analysis
(small and large therapy groups vs. control group) were conducted
using Bonferroni correction for multiple testing. Standardised
mean differences (Cohen’s d ) were computed by subtracting the
mean score of the intervention group from the mean score of the
control group divided by the pooled standard deviation of both
groups at the second assessment. Standardised effects were consid-
ered small ( d= 0.2), medium ( d= 0.5) or large ( d= 0.8) in size
[22] .
Our primary analysis was based on the intention-to-treat principle
for all patients who were randomly allocated to one of the trial
conditions.
Since handling of missing data was not addressed in the re-
search protocol of the study, we followed the recommendations by
White et al.
[23] for the evaluation of randomised trials with miss-
ing data. In our primary analysis, we imputed missing data using
mean proportions of improvement which were based on the pri-
mary outcome scores of similar patients from the study. For pa-
tients with missing data from the waiting list and for patients with
missing data who did not start treatment, the reference group con-
sisted of those patients from the waiting list who attended the sec-
ond assessment. For all other patients with missing data from the
intervention condition, the reference group consisted of those
patients who withdrew from treatment but attended the second
assessment.
Sensitivity analysis included two alternative approaches for the
imputation of missing data focusing on the primary outcome mea-
sures of the primary analysis. The first approach was multiple im-
putation using fully conditional specification with three imputa-
tions based on the assumption that data were missing at random.
The second approach was based on a conservative imputation sce-
nario in which we again used the mean proportion of improve-
ment of the reference group to impute missing scores for patients
from the waiting list but assumed that all patients from the inter-
vention condition would show no improvement from the baseline
assessment on their missing data. Systematic deterioration of
symptoms in one of the conditions was not assumed based on pre-
vious findings
[18, 19] .
Since some studies have reported that a significant minority of
patients recovered from CFS following individual CBT, we decid-
ed to conduct a post hoc analysis examining rates of clinically sig-
nificant improvement and recovery in our sample. Our definition
for clinically significant improvement included a reliable change
index of >1.96 on the CIS fatigue subscale, a CIS fatigue score of
<35 and an SF-36 physical functioning score of 65 in combina-
tion with a SIP overall impairment score of <700
[7] . Our defini-
tion for recovery was based on mean scores of healthy controls +
1 standard deviation on the primary outcome measures and was
operationalised as a CIS fatigue score of <27, an SF-36 physical
functioning score of 80 and a total score of <203 on the SIP
[14] .
Differences in improvement and recovery rates between the inter-
vention and control group were tested using Fisher’s exact test.
Analyses were carried out using IBM SPSS statistics 20. The re-
searcher who conducted the statistical analysis was not masked to
treatment allocation.
Results
In total, 485 adult patients were diagnosed with CFS
during the inclusion period at our clinic ( fig.1 ). One hun-
dred and fifty-seven patients were excluded from the tri-
al because they declined treatment at our clinic, were al-
ready asked to participate in research incompatible with
inclusion (e.g. research focusing on individual CBT for
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CBT in Patients with Chronic Fatigue
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DOI: 10.1159/000438867
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CFS) or had a clinical reason for exclusion (i.e. they re-
ceived specifically tailored interventions because they
were already unsuccessfully treated with individual CBT
for CFS outside our clinic or were between 18 and 21
years of age and the family had to be involved in the ther-
apy). Of the 328 patients who were asked to engage in
group therapy, 99 (30%) patients indicated that they were
unwilling to receive group therapy. In 25 patients, the rea-
son for refusal was not recorded. Two hundred and four
patients were randomly allocated to one of the three trial
conditions. Baseline characteristics of the study sample
are presented in table1 . In total, 34 (17%) patients were
lost to follow-up. Of the remaining 170 patients, 1 patient
had incomplete primary outcome data and 6 patients had
incomplete secondary outcome data.
In the intervention group, 4 patients had less than 4
additional symptoms at the baseline assessment, 2 pa-
tients were diagnosed with a medical condition during
the trial accounting for the complaints and received ad-
ditional therapy tailored to their needs, 2 patients dis-
closed a dispute over a disability pension, and 1 patient
received individual CBT for CFS. In the waiting list con-
485 patients with CFS were
assessed for eligibility following
routine assessments at our clinic
(baseline assessment)
136 included in analysis
68 assigned to receive intervention
in large group of 8 patients
60 received CBT as assigned
1 received wrong intervention
7 did not start intervention
5 discontinued intervention
68 assigned to receive intervention
in small group of 4 patients
60 received CBT as assigned
8 did not start intervention
13 discontinued intervention
204 randomised
157 excluded
60 declined treatment at our clinic
88 already asked to participate in research
incompatible with group therapy
9 clinical reason for exclusion
124 refused to participate
99 preferred individual therapy
25 unrecorded
328 asked to participate in trial
68 assigned to waiting list
2 received intervention
68 included in analysis
Reassessment scheduled at least 6 months after baseline assessment following the intervention or waiting period
10 lost to follow-up 16 lost to follow-up 8 lost to follow-up
Fig. 1. Trial profile.
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dition, 3 patients had less than 4 additional symptoms, 1
patient had a score of less than 700 on the SIP at baseline
assessment, and 2 patients received individual CBT for
CFS. Ten patients of the waiting list and 1 patient of the
intervention group were prematurely reassessed 4 or
5months after the baseline assessment. In total, 18 pa-
tients discontinued the intervention including 5 patients
from the large group condition with a median number of
6 attended sessions (range 1–8) and 13 patients from the
small group condition with a median number of 7 attend-
ed sessions (range 1–11). Following the intention-to-treat
principle, we did not exclude cases with protocol devia-
tions from our primary analysis.
The mean time between baseline and second assess-
ment was 6.2 months (SD= 0.9) in the control condition
and 12.0 months (SD= 2.4) in the intervention group.
This difference in assessment duration was significant
(p< 0.001) and was mainly due to the fact that the start of
the therapy groups had to be frequently postponed be-
cause of an irregular patient flow and limited treatment
capacities for group therapy at our clinic. In accordance
with the treatment manual, the second assessment was
postponed until the fourteenth group session was accom-
plished. The mean time between the last group session
and the second assessment was 3.3 weeks (SD = 3.5).
Based on the respective reference group, imputation of
missing data for our primary analysis included a mean
proportion of 6% improvement from the baseline assess-
ment for patients from the waiting list and patients who
did not start with treatment and an 18% improvement for
the remaining patients from the intervention condition.
We found significant effects in favour of the interven-
tion group in comparison with the control group on all
outcome measures in our primary analysis ( table2 ). Stan-
Table 1. Baseline characteristics of the study sample (n= 204)
Intervention Waiting list
large group small group total group
Number 68 68 136 68
Age, years 36.4 (11.6) 39.9 (11.3) 38.1 (11.5) 37.3 (10.8)
Female, n 51 (75%) 50 (74%) 101 (74%) 56 (82%)
Illness duration, years 8.6 (9.5) 7.6 (9.7) 8.1 (9.6) 10.0 (10.6)
Number of additional symptoms 7.09 (1.9) 6.72 (1.9) 6.90 (1.9) 7.04 (2.0)
Fatigue severity (CIS) 51.4 (4.8) 50.5 (4.5) 50.9 (4.7) 49.9 (4.8)
Overall Impairment (SIP) 1,518 (471) 1,590 (591) 1,554 (533) 1,495 (453)
Physical functioning (SF-36) 57.3 (17.8) 53.6 (19.6) 55.4 (18.8) 60.0 (20.0)
Psychological distress (SCL-90) 162 (31.1) 171 (42.3) 166 (37.3) 159 (38.3)
Scores are means with standard deviations in parentheses unless otherwise indicated. Additional symptoms
had to be present for at least 6 months. SCL-90= Symptom Checklist 90.
Table 2. Effects of the intervention on primary and secondary outcome measures based on the intention-to-treat
principle (n= 204)
Intervention
(n= 136)
Waiting list
(n= 68)
Treatment effect Cohen’s d
Fatigue severity 33.5 (13.6) 46.6 (8.5) –13.8 [–17.2 to –10.3] –1.08 [–1.38 to –0.77]
Overall impairment 800 (664) 1,389 (561) –623 [–788 to –458] –0.93 [–1.23 to –0.62]
Physical functioning 74.4 (22.0) 63.3 (21.1) 14.1 [9.0 to 19.3] 0.51 [0.22 to 0.81]
Psychological distress 135 (32.0) 153 (38.5) –22.1 [–29.9 to –14.4] –0.52 [–0.82 to –0.23]
Scores are means with standard deviations in parentheses at the second assessment unless otherwise indi-
cated; figures in square brackets indicate 95% confidence intervals. All treatment effects are significant at p<
0.001 (adjusted for the baseline score of the outcome measure). Missing data were imputed using mean propor-
tions of improvement based on the outcome scores of similar patients with a second assessment.
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CBT in Patients with Chronic Fatigue
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DOI: 10.1159/000438867
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dardised mean differences (Cohen’s d ) ranged between
large effect sizes for improvement on fatigue severity and
overall impairment and medium effect sizes for improve-
ment on physical functioning and psychological distress.
Effects remained significant in our sensitivity analysis, re-
sulting in 20–25% larger effects in the multiple imputa-
tion scenario and 5–9% smaller effects in the conservative
imputation scenario than in our primary analysis (data
not shown). We also conducted per-protocol analysis by
excluding 25 patients with deviations from the protocol
using the imputation scenario of the primary analysis.
This analysis also produced significant treatment effects
in favour of the group intervention (data not shown).
Based on the finding that the mean time between the
assessments was about twice as long in the intervention
condition, we repeated our analyses of covariance for the
primary outcome measures by adjusting for the covari-
ates illness duration and assessment duration. We used
data from patients who completed the second assessment
for this analysis and found significant and stable treat-
ment effects of –15.8 (from –22.2 to –9.4; p 0.001) for
fatigue severity, –660 (from –962 to –359; p 0.001) for
overall impairment and 14.8 (5.2–24.4; p = 0.003) for
physical functioning. The covariates illness duration (p>
0.40) and assessment duration (p> 0.20) did not yield
significance in this analysis. In addition, we computed
Pearson’s correlation coefficients of the potential con-
founders illness duration and assessment duration with
the primary outcome measures of our study in the inter-
vention and in the control condition. None of these cor-
relation coefficients was significant ( table3 ).
Subgroup analysis included separate testing of the ef-
fects of the intervention on all primary outcome measures
for the large and the small therapy group condition
against the waiting list condition using Bonferroni cor-
rection for multiple testing. These tests resulted in sig-
nificant effects for both group sizes ( table4 ). Cluster ef-
fects were tested in the small group condition using gen-
eral linear models with therapist as random effect which
did not yield significance (data not shown). We did not
Table 4. Subgroup analysis of the effects of the intervention on primary outcome measures (n= 204)
Intervention condition Treatment effect
large group
(n= 68)
small group
(n= 68)
large group vs.
waiting list
small group vs.
waiting list
Fatigue severity 33.7 (13.8) 33.4 (13.5) –13.9 [–18.7 to –9.0] –13.6 [–18.5 to –8.7]
Overall impairment 744 (696) 856 (629) –658 [–891 to –425] –587 [–821 to –354]
Physical functioning 77.4 (20.6) 71.3 (23.0) 15.9 [8.6 to 23.2] 12.3 [5.0 to 19.6]
Scores are means with standard deviations in parentheses at the second assessment unless otherwise indi-
cated; figures in square brackets indicate 95% confidence intervals. All treatment effects are significant at p<
0.001 using Bonferroni correction for multiple testing and adjustment for the baseline score of the outcome mea-
sure. Missing data were imputed using mean proportions of improvement based on the outcome scores of simi-
lar patients with a second assessment.
Table 3. Pearson’s correlation coefficients (with p values in parentheses) of the potential confounders assessment
duration and illness duration with the primary outcome measures of the study
Intervention condition Control condition
illness duration
(n= 136)
assessment duration
(n= 110)1
illness duration
(n= 68)
assessment duration
(n= 60)2
Fatigue severity 0.03 (0.71) –0.02 (0.86) 0.01 (0.96) 0.00 (0.98)
Overall impairment –0.06 (0.53) –0.04 (0.71) –0.06 (0.61) –0.09 (0.48)
Physical functioning 0.00 (0.98) 0.09 (0.34) –0.20 (0.10) –0.23 (0.07)
1Twenty-six patients lost to follow-up.
2Eight patients lost to follow-up.
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test cluster effects in the large group condition due to the
numerous combinations of individual therapists. In our
post hoc analysis, we tested differences in improvement
and recovery rates between the intervention and the wait-
ing list group. We found significantly higher improve-
ment and recovery rates in the intervention condition
than in the control group ( table5 ). The only patient who
reached criteria for recovery on all primary outcome
measures in the control group had received CBT for CFS
during the waiting list period. Both, subgroup and post
hoc analysis, were based on the imputation scenario of the
primary analysis.
Discussion
In this study, we present the largest RCT to date testing
the efficacy of group CBT for patients with CFS. We
found consistent treatment effects on all outcome mea-
sures in favour of the intervention group which remained
significant in sensitivity and per-protocol analyses. In ad-
dition, sensitivity analysis suggested that the imputation
scenario for our primary analysis was unlikely to overrate
treatment effects. In a meta-analysis which previously
evaluated the effect size of group CBT for CFS, a stan-
dardised mean difference in fatigue after treatment of
–0.30 (95% confidence interval –0.60 to 0.00) was report-
ed
[1] . Since the confidence interval of the standardised
mean difference (Cohen’s d ) in fatigue found in our trial
does not overlap the confidence interval of the meta-anal-
ysis, we may conclude that group therapy for CFS can be
significantly more effective than currently reported.
Results from our post hoc analysis showed that about
40–50% of the intervention group reached criteria for clin-
ically significant improvement. Still about 15% reached
rigorous criteria for normal functioning on all primary
outcome measures. These findings are generally in line
with current studies focusing on improvement and recov-
ery following CBT for CFS
[7, 24, 25] . In the control group,
in contrast, few patients reached criteria for improvement,
and virtually none reached criteria for recovery, which is
in line with prognostic research on CFS
[26] . Our findings
also suggest that groups with 4 patients are an effective al-
ternative for groups with 8 patients, which should help to
increase the flexibility of the group size for implementation
of the intervention outside academic settings. Although we
did not test differences statistically to avoid type II error,
the amount of beneficial change was at least as high in the
large as compared to the small group condition. Based on
these findings, there is thus no reason to prefer small
groups when enough patients for a large group are avail-
able. Instead, in future trials the number of patients could
even be further increased to experiment with the maxi-
mum capacity that is adequate for the delivery of group
CBT for CFS. Such experimentation might have vital im-
plications for the cost-efficiency of the group intervention.
We attribute the favourable results of the group inter-
vention in this trial to the advancement of the therapy
manual compared to our previous work
[4] . This ad-
vancement includes communicating recovery as attain-
able goal of the intervention and inviting patients to give
feedback to fellow patients about cognitive and behav-
ioural changes. These aspects may have better stimulated
an increase in perceived control over the symptoms which
has been shown to be linked to improvement in individ-
ual CBT for CFS
[27] . Other benefits of the group inter-
vention are imaginable which may have facilitated a re-
duction in symptomatology. Patients may find it easier to
change by observing how other patients change rather
than by just talking about their own process. This aspect
Table 5. Improvement and recovery rates based on the intention-to-treat principle (n= 204)
Intervention
(n= 136)
Waiting list
(n= 68)
Odds ratio 95% CI
Improvement
Fatigue severity 67 (49.3%) 6 (8.8%) 10.0 4.1–24.8
All primary outcomes 52 (38.2%) 2 (2.9%) 20.4 4.8–87.0
Normal functioning
Fatigue severity 44 (32.4%) 2 (2.9%) 15.8 3.7–67.4
All primary outcomes 21 (15.4%) 1 (1.5%) 12.2 1.6–93.0
All differences are significant at p< 0.001. Missing data were imputed using mean proportions of improve-
ment based on the outcome scores of similar patients with a second assessment. CI= Confidence interval.
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CBT in Patients with Chronic Fatigue
Syndrome
Psychother Psychosom 2015;84:368–376
DOI: 10.1159/000438867
375
may be of particular importance in the context of CFS
because some patients continue to attribute their symp-
toms to a somatic cause despite medical reassurance that
such a cause is unlikely. Such an attribution is usually ac-
companied by ambivalence with respect to the adequate
management of their condition and can lead to stagna-
tion and therapy drop-out. Seeing that fellow patients ac-
tually improve during the course of the therapy might be
a powerful challenge to their perception of the condition.
Patients may also accept feedback from the group which
they may not have tolerated from their therapist in indi-
vidual treatment. Such a feedback from the group may
help to address important issues in a straightforward
manner and stimulate a unique therapeutic process from
which all group members can profit. Finally, the recogni-
tion and support from fellow group members may help
patients to participate in a therapeutic process which can
be confronting and demanding. Additional research is
needed to test these and other hypotheses about the (so-
cial) mechanisms which underlie the efficacy of group
therapy for patients with CFS.
Our study has several potential limitations. First of all,
the start of the therapy groups had to be frequently post-
poned which delayed the second assessment in the inter-
vention condition. This delay may have inflated treatment
effects by giving patients of the intervention condition
more time to improve. However, since most of the delay
was caused before patients started with the intervention in
our trial, such a bias would contradict prognostic research
[26] which showed that spontaneous improvement with-
out specific intervention is unusual in CFS patients. Con-
sistently, we did not find a meaningful relationship be-
tween time (i.e. assessment duration and illness duration)
and the effect of the intervention in our analyses.
Another potential bias of this study is the fact that our
control condition was based on a waiting list for individ-
ual therapy. This fact may also have resulted in an infla-
tion of the therapy effects in our trial in comparison with
trials using treatment as usual as control condition. How-
ever, a systematic evaluation of CBT for CFS trials showed
that trials which used treatment as usual as control condi-
tion generally produced larger effects in the intervention
condition than trials using a waiting list control condition
[1] . The drop-out rate of our trial is thereby in line with
previous RCTs focusing on CBT for CFS
[1] .
Finally, patients from the waiting list received indi-
vidual CBT for CFS after the second assessment in our
study so that no controlled follow-up data were available
to determine whether the effect of the group interven-
tion was sustained over time. Studies about the long-
term effects of CBT for CFS are generally scarce. This
aspect needs to be addressed in future trials. Based on
the findings of the present study, such trials could di-
rectly compare the efficacy of group versus individual
CBT for CFS. Such a comparison could be realised as
superiority trial in which the efficacies of the group and
the individual treatment are compared in terms of clin-
ical outcomes (i.e. fatigue and disabilities) and in terms
of the costs of the intervention. In a parallel group de-
sign similar to that of our trial, different group sizes (e.g.
with up to 16 patients) could be compared with indi-
vidual therapy.
In conclusion, findings from the largest RCT to date
focusing on group CBT for CFS suggest that patients with
CFS can be treated effectively in groups. These findings
should help to resolve existing ambiguities concerning
the efficacy of group CBT for CFS.
Disclosure Statement
There are no conflicts of interest.
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... These 14 studies included a total of 2094 patients (intervention: n ¼ 1134; control: n ¼ 960 (of whom n ¼ 162 were attentionmatched controls)). The participants comprised 1864 adults (average age (mean (standard deviation (SD)) ¼ 42.6 (4.2) years, average illness duration 6.7 (3.4) years; 78% female) [9,12,38-49] and 230 adolescents (average age 14.3 (1.8) years, average illness duration 0.95 (0.63) years; 81% female) [9, 12,[38][39][40][41][42][43][44][45][46][47][48][49]. ...
... The health professionals who delivered the interventions included nurses [12,38,40,43], cognitive behavioural therapists [9, 44,48,49], psychologists [12,45,46], occupational therapists [12], clinical psychologists [12], child therapists [39], paediatric psychotherapist [41], social workers [45] and a therapist with a degree in pedagogy [45]. Only five studies specifically trained the therapists in delivery of CBT for participants with CFS [9, 40,44,45,48,49]. ...
... The health professionals who delivered the interventions included nurses [12,38,40,43], cognitive behavioural therapists [9, 44,48,49], psychologists [12,45,46], occupational therapists [12], clinical psychologists [12], child therapists [39], paediatric psychotherapist [41], social workers [45] and a therapist with a degree in pedagogy [45]. Only five studies specifically trained the therapists in delivery of CBT for participants with CFS [9, 40,44,45,48,49]. ...
Article
Purpose: To investigate whether activity pacing interventions (alone or in conjunction with other evidence-based interventions) improve fatigue, physical function, psychological distress, depression, and anxiety in people with chronic fatigue syndrome (CFS). Materials and methods: Seven databases were searched until 13 August 2022 for randomised controlled trials that included activity pacing interventions for CFS and a validated measure of fatigue. Secondary outcomes were physical function, psychological distress, depression, and anxiety. Two reviewers independently screened studies by title, abstract and full text. Methodological quality was evaluated using the PEDro scale. Random-effects meta-analyses were performed in R. Results: 6390 articles were screened, with 14 included. Good overall study quality was supported by PEDro scale ratings. Activity pacing interventions were effective (Hedges' g (95% CI)) at reducing fatigue (-0.52 (-0.73 to -0.32)), psychological distress (-0.37 (-0.51 to -0.24)) and depression (-0.29 (-0.49 to -0.09)) and improving physical function (mean difference 7.18 (3.17-11.18)) when compared to no treatment/usual care. The extent of improvement was greater for interventions that encouraged graded escalation of physical activities and cognitive activities. Conclusion: Activity pacing interventions are effective in reducing fatigue and psychological distress and improving physical function in CFS, particularly when people are encouraged to gradually increase activities. Registration: PROSPERO CRD42016036087. IMPLICATIONS FOR REHABILITATIONA key feature of chronic fatigue syndrome (CFS) is a prolonged post-exertional exacerbation of symptoms following physical activities or cognitive activities.Activity pacing is a common strategy often embedded in multi-component management programs for CFS.Activity pacing interventions are effective in reducing fatigue and psychological distress and improving physical function in CFS, particularly when patients are encouraged to gradually increase their activities.Healthcare professionals embedding activity pacing as part of treatment should work collaboratively with patients to ensure successful, individualised self-management strategies.
... Tuina [47] and moxibustion [48]-all of which aim to stimulate or otherwise influence physiological processes (for example, increasing oxidation of the blood). Second, psychological or psycho-spiritual therapies such as cognitive behavioural therapy (CBT) [14,[49][50][51][52][53], behavioural self-regulation [54], operant learning [55] and Three Principles/Innate Health [56] which focus on influencing cognitive processes, building self-awareness and education. Third, physical interventions that require active physical input or participation from the individual, and which may or may not comprise a 'mind-body' component, such as Graded Exercise Therapy (GET) [57][58][59][60][61][62], Oriental Medicine Music Therapy [63], Tai Ji Quan [64] and yoga [65], and finally multi-modal interventions which comprise a either a mixture of the afore-mentioned activities or one or more activities plus pharmacological components [66][67][68][69][70]. ...
... In nine studies, the interventions were delivered solely in community settings such as general and specialist clinics [41,43,46,47,55,58,65,70,72], while a further nine comprised elements of home-based self-management combined with primary or outpatient care [53,54,61,62,64,71,[73][74][75]. Two studies combined primary and secondary/specialist care [51,52], while 11 studies combined secondary/specialist care with outpatient care and laboratory-based assessment [14,38,42,49,50,57,59,60,63,67,68]. Five studies were entirely laboratorybased [40,44,45,48,76], while four studies omitted details of treatment setting [39,56,66,69]. ...
... The intervention that resulted in the largest mean difference in fatigue severity for participants compared to a control was the Three Principles/Innate Health (3P/IH) psycho-spiritual mental health education programme [56] (MD -39.0, 95% CI -51.8 to -26.2, SMD = 1.670) (Fig 2). Interventions employing group-based CBT were also found to result in large reductions in fatigue severity compared to a control (MD -27.5, 95% CI -33.7 to -21.3, SMD = 1.170 [50]; MD -23.7, 95% CI -29.2 to -18.2, SMD = 2.266 [51]). ...
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Objectives Fatigue syndromes have been widely observed following post-viral infection and are being recognised because of Covid19. Interventions used to treat and manage fatigue have been widely researched and this study aims to synthesise the literature associated with fatigue interventions to investigate the outcomes that may be applicable to ‘long Covid’. Method The study was registered with PROSPERO (CRD42020214209) in October 2020 and five electronic databases were searched. Papers were screened, critically appraised and data extracted from studies that reported outcomes of fatigue interventions for post-viral syndromes. The narrative synthesis includes statistical analysis associated with effectiveness and then identifies the characteristics of the interventions, including identification of transferable learning for the treatment of fatigue in long Covid. An expert panel supported critical appraisal and data synthesis. Results Over 7,000 research papers revealed a diverse range of interventions and fatigue outcome measures. Forty papers were selected for data extraction after final screening. The effectiveness of all interventions was assessed according to mean differences (MD) in measured fatigue severity between each experimental group and a control following the intervention, as well as standardised mean differences as an overall measure of effect size. Analyses identified a range of effects–from most effective MD -39.0 [95% CI -51.8 to -26.2] to least effective MD 42.28 [95% CI 33.23 to 51.34]–across a range of interventions implemented with people suffering varying levels of fatigue severity. Interventions were multimodal with a range of supportive therapeutic methods and varied in intensity and requirements of the participants. Those in western medical systems tended to be based on self- management and education principles (i.e., group cognitive behavioural therapy (CBT). Conclusion Findings suggest that the research is highly focussed on a narrow participant demographic and relatively few methods are effective in managing fatigue symptoms. Selected literature reported complex interventions using self-rating fatigue scales that report effect. Synthesis suggests that long Covid fatigue management may be beneficial when a) physical and psychological support, is delivered in groups where people can plan their functional response to fatigue; and b) where strengthening rather than endurance is used to prevent deconditioning; and c) where fatigue is regarded in the context of an individual’s lifestyle and home-based activities are used.
... 15 This finding was supported by 2 subsequent clinical trials for ME/CFS that found evidence for cognitive-behavioral therapy's improving physical functioning. 17,18 There was also strong evidence supporting mindfulness-based therapies for patients with CMI and symptoms consistent with FMS, IBS, or ME/CFS. A clinical trial for patients with FMS found that mindfulnessbased stress reduction reduced functional impairment more than treatment as usual at the end of treatment and at 12-month follow-up. ...
... A systematic review and meta-analysis of RCTs compared the efficacy of rifaximin (550 mg, 3 times a day for 14 days) vs placebo in 2 RCTs involving 1260 participants (625 assigned to rifaximin, 635 assigned to placebo) meeting Rome II criteria for IBSdiarrhea or IBS-mixed. 17 This study found that those randomly assigned to rifaximin were significantly less likely to fail to achieve FDA-defined treatment response and to experience improvements in stool consistency at 12-week follow-up. 38 The CMI CPG makes no recommendation in favor of any pharmacologic agent for the management of CMI and symptoms consistent with ME/CFS but does recommend against the use of stimulants. ...
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In 2019, senior leaders within the US Department of Veterans Affairs and the US Department of Defense commissioned the update of a clinical practice guideline for managing chronic multisymptom illness. Clinical experts were assembled across both agencies to systematically review evidence and to develop treatment recommendations based on that evidence. This effort resulted in the development of 29 evidence-based recommendations for providing care for individuals with chronic multisymptom illness.
... We confirmed the paucity of empirical research on group size and intervention effectiveness by conducting a literature review, which resulted in identification of just seven articles that presented findings related to the association between group size and treatment outcomes. Psychotherapy groups represented in these seven articles included a cognitive behavioral therapy group for chronic pain (Wilson et al., 2018), a group treatment for internet addiction among Korean adolescents (Chun et al., 2017), therapy groups for borderline personality disorder (McLaughlin et al., 2019), a cognitive behavioral therapy group for chronic fatigue (Wiborg et al., 2015), an eating disorder treatment group (Butryn et al., 2014), a divorce support group (Øygard & Hardeng, 2002), and anxiety management training groups that were categorized as either large (i.e., 10-12 members) or very large (i.e., 20 members; Daley et al., 1983). ...
... In a similar vein, Øygard and Hardeng (2002) found that men participating in divorce support groups experienced greater benefits when they were in a group with between five and seven members than when they were in groups of more than eight members, and Daley et al. (1983) found that members of anxiety management training groups with 10-12 members reported significantly greater improvement than those in groups with 20 members. Other studies (e.g., Butryn et al., 2014;Wiborg et al., 2015) found group size was unassociated with intervention effectiveness or did not evidence a consistent association across programs (e.g., Wilson et al., 2018). Taken together, these findings suggest a paucity of empirical investigations of group size as it relates to symptom reduction, and in particular, we were not able to find any empirical tests of optimal group size for trauma treatment groups. ...
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Survivors Healing from Abuse: Recovery through Exposure (SHARE) is an eight-week therapy group for incarcerated women who have experienced sexual violence victimization. SHARE requires each member to complete an imaginal exposure and to listen when others share their experiences of victimization. While trauma-focused group interventions including SHARE are associated with reductions in internalizing symptoms, little work has examined how group characteristics predict symptom decreases. The purpose of this study was to examine whether group size was associated with symptom changes pre- to post-treatment. Participants (n=140 across 29 groups) completed self-report measures of posttraumatic stress symptoms before and after completing SHARE. Multilevel modeling revealed the majority of the variance in post-treatment symptoms was attributed to individual factors rather than group factors. Symptom change was comparable for groups of two to eight women; declines in symptom improvement were observed at a group size of ten participants.
... The weighted subscale score ranges from 0 to 100, with a higher score indicating less limitations. A score of ≤ 65 is indicative of substantial limitations in physical functioning [63]. The SF-36 is a reliable and valid instrument [64]. ...
... Although a duration of 6 months is generally used to define chronic fatigue, this cut-off is somewhat arbitrary. Also in cases where fatigue is present since 12 months after COVID-19 it can be considered as a relatively short duration compared to previous intervention studies where patients have been included with an average fatigue duration up to 5 years [29,63]. ...
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Full-text available
Background Coronavirus disease 2019 (COVID-19) results in debilitating long-term symptoms, often referred to as Post-Acute Sequelae of SARS-CoV-2 Infection (PASC), in a substantial subgroup of patients. One of the most prevalent symptoms following COVID-19 is severe fatigue. Prompt delivery of cognitive behavioural therapy (CBT), an evidence-based treatment that has shown benefit in reducing severe fatigue in other conditions, may reduce post-COVID-19 fatigue. Based on an existing CBT protocol, a blended intervention of 17 weeks, Fit after COVID , was developed to treat severe fatigue after the acute phase of infection with SARS-CoV-2. Method The ReCOVer study is a multicentre 2-arm randomised controlled trial (RCT) to test the efficacy of Fit after COVID on severe post-infectious fatigue. Participants are eligible if they report severe fatigue 3 up to and including 12 months following COVID-19. One hundred and fourteen participants will be randomised to either Fit after COVID or care as usual (ratio 1:1). The primary outcome, the fatigue severity subscale of the Checklist Individual Strength (CIS-fatigue), is assessed in both groups before randomisation (T0), directly post CBT or following care as usual (T1), and at follow-up 6 months after the second assessment (T2). In addition, a long-term follow-up (T3), 12 months after the second assessment, is performed in the CBT group only. The primary objective is to investigate whether CBT will lead to a significantly lower mean fatigue severity score measured with the CIS-fatigue across the first two follow-up assessments (T1 and T2) as compared to care as usual. Secondary objectives are to determine the proportion of participants no longer being severely fatigued (operationalised in different ways) at T1 and T2 and to investigate changes in physical and social functioning, in the number and severity of somatic symptoms and in problems concentrating across T1 and T2. Discussion This is the first trial testing a cognitive behavioural intervention targeting severe fatigue after COVID-19. If Fit after COVID is effective in reducing fatigue severity following COVID-19, this intervention could contribute to alleviating the long-term health consequences of COVID-19 by relieving one of its most prevalent and distressing long-term symptoms. Trial registration Netherlands Trial Register NL8947 . Registered on 14 October 2020.
... At referral, all patients were screened by a consultant of the outpatient clinic of the department of Internal Medicine of the hospital, to confirm if patients met CDC criteria for CFS/ME [18]. In accordance with existing literature [19,20], presence of severe fatigue was operationalized as having a fatigue severity score of ≥35 of the Checklist Individual Strength (CIS; [19]) and substantial disability by a score of ≥700 on the Sickness Impact Profile-8 (SIP8; [21]). ...
Article
Full-text available
Objective This study aimed to explore the associations between cognitions, behaviours and affects and fatigue in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME), and their relation to reduction of fatigue after cognitive behaviour therapy (CBT). Methods In CFS/ME patients, 22 behaviours, cognitions and affects, potentially perpetuating fatigue were registered 5 times a day using ecological momentary assessment (EMA) and an actigraphy. Simultaneous Components Analysis (SCA) was used to identify components of perpetuation, that were tested for their associations with fatigue in multilevel vector autoregressive (VAR) modelling. Fatigue severity was measured pre- and posttreatment with the Checklist Individual Strength. The relationship between perpetuation (the strength and direction of the possible associations between fatigue and the components) and therapy outcome was investigated. Results 58 patients met inclusion criteria (m age = 36.5; 65.5% female) and data of 50 patients were analysed in the multilevel analysis. Two perpetuating components were found: “psychological discomfort” and “activity”. For the total group, both perpetuating components did not predict fatigue on a following time-point. For individual patients the strength and direction of the associations varied. None of the associations between perpetuating components and fatigue significantly predicted treatment outcome. Conclusion Results suggest that there is heterogeneity in perpetuation of fatigue in CFS/ME. Investigating fatigue and perpetuators on an individual rather than group level could lead to new insights.
... Caveats and cautions. The subjective fatigue (also called fatigue severity) subscale of the CIS has been the most widely used in the field of CFS (75,(77)(78)(79). Because this subscale asks general questions about fatigue with responses such as "I feel tired" or "I feel weak," patients with CFS often score close to the maximum score (56). ...
... The CBT framework for addressing fatigue and sleep disturbance was adapted from previous treatment manuals for Chronic Fatigue Syndrome and insomnia, with further modifications made to its content and delivery [27,28]. To account for possible cognitive impairments frequently encountered in schizophrenia, a specific focus was made on implementing cognitive strategies (e.g., preventing information overload, memory aids, timepressure management), specific napping schedules, and re-organizing activity levels as a means of energy conservation in addition to pacing and graded activity exposure. ...
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This systematic review investigated randomized controlled trials evaluating cognitive behav-ioral therapy (CBT) and graded exercise therapy (GET) for adults with chronic fatigue syndrome (CFS). The objective was to determine prognosis following treatment. Studies were eligible if they were peer-reviewed and investigated treatment at least 12 weeks in duration. Studies were excluded if they used co-morbid diagnoses as entry criteria or if they did not measure fatigue, disability, or functioning. Literature published between 1988 and 2021 was searched using MEDLINE, EMBASE, PsycINFO, and Web of Science. Study quality was assessed using the Effective Public Health Practice Project assessment tool. Outcomes were synthesized when three or more studies reported outcomes obtained from the same validated measurement tool. The review included 15 publications comprising 1990 participants. Following CBT, and at short-term to medium-term follow-up, 44% considered themselves better and 11% considered themselves worse. Following GET, and at post-treatment to short-term follow-up, 43% considered themselves better and 14% considered themselves worse. These outcomes were 8-26% more favorable compared to control conditions. Two-thirds of studies were of moderate quality and the remainder were of weak quality. Limitations of this review relate to the clinical heterogeneity of studies and that most outcomes were self-reported. Results suggest some support for the positive effects of CBT and GET at short-term to medium-term follow-up although this requires further investigation given the inconsistent findings of previous reviews. Findings may not be generalizable to severe CFS. This review was registered with PROSPERO (CRD42018086002).
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[Clin Psychol Sci Prac 18: 311–324, 2011] Several reviews have concluded that graded exercise therapy (GET) and cognitive behavioral therapy (CBT) may be the most efficacious treatments for chronic fatigue syndrome (CFS). The current review extends the evidence for overall and outcome-specific effects of CBT and GET by directly comparing the treatments and addressing the methodological limitations of previous reviews. GET (n = 5) and CBT (n = 16) randomized controlled trials were meta-analyzed. Overall effect sizes suggested that GET (g = 0.28) and CBT (g = 0.33) were equally efficacious. However, CBT effect sizes were lower in primary care settings and for treatments offering fewer hours of contact. The results suggested that both CBT and GET are promising treatments for CFS, although CBT may be a more effective treatment when patients have comorbid anxiety and depressive symptoms.
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• The complexities of the chronic fatigue syndrome and the methodologic problems associated with its study indicate the need for a comprehensive, system­ atic, and integrated approach to the evaluation, classi­ fication, and study of persons with this condition and other fatiguing illnesses. We propose a conceptual framework and a set of guidelines that provide such an approach. Our guidelines include recommendations for the clinical evaluation of fatigued persons, a revised case definition of the chronic fatigue syndrome, and a strategy for subgrouping fatigued persons in formal investigations.
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