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

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1 Regular Article Received: March 21, 2015 Accepted after revision: July 20, 2015 Published online: September 25, 2015 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 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) 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. 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 interven- 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 importance for settings in which large treatment groups are not feasible due to limited referral S. Karger AG, Basel Introduction According to recent meta-analyses [1 3], cognitive behaviour therapy (CBT) is an evidence-based intervention for the treatment of individual patients with chronic fatigue syndrome (CFS) that leads to moderate improvement of fatigue and disabilities. There are also approaches 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-analyses. 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] karger@karger.com S. Karger AG, Basel /15/ $39.50/0 Dr. Hans Knoop Expert Centre for Chronic Fatigue Radboud University Medical Center, PO Box 9101 NL 6500 HB Nijmegen (The Netherlands) radboudumc.nl

2 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 difference in available studies cannot explain these contrasting 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 clinical 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 remain 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 referred for treatment in community-based settings can be substantially lower than in academic settings [7]. To increase the flexibility of the group size for an implementation of the group intervention outside academic settings, we decided to also deliver treatment in groups of 4 patients and 1 therapist and tested the efficacy of the different 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 assessment 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 receive 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 intervention 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 org, No. ISRCTN Participants All patients were referred to our outpatient clinic for the management 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 accordance with the US Centers for Disease Control [9], CFS was defined 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 Checklist 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 disability pension were temporarily excluded from the trial [4]. The Department of Internal Medicine at the Radboud University Medical Center assessed the medical examination status of all patients and decided whether patients had been sufficiently examined 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 Internal Medicine prior to referral to our outpatient clinic. In accordance with recommendations by the Centers for Disease Control, sufficient medical examination included evaluation of somatic parameters that may provide evidence for a plausible somatic explanation 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 Medicine 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 unstructured 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 intervention 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 setting, fixing sleep-wake cycles, reducing the focus on bodily symptoms, 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 communicated recovery in terms of fatigue and disabilities as general goal of the intervention [14]. CBT in Patients with Chronic Fatigue Syndrome 369

3 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 individual 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 research group [4, 7, 11, 14]. Our fatigue assessment was complemented by additional questions about other clinical features relevant 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 functioning subscale of the Short Health Survey 36 (SF-36) [16]. Scores on this scale range from 0 (worst possible functioning) to 100 (optimal 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 based on the two different kinds of the primary outcomes fatigue and disabilities. We assumed 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 covariance 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 considered 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 research protocol of the study, we followed the recommendations by White et al. [23] for the evaluation of randomised trials with missing data. In our primary analysis, we imputed missing data using mean proportions of improvement which were based on the primary outcome scores of similar patients from the study. For patients with missing data from the waiting list and for patients with missing data who did not start treatment, the reference group consisted of those patients from the waiting list who attended the second 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 measures of the primary analysis. The first approach was multiple imputation using fully conditional specification with three imputations based on the assumption that data were missing at random. The second approach was based on a conservative imputation scenario in which we again used the mean proportion of improvement of the reference group to impute missing scores for patients from the waiting list but assumed that all patients from the intervention 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 previous findings [18, 19]. Since some studies have reported that a significant minority of patients recovered from CFS following individual CBT, we decided to conduct a post hoc analysis examining rates of clinically significant 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 combination with a SIP overall impairment score of <700 [7]. Our definition 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 intervention and control group were tested using Fisher s exact test. Analyses were carried out using IBM SPSS statistics 20. The researcher 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 hundred and fifty-seven patients were excluded from the trial because they declined treatment at our clinic, were already asked to participate in research incompatible with inclusion (e.g. research focusing on individual CBT for 370 Wiborg/van Bussel/van Dijk/Bleijenberg/ Knoop

4 485 patients with CFS were assessed for eligibility following routine assessments at our clinic (baseline assessment) 157 excluded 60 declined treatment at our clinic 88 already asked to participate in research incompatible with group therapy 9 clinical reason for exclusion 328 asked to participate in trial 124 refused to participate 99 preferred individual therapy 25 unrecorded 204 randomised 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 68 assigned to waiting list 2 received intervention 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 136 included in analysis 68 included in analysis Fig. 1. Trial profile. CFS) or had a clinical reason for exclusion (i.e. they received 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 therapy). 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 reason 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 patients were diagnosed with a medical condition during the trial accounting for the complaints and received additional therapy tailored to their needs, 2 patients disclosed a dispute over a disability pension, and 1 patient received individual CBT for CFS. In the waiting list con- CBT in Patients with Chronic Fatigue Syndrome 371

5 Table 1. Baseline characteristics of the study sample (n = 204) Intervention large group small group total group Waiting list Number 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 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 indicated; figures in square brackets indicate 95% confidence intervals. All treatment effects are significant at p < (adjusted for the baseline score of the outcome measure). Missing data were imputed using mean proportions of improvement based on the outcome scores of similar patients with a second assessment. 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 patients 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 attended sessions (range 1 11). Following the intention-to-treat principle, we did not exclude cases with protocol deviations from our primary analysis. The mean time between baseline and second assessment 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 because 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 accomplished. 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 assessment 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 intervention group in comparison with the control group on all outcome measures in our primary analysis ( table 2 ). Stan- 372 Wiborg/van Bussel/van Dijk/Bleijenberg/ Knoop

6 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 illness duration (n = 136) Control condition assessment duration (n = 110) 1 illness duration 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. Table 4. Subgroup analysis of the effects of the intervention on primary outcome measures (n = 204) Intervention condition Treatment effect large group small group 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 indicated; figures in square brackets indicate 95% confidence intervals. All treatment effects are significant at p < using Bonferroni correction for multiple testing and adjustment for the baseline score of the outcome measure. Missing data were imputed using mean proportions of improvement based on the outcome scores of similar patients with a second assessment. dardised mean differences (Cohen s d ) ranged between large effect sizes for improvement on fatigue severity and overall impairment and medium effect sizes for improvement on physical functioning and psychological distress. Effects remained significant in our sensitivity analysis, resulting in 20 25% larger effects in the multiple imputation 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 covariates illness duration and assessment duration. We used data from patients who completed the second assessment for this analysis and found significant and stable treatment 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 ( ; 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 confounders illness duration and assessment duration with the primary outcome measures of our study in the intervention and in the control condition. None of these correlation coefficients was significant ( table 3 ). Subgroup analysis included separate testing of the effects of the intervention on all primary outcome measures for the large and the small therapy group condition against the waiting list condition using Bonferroni correction for multiple testing. These tests resulted in significant effects for both group sizes ( table 4 ). Cluster effects were tested in the small group condition using general linear models with therapist as random effect which did not yield significance (data not shown). We did not CBT in Patients with Chronic Fatigue Syndrome 373

7 Table 5. Improvement and recovery rates based on the intention-to-treat principle (n = 204) Intervention (n = 136) Waiting list Odds ratio 95% CI Improvement Fatigue severity 67 (49.3%) 6 (8.8%) All primary outcomes 52 (38.2%) 2 (2.9%) Normal functioning Fatigue severity 44 (32.4%) 2 (2.9%) All primary outcomes 21 (15.4%) 1 (1.5%) All differences are significant at p < Missing data were imputed using mean proportions of improvement based on the outcome scores of similar patients with a second assessment. CI = Confidence interval. 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 waiting list group. We found significantly higher improvement 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 measures in favour of the intervention group which remained significant in sensitivity and per-protocol analyses. In addition, 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 standardised mean difference in fatigue after treatment of 0.30 (95% confidence interval 0.60 to 0.00) was reported [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-analysis, 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 clinically 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 recovery 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 alternative 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 available. Instead, in future trials the number of patients could even be further increased to experiment with the maximum capacity that is adequate for the delivery of group CBT for CFS. Such experimentation might have vital implications for the cost-efficiency of the group intervention. We attribute the favourable results of the group intervention in this trial to the advancement of the therapy manual compared to our previous work [4]. This advancement includes communicating recovery as attainable goal of the intervention and inviting patients to give feedback to fellow patients about cognitive and behavioural 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 individual CBT for CFS [27]. Other benefits of the group intervention are imaginable which may have facilitated a reduction 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 374 Wiborg/van Bussel/van Dijk/Bleijenberg/ Knoop

8 may be of particular importance in the context of CFS because some patients continue to attribute their symptoms to a somatic cause despite medical reassurance that such a cause is unlikely. Such an attribution is usually accompanied by ambivalence with respect to the adequate management of their condition and can lead to stagnation and therapy drop-out. Seeing that fellow patients actually 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 individual 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 recognition 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 (social) 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 postponed which delayed the second assessment in the intervention 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 without specific intervention is unusual in CFS patients. Consistently, we did not find a meaningful relationship between 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 individual therapy. This fact may also have resulted in an inflation of the therapy effects in our trial in comparison with trials using treatment as usual as control condition. However, a systematic evaluation of CBT for CFS trials showed that trials which used treatment as usual as control condition 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 individual 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 intervention was sustained over time. Studies about the longterm 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 directly 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 clinical outcomes (i.e. fatigue and disabilities) and in terms of the costs of the intervention. In a parallel group design similar to that of our trial, different group sizes (e.g. with up to 16 patients) could be compared with individual 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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