Title: Fatigue and psychosocial variables in autoimmune rheumatic disease and chronic

fatigue syndrome: a cross-sectional comparison.

Running head: Running title: Fatigue in autoimmune rheumatic diseases and CFS.

Abstract

Objective

Fatigue is common in autoimmune rheumatic diseases (ARD). This study compared

symptom-related cognitions, beliefs, behaviours, quality of sleep, lack of acceptance and

distress in participants with ARD such as rheumatoid arthritis(RA), spondyloarthropathy

(SpA), and connective tissue disease (CTD), and participants with chronic fatigue syndrome

(CFS).

Methods

303 participants with RA, SpA, CTD and CFS completed questionnaire measures of fatigue,

social adjustment, cognitive-behavioural responses, lack of acceptance, distress and quality of

sleep. The RA, SpA and CTD groups were first compared with each other. They were then

combined into one group and compared with the CFS group.

Results

There were no statistically significant differences between the RA, SpA or CTD groups for

any of the measures. The CFS group were more fatigued, reported more distress and sleep

disturbance and had worse social adjustment than the ARD group after adjustment for age

and illness duration. After adjustment for fatigue, age, and illness duration, the CFS group

scored more highly on lack of acceptance and avoidance/resting behaviour while the ARD

group showed significantly higher levels of catastrophising, damage beliefs, and symptom

focusing than the CFS group.

1

Conclusion

Fatigue in rheumatic diseases may be perpetuated by similar underlying transdiagnostic

processes. The ARD and CFS groups showed similarities but also key differences in their

responses to symptoms. Specific aspects of treatment may need to be tailored towards each

group. For example, lack of acceptance and avoidance behaviour may be particularly

important in perpetuating fatigue in CFS.

Key words: fatigue, rheumatology, transdiagnostic, cognitive behavioural responses,

acceptance.

Highlights

Patients with ARD show similar cognitive-behavioural responses.

Transdiagnostic treatment approaches may be beneficial for fatigue in ARD.

Lack of acceptance is associated with fatigue severity in CFS and ARD.

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Introduction

Transdiagnostic theory proposes that heterogeneous illnesses share similar underlying

emotional, cognitive and behavioural processes, and that the same treatment can be used

across different diagnoses[1, 2]. This approach can be applied to fatigue in chronic illnesses.

Fatigue is common in the general population, with 18.3% of the general population reporting

substantial fatigue for six months or longer [3]. It is a significant feature of CFS (Chronic

Fatigue syndrome). Fatigue is also a ubiquitous symptom of many chronic diseases [4],

including ARD (autoimmune rheumatic diseases). From a transdiagnostic perspective, the

cognitive and behavioural responses to fatigue may be similar across different rheumatic

diseases and CFS, and may respond to similar treatment approaches regardless of the specific

diagnosis.

CFS is characterised by long-standing fatigue and includes physical and mental symptoms

such as muscle pain and concentration difficulties, which can impact on physical and social

functioning [5, 6]. Moreover, patients often report sleep disturbance and distress [7-10]. In

ARD such as rheumatoid arthritis (RA), seronegative spondyloarthropathies (SpA) and

connective tissue diseases (CTD), fatigue is a pervasive symptom which affects every day

functioning, and has been associated with decreased quality of life and increased disease

burden[11-19]. Fatigue often persists even after disease activity has been managed with

disease-modifying medication[20].

There is some evidence that fatigue in ARD could be associated with cognitive and

behavioural factors. For example, cognitive factors such as self-efficacy and pain

catastrophizing have been shown to correlate with fatigue and distress in both SLE (systemic

lupus erythematosus) [21] and Sjögren's syndrome[22]. In RA a systematic review of

3

psychological correlates of fatigue [23]found evidence that RA-related unhelpful cognitions

such as lower arthritis self-efficacy were associated with higher levels of fatigue [24, 25].

Similarly, research suggests that fatigue in CFS may also be maintained by a complex

interplay of cognitive, behavioural and physiological factors. According to the cognitive-

behavioural model of fatigue in CFS, unhelpful beliefs about physical activity can perpetuate

fatigue severity, and an individual may reduce or avoid certain activities for fear of

worsening symptoms. This can lead to a vicious cycle of negative beliefs about activity,

avoidance of activity, prolonged rest, and worsening symptoms, along with a reinforced

belief that activity is harmful [26, 27]. This model is supported by Petrie et al’s finding that

catastrophic beliefs were associated with worse fatigue and functioning in patients with CFS

[28]. Another view is that lack of acceptance, or a desire to control symptoms, may cause

distress and impaired functioning. Research suggests that a lack of acceptance of symptoms is

associated with higher levels of fatigue and disability, and in turn higher levels of acceptance

are associated with better psychological well-being [29, 30].

We know of only one study to date which has compared the illness-related cognitions of

patients with CFS and those with a rheumatic disease. Moss-Morris and

Chalder[31]compared illness-related cognitions of RA patients with cognitions of patients

with CFS, and found that the patients with CFS had more negative illness beliefs than

patients with RA as well as more negative beliefs about the course and prognosis of their

illness. This may be due to differences in the way that CFS and RA are defined and

diagnosed. For example, rheumatoid arthritis includes objective manifestations of disease

such as joint swelling or damage as well as subjective symptoms such as pain, whereas the

diagnosis of chronic fatigue syndrome relies largely on subjective self-reports of

symptomatology [31]. Patients with CFS report experiencing stigma and scepticism from

4

health professionals, and difficulties with obtaining a diagnosis [32, 33]. Therefore their

experiences may differ from those of RA patients.

In this paper, we suggest that the processes that maintain fatigue in the context of CFS, which

is defined by fatigue, may be similar to the processes that perpetuate fatigue in chronic

diseases such as autoimmune rheumatic diseases (ARD). The purpose of the current study

was to examine the levels of fatigue, disability, distress and sleep problems in participants

with ARD such as RA, CTD and SpA. We also sought to examine the symptom-related

cognitive and behavioural responses of these participants. We hypothesised that there would

be no differences between the three ARD groups on the cognitive and behavioural responses

subscales. Another aim of the study was to compare the fatigue, cognitions and behaviours of

participants with CFS and a heterogeneous group of participants with ARD. It was

hypothesised that the CFS group would show higher levels of fatigue and disability than the

ARD group. Also, given the previous research showing differences between participants with

CFS and RA in terms of illness-related cognitions [31], we hypothesised that participants

with CFS would show more extreme cognitive behavioural responses and a higher lack of

acceptance than participants with ARD.

Methods

Participants and procedure

This cross-sectional questionnaire study compared the questionnaire data of participants with

rheumatoid arthritis (RA), seronegative spondyloarthropathies (SpA) and connective tissue

diseases (CTD). These ARD groups were subsequently compared with a group of participants

with CFS. Data was collected in accordance with the ethical principles of the Declaration of

Helsinki. Data collection for the participants with ARD was approved by the London

5

Dulwich Research Ethics Committee; REC reference number: 10/H0808/135. Collection of

data from the CFS patients was approved by the audit committee of the South London and

Maudsley NHS Foundation Trust. Data collection took place from November 2011 to March

2013.

Autoimmune rheumatic disease groups

Participants with ARD were recruited consecutively from outpatient rheumatology clinics.

They were approached by a rheumatologist or a researcher and invited to participate in the

study. Participants gave written, informed consent. Participants with ARD completed

questionnaires at an outpatient appointment with a rheumatologist. Questionnaires were

completed in the waiting room of the hospital or in the participant’s home. Patients were

diagnosed by a rheumatologist in accordance with accepted diagnostic or classification

criteria, where appropriate [34-39].

Participants were subsequently grouped into three broad categories according to their

clinician-verified diagnosis. The categories were: Rheumatoid Arthritis (RA), Seronegative

Spondyloarthropathy (SpA) and Connective tissue disease (CTD). The SpA group included

the following diagnoses (in order of prevalence): psoriatic arthritis, seronegative

spondyloarthritis (unspecified), enteropathic arthritis, ankylosing spondylitis and reactive

arthritis. The CTD group included the following diagnoses (in order of prevalence):

connective tissue disease (unspecified), systematic lupus erythematosus, myositis, vasculitis,

Behçet's disease and Sjögren's syndrome. Participants were excluded from the analysis if they

did not have a clinician-verified diagnosis, or if their diagnosis did not fit into the categories

of RA, SpA or CTD. Subsequently, participants in the RA, SpA and CTD groups were

combined to form a group of ARD in order to be compared with the CFS group.

6

Chronic Fatigue Syndrome group

Participants with CFS were recruited consecutively from a specialist outpatient clinic for

chronic fatigue syndrome. A medical assessment was undertaken in accordance with NICE

Guidelines[40] to confirm a diagnosis of CFS and rule out other causes of fatigue.

Participants were excluded from the analysis if they did not have a diagnosis of CFS or if

they had a comorbid illness which may account for the fatigue (e.g. bipolar disorder).

Participants completed questionnaires after the specialist assessment by a clinician and prior

to starting treatment for CFS.

Questionnaires

All participants completed questionnaires including the following:

Chalder Fatigue Questionnaire[41, 42]

This is an 11-item scale which measures physical and mental fatigue. It has been validated in

fatigue and CFS. Scores on the 11 items can be summed to calculate a fatigue score out of 33.

A higher score is associated with greater levels of fatigue. It is reliable and valid. Reliability

in this sample, as measured using Cronbach’s alpha, was 0.93 and 0.92 for the CFS and ARD

groups respectively.

Cognitive Behavioural Responses Questionnaire[8, 43, 44]

The cognitive and behavioural responses questionnaire (CBRQ) is a measure of beliefs about

symptoms and behavioural responses to symptoms. It was developed specifically to examine

unhelpful symptom-related beliefs and coping behaviour, for example, avoidance of activity,

symptom focusing, catastrophic thoughts about symptoms, and embarrassment about

symptoms. This questionnaire has been shown to be reliable and valid in patients with CFS

7

and multiple sclerosis [8, 43, 44]. The questionnaire consists of seven subscales. There are

five subscales which measure cognitive responses (fear avoidance, symptom focusing,

catastrophizing, embarrassment avoidance, damage beliefs). There are also two subscales

which measure behavioural responses (avoidance/resting behaviour and all-or-nothing

behaviour). Participants are presented with a series of statements which they are asked to rate

on a scale of 0 (strongly disagree) to 4 (strongly agree). Totals are calculated for each

subscale. Higher scores indicate more extreme beliefs or behavioural responses. Examples of

items from these subscales can be seen in table A1 in the appendix. Examination of internal

consistency showed that the acceptance measure and the subscales of the CBRQ were reliable

in both the CFS and ARD groups (see Table A2 in appendix).

Work and Social adjustment Scale[45, 46]

This is a five-item scale which measures social functioning and social adjustment. Each item

has a maximum score of 8 and the five items summed can give a maximum total score of 40.

A higher score indicates worse social adjustment. It has good reliability and is valid in

patients with CFS [46]. Cronbach’s alpha for the CFS and ARD groups were 0.88 and 0.95

respectively.

Jenkins sleep questionnaire [47]

The Jenkins sleep questionnaire is a measure of sleep disturbance. Four items are combined

to create a total out of 40. A higher score indicates worse sleep disturbance. Cronbach’s alpha

for the CFS and ARD groups were 0.75 and 0.84 respectively.

Hospital Anxiety and Depression Scale [48]

This is a measure of mood, with subscales for anxiety and depression. There are fourteen

items, with seven items for anxiety and seven items for depression. Higher scores indicate 8

more severe anxiety or depression. The scale is reliable and valid. For anxiety, Cronbach’s

alpha for the CFS and ARD groups were 0.88 and 0.86 respectively. For depression,

Cronbach’s alpha for the CFS and ARD groups were 0.85 and 0.86 respectively.

Fatigue acceptance questionnaire [30, 49, 50])

This is a measure of lack of acceptance of fatigue. It is adapted from the pain willingness

subscale of the Chronic Pain Acceptance Questionnaire[49]. In each item, the word pain was

substituted by fatigue. It consists of nine items, which are listed in table A3 in the

supplementary material. Each item is scored on a scale of 0 (never true) to 6 (always true).

The nine items of the scale are summed to create a total score. A higher score indicates a

greater lack of acceptance and less willingness to be in direct confrontation with fatigue

symptoms. Cronbach’s alpha for the CFS and ARD groups were 0.79 and 0.95 respectively.

Statistical analysis

Data were analysed using version 21 of the Statistical Package for the Social Sciences [51].

Examination of the residuals indicated that parametric statistics were appropriate for this

analysis.

For the main analyses, missing data were pro-rated. Therefore if 25% or less of the items

were missing for each scale, a prorated total was calculated which substituted the missing

items with the mean of the remaining items of the scale for the same individual.

Analysis of Covariance (ANCOVA) was used to compare the three ARD illness groups on

CBRQ, fatigue, social adjustment, anxiety, depression, quality of sleep and lack of

acceptance while taking into account the effect of age and illness duration.

9

As previously mentioned, the three ARD groups were combined into one group (ARD) and

compared with the CFS group. Separate one-way ANCOVA analyses were carried out for

fatigue, social adjustment, anxiety, depression, quality of sleep, lack of acceptance and each

of the CBRQ subscales. Age and illness duration were added as covariates, and estimated

marginal means and standard errors were computed.

In order to assess for the potential impact of fatigue, the ANCOVA analyses were repeated

with the inclusion of fatigue as a covariate in addition to the other covariates of age and

illness duration. Bivariate correlations were also carried out in order to assess the relationship

between fatigue and each of the CBRQ subscales as well as lack of acceptance. Bivariate

correlations were also performed to investigate relationships between social adjustment and

CBRQ as well as acceptance. Differences between the correlations were assessed using the

Fisher’s r to Z transformation [52, 53].

10

Results

Demographics

A total of 303 participants were included in the final analysis. The demographic

characteristics of study participants are shown in table 1.

[Insert table 1 here]

Of 232 patients from the rheumatology clinic who were assessed for eligibility for the study,

70 were excluded because they did not have a clinician-verified diagnosis of a disease that

could be classified under the groups of RA, CTD, or SpA. Therefore 162 rheumatology

patients were included in the final analysis. In this group, 56 patients had a diagnosis of RA,

69 had a diagnosis of CTD, and 37 had a diagnosis of SpA.

151 patients from the CFS clinic were assessed for inclusion in the study. Ten of these were

excluded because they did not have a clinician-verified diagnosis of CFS. 141 CFS patients

were included in the final analysis. Patients self-reports of their symptoms indicated that 141

(100%) met NICE[40] criteria for CFS, 87(61.7%) met Oxford criteria for CFS, and 70

(49.6%) met CDC criteria for CFS.

ANCOVA analyses

Table 2 shows the results of one-way ANCOVA analyses comparing the three ARD groups

for all of the questionnaire measures. There were no statistically significant differences

between the groups for any of the measures and the differences between the mean scores

were very small.

11

[Insert table 2 here]

Subsequently, pairwise group comparisons were carried out between the ARD and CFS

groups for each of the measures (see table 3). The CFS group were significantly more

fatigued and had worse social adjustment than the ARD group. The CFS group also had more

sleep and mood problems and a higher lack of acceptance. In addition, the CFS group scored

significantly higher than the ARD group for fear avoidance, embarrassment avoidance, all or

nothing behaviour, and avoidance resting behaviour.

[Insert table 3 here]

The ANCOVA analyses were repeated with fatigue as covariate in addition to age and illness

duration. As seen in Table 4, after adjusting for fatigue, age and illness duration, the CFS

patients still had worse social adjustment and higher lack of acceptance than the ARD

patients. The CFS patients also showed more avoidance/resting behaviour than the ARD

patients. However the difference between the groups for fear avoidance beliefs, anxiety,

depression, embarrassment avoidance and all or nothing behaviour became non-significant.

Also, after this additional adjustment for fatigue, significantly higher levels of

catastrophising, symptom focusing and damage beliefs were seen in the ARD group.

[Insert table 4 here]

Correlation analyses

As seen in Table 5, for the CFS patients, fatigue was correlated with fear avoidance,

catastrophizing, embarrassment avoidance, all or nothing behaviour, avoidance resting

behaviour and lack of acceptance. The correlation coefficients ranged between 0.12 and 0.38.

In the ARD group, fatigue was correlated with all of the CBRQ subscales, with lack of

acceptance and catastrophizing showing the strongest associations with fatigue. Overall the 12

ARD group showed stronger correlations between fatigue and the CBRQ subscale, with

correlation coefficients ranging between .38 and .53. The associations were most pronounced

for fear avoidance, catastrophizing, damage beliefs, symptom focusing, and lack of

acceptance. Similarly, as seen in Table 6, the ARD group showed stronger associations

between social adjustment and the CBRQ subscales as well as lack of acceptance. These

associations were all significantly higher than the CFS group with the exception of all or

nothing behaviour. In the ARD group, lack of acceptance showed the strongest association

with both fatigue and social adjustment.

[Insert tables 5 and 6 here]

Discussion

Summary of findings

This study investigated the symptom-related beliefs and behavioural responses of participants

with ARD such as RA, CTD and SpA, and participants with CFS.

To our knowledge, this is the first study to measure these psychological constructs in a

sample of people with varied rheumatological diagnoses and to show that the results were

similar regardless of the specific diagnosis.

As hypothesised, results showed that the three ARD groups did not differ from each other for

fatigue, social adjustment, sleep, mood, lack of acceptance, or any of the cognitive-

behavioural responses to symptoms. This suggests that patients with heterogeneous diagnoses

of rheumatic disease report similar levels of fatigue, work and social adjustment, sleep

problems, anxiety and depression. They also appear to respond to symptoms similarly.

13

The findings also showed that there were cross cutting concerns in ARD illness groups and

CFS. For example both groups showed statistically significant associations between fatigue

and symptom-related cognitions and behaviours. This finding requires further exploration,

but it may indicate that there are similar underlying processes which are maintaining fatigue

in CFS and ARD, but to differing degrees. Long-term fatigue in both illnesses could be

perpetuated by cognitions such as fear avoidance beliefs and avoidance behaviour.

The groups also showed some differences. In line with hypotheses, participants in the CFS

group reported more fatigue, worse social adjustment, and higher levels of sleep disturbance,

anxiety and depression than the ARD group when adjusting for age and illness duration. In

addition, the CFS group had significantly higher scores than the ARD group for fear

avoidance beliefs, embarrassment avoidance beliefs, all or nothing behaviour, avoidance

resting behaviour and lack of acceptance. When fatigue was added as an additional covariate

to the ANCOVA analysis, the difference between the two groups for avoidance behaviour,

social adjustment and lack of acceptance remained. However, in contrast to hypotheses, the

ARD group showed higher levels of catastrophising, damage beliefs, and symptom focusing

than the CFS group. Also, after this additional adjustment for fatigue there was no longer a

significant difference between groups for anxiety, depression, fear avoidance, embarrassment

avoidance and all or nothing behaviour.

Another key difference between the groups was that the ARD group showed stronger

associations between fatigue severity and symptom-related beliefs and behaviours than the

CFS group. These findings may indicate that fatigue plays a more important role in the

symptom-related cognitions of the ARD group compared to the CFS group. The correlations

between cognitive-behavioural responses and social adjustment were also higher in the ARD

14

group than in the CFS group, suggesting that beliefs need to be targeted in the context of

treatment for fatigue.

Findings in the context of previous literature

In support of previous literature [11, 16, 54] this study confirmed that fatigue is prevalent in

ARD such as RA, SpA and CTD.

These findings add to the previous findings of Moss-Morris and Chalder[31], who showed

that CFS patients had more negative illness beliefs and negative perceptions of illness

consequences compared to RA patients. In this study, CFS patients showed significantly

more avoidance behaviour than the ARD group, and the difference remained significant after

adjustment for fatigue severity. The literature suggests that avoidance may be used as a

coping strategy, with the aim of allowing the patient to exert some control over the

illness[26]. Although this strategy may be useful in terms of alleviating symptoms in the

short term, it may not be helpful in the long term. Avoidance behaviour may be related to

more extreme fear avoidance beliefs. On the other hand, it may also be a consequence of

more severe symptoms of fatigue. As previously mentioned, the diagnosis of CFS is made by

the exclusion of organic pathology, whereas most ARD have objective diagnostic features

such as swollen joints to confirm diagnosis. This gives patients more certainty [31].

However, some of the findings of this study also contrast with those of Moss-Morris and

Chalder [31]. For example, we found catastrophising and damage beliefs were significantly

higher in ARD patients after adjustment for fatigue as well as age and illness duration.

The findings of this study add to the literature in rheumatic disease by demonstrating a link

between fatigue and cognitions [23, 24, 55, 56]. Cognitive-behavioural models of fatigue

assume that a multifaceted and complex relationship exists between cognitions, behaviours

15

and symptoms, along with other psychosocial and biological factors, which all interact to

maintain fatigue in the long term. Similar factors may perpetuate the fatigue, whatever the

trigger or contribution of disease-related factors [23, 57, 58].

Given the emerging evidence that cognitive-behavioural interventions are effective for

reducing fatigue not only in CFS[44] but also RA[59] in addition to other illnesses such as

multiple sclerosis[60] and cancer [61], transdiagnostic interventions using similar principles

could be used for fatigue that occurs in many different types of rheumatic diseases, regardless

of the specific diagnosis.

Fatigue has an impact on quality of life and levels of occupational and social functioning in

rheumatic diseases, yet it often remains unaddressed. [16, 62]. The potential benefits for

treatment are manifold: an intervention for fatigue symptoms can potentially improve a

person’s functioning and participation in life.

Although there is evidence that CBT for rheumatic disease can lead to improvements in

fatigue [58, 59], most studies do not specify whether the improvement was clinically

significant or mention other important outcomes such as employment. Similarly, in the CFS

literature, there is a dearth of research about occupational outcomes in chronic fatigue

syndrome, and no consensus on how the outcomes are defined[63].

Clinical implications

As these results suggest that avoidance behaviour may be less marked in ARDs, a briefer

approach which targets specific cognitive processes such as lack of acceptance,

catastrophizing, symptom focusing and damage beliefs may be warranted. Specific attention

should be focused on damage beliefs and symptom focusing as these may vary in magnitude

during flare-ups. Interventions could be delivered by health professionals within an outpatient

16

clinic in the acute hospital setting or primary care. To our knowledge, the only CBT based

fatigue interventions so far have been tested on patients with RA [59, 64]and there is a dearth

of research on the effectiveness of CBT for other autoimmune rheumatic diseases.

The finding that CFS patients showed higher lack of acceptance than ARD patients, after key

demographic variables had been controlled for warrants discussion. In keeping with this

finding, our previous study of CFS patients showed that lack of acceptance changed

significantly after treatment with more conventional CBT where acceptance was not the main

focus [30]. There is emerging evidence however that newer, third wave therapies such as

ACT (acceptance and commitment therapy) can be effective for increasing acceptance in

individuals with chronic illnesses such as long-standing chronic pain[65]. This evidence and

the fact that lack of acceptance is problematic for people with CFS suggests that acceptance

should be targeted during treatment. There is a need for further research into the effectiveness

of these treatments for illnesses such as CFS.

Limitations

This study has some limitations which must be considered. For example, we included

covariates such as age and illness duration in our analysis, however, due to the observational

nature of this study, it was not possible to control for many other potential confounding

variables such as disease activity and medication usage. In addition, controlling for fatigue in

CFS is potentially problematic because it is the primary symptom of CFS.

The ANCOVA analyses showed no differences between the three ARD groups, and this was

interpreted as showing that the groups were similar. However, a more sophisticated statistical

method such as equivalence testing[66] is needed in order to establish whether the groups

were statistically equivalent to each other. Also, given that the groups were relatively small in

17

size, the study may have lacked power. Furthermore the analysis consisted of a number of

comparisons which may have increased the likelihood of type 1 error. This limitation should

be considered in future studies.

Conclusion

The results of this study suggest that although cognitive behavioural approaches may be

suitable for both CFS and ARD, there are specific variables that might need to be targeted in

each of the illnesses. For example, lack of acceptance and avoidance behaviour, which

appears to be important in CFS, could be addressed with acceptance and commitment therapy

which targets these processes specifically with valued based goals or mindfulness-based

treatment approaches.

Fatigue continues to be a debilitating symptom in ARD, yet it is inadequately addressed by

clinicians. Further research is needed into factors that maintain fatigue in ARD. This will

allow for transdiagnostic interventions to be developed and individualised to improve

symptoms, functioning, and quality of life.

18

Acknowledgements:

We would like to thank the patients who gave their time to take part in this study. We also

thank Ms Suzanne Roche, Ms Barbara Bowman, Dr Mary Burgess, Dr Antonia Dittner, Dr

Caroline Stokes, Ms Radka Chura, Mr Putu Khorisantono, Mr James Gwinnutt, Ms Fatma

Mehmet, and Ms Egli Ioannou for their assistance with gathering data for this study. We

would like to thank Dr Kimberley Goldsmith for statistical advice.

FM and TC receive salary support from the National Institute for Health Research (NIHR)

Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation

Trust and King’s College London. The views expressed in this article are those of the authors

and not necessarily those of the NIHR or the NHS.

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