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Depressive symptoms and pragmatic rehabilitation for chronic fatigue syndrome (FINE Trial paper)

Dolphin

Senior Member
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17,567
http://bjp.rcpsych.org/content/early/2012/07/25/bjp.bp.111.107474.abstract
This journal (British Journal of Psychiatry) takes e-letters, some of which then go on to be published in the full journal. To get published, would need to fit these criteria http://bjp.rcpsych.org/site/misc/ifora.xhtml#Letters:

Letters to the Editor
Letters may be submitted online either as responses to published articles (follow the link 'submit a response' when viewing an article online) or as general letters to the Editor (from the general eLetter submission page). A selection from these eLetters will subsequently be included in the printed Journal. Correspondence submitted for publication in the print edition without prior online publication as eLetters should be sent to bjpletters@rcpsych.ac.uk. Letters may be up to 500 words in length with a maximum of 5 references.

However, e-letters can be longer. And the standard to get an e-letter up would be lower.

Research Articles


Depressive symptoms and pragmatic rehabilitation for chronic fatigue syndrome

A. J. Wearden,
G. Dunn,
C. Dowrick and
R. K. Morriss

+ Author Affiliations

A. J. Wearden, PhD, School of Psychological Sciences, University of
Manchester, Manchester; G. Dunn, PhD, School of Community Based
Medicine, University of Manchester, Manchester; C. Dowrick, MD,
Institute of Psychology, Health and Society, University of Liverpool,
Liverpool; R. K. Morriss, MD, School of Community Health Sciences,
University of Nottingham, Nottingham, UK

Correspondence: A. J. Wearden, University of Manchester, School of
Psychological Sciences, Coupland 1 Building, Oxford Road, Manchester
M13 9PL, UK. Email: Alison.wearden@manchester.ac.uk

Declaration of interest: None.

Abstract*

Background

Previous research has suggested that depressed mood may predict
outcome and moderate response to treatment in chronic fatigue
syndrome, although findings have differed between studies.

Aims

To examine potential moderators of response to pragmatic
rehabilitation v. general practitioner treatment as usual in a recent
randomised trial for patients with chronic fatigue syndrome in primary
care (IRCTN74156610).

Method

Simple regressions, with weighting adjustments to allow for missing
data, were calculated. Demographic, medical and psychological
variables, and treatment arm, were entered separately and as an
interaction term. The outcome variable in each case was change in
Chalder Fatigue Scale scores, from baseline to 1-year follow-up, our
primary outcome point.

Results

Longer illness durations predicted poorer outcome across the two
treatment arms. For patients allocated to pragmatic rehabilitation
compared with those allocated to treatment as usual, higher levels of
depressive symptoms at baseline were associated with smaller
improvements in fatigue (P = 0.022).

Conclusions

For patients in primary care with higher levels of depressive
symptoms, either more intensive or longer pragmatic rehabilitation, or
cognitive–behavioural therapy, may be required in order to show a
significant improvement in fatigue.
 

Snow Leopard

Hibernating
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Those who have more depressive symptoms are going to have less change in questionnaire answering behaviour as a result of CBT? Not much of a surprise there. ;)

I haven't read this one, but what variables did they control for? (eg longer duration may have an effect on depressive symptoms, so it might be longer duration predicting both depressive symptoms and poorer outcome)
Was depressive symptoms at follow-up associated with poorer questionnaire outcomes?

Additional:
I found that the supplemental data is accessible:
http://bjp.rcpsych.org/content/suppl/2012/07/25/bjp.bp.111.107474.DC1/ds107474.pdf

I also note they have an EQ-5D dataset. If only it was EQ-5D+ dataset (which I have a special use for...) (I wonder if they used a question equivalent to the EQ-5D+ cognitive impairment question?)
 
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13,774
Ta SL.

I just had a quick glance that those figures... did they indicate that being in receipt of benefits and being a member of an ME support group were associated with more positive outcomes?

I'm surprised by the benefits one, as would have thought that would correlate with severity, which seems to correlate with worse outcomes. The effect size wasn't large, but it's still of interest (actually, my stats suck... I've got no instinctive understanding as to how large an affect one would need in this context for it to be of interest).
 

Simon

Senior Member
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3,789
Location
Monmouth, UK

Now that I've read the full text:

Background
This study uses data from the 2010 FINE Trial which presumed that CFS is perpetuated by deconditioning and secondary biological changes and can be reversed by gradually increasing activity levels - Pragmatic Rehabilitation (PR). It found that the therapy, compared with GP treatment as usual, made no significant difference to either fatigue of function at the primary endpoint of 70 weeks:

there were no statistically significant differences in fatigue or physical functioning between patients allocated to pragmatic rehabilitation and those on treatment as usual
However, in a Rapid Response to their own paper, the authors reanalysed the Fatigue results using a different scoring method (Likert, as opposed to bimodal), concluding:
With the fatigue scale re-scored 0123, we are able to demonstrate a clinically modest, but statistically significant effect of PR compared with GPTAU at both outcome points. Given the chronicity of CFS/ME in our sample, we believe that this on average small improvement in fatigue is important to these individuals.

[Effect estimates [95% confidence intervals] for 70 week comparisons are: PR versus GPTAU -2.55 [-4.99,-0.11], SE 1.24, P=0.040]
Regardless of the debate over how much weight should be given to this post-hoc analysis, this means that they are looking at what baseline variables predict or moderate a rather small effect.

Note that a Predictor is a factor that predicts outcome (in this case a change in fatigue score) across all treatment groups, while a Moderator (the focus of this paper) is a factor that is only relevant in one (or some) types of treatment.

Moderators: Depression? (probably not)
The main conclusion of the paper was that, for Pragmatic Rehabilitation, patients with higher depression scores were likely to show (even) smaller gains than those with less depression. There is, though, one rather big caveat: the authors didn't correct for the large number of comparisons they made, increasing the chance that the finding is a false positive. As they put it:
Our findings need to be interpreted with caution: we investigated the potential moderating effects of over 20 baseline variables, although most of these were prespecified in our protocol,16 and our two positive findings may be type 1 errors [false positives].

Further research to replicate the finding that level of depressive symptoms moderates the effect of pragmatic rehabilitation treatment on fatigue is needed before we can have confidence in the result.
Note they found the Depression score was a signifiant moderator with p=0.022, which is within a 'standard' confidence level of p=0.05. With so many comparisons it would have been appropriate to correct for multiple comparisons with a much lower p value; there are arguments over the best method to use but the most common one, Bonferroni, would have required a p value of 0.0025, 9x lower than achieved. The Bonferroni correction is very conservative, but other methods available would also almost certainly give a p value requirement much smaller than the 0.022 acheived. To add doubt to the findings, a depression diagnosis (yes/no), as opposed to Depression score (HADS), was not a moderator.

Predictors. Myths busted? Membership of self-help group or receipt of benefits don't predict outcome

The study specifically looked at the possibility that belonging to a ME self-help group, or receiving benefits could moderate treatment. Others have argued that these factors could even help prevent recovery (@Dolphin, can you help here?). Instead the study found that they were neither predictors nor moderators: being on benefits or in a self-help group does not affect the prospects for improvement. However, it's probably wise not to read too much into this: as the overall improvement in fatigue was small, it would be hard to detect any kind of effect.

Number of co-morbid illnesses at baseline also didn't predict fatigue outcome.

Younger age and shorter illness improve prospects
Across both the PR and treatment as usual group both age and illness duration were predictors of fatigue outcome. The regression coefficients (Table 5) were given as:
Age = -0.1
Illness duration= -0.01
I don't really know anything about how to interpret the size of these effects, and haven't been able to reach the authors yet for clarification, but those effects look rather small to me.

Washing up: the authors did find other significant effects, but for tiny groups of patients so its impossible to generalise from these findings. They also reported moderator effect trends (i.e. p values just above p=0.05) but given the problem with multiple comparisons I haven't included those here.
 
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13,774
Thanks for the comments Simon.

I've got to repeat my earlier comment. The way that they're able to get a string of papers supporting their own prior position out of the FINE trial just shows how poorly our current systems for medical research are working.

I can't believe how shamelessly they're wiling to use an RCT which showed their treatment to be ineffective to argue that more money should be spent on their treatments. It impresses a part of me that I'm ashamed of.
 

user9876

Senior Member
Messages
4,556
Thanks for the comments Simon.

I've got to repeat my earlier comment. The way that they're able to get a string of papers supporting their own prior position out of the FINE trial just shows how poorly our current systems for medical research are working.


Can you imagine a paper saying drug x wasn't provide a statisitcally significant effect. The effect was even smaller with a particular group of people y. So we conclude that group y require more of the drug than others to get a benefit.

Add to that using a sensor mechanism with a very high degree of error.
 

Simon

Senior Member
Messages
3,789
Location
Monmouth, UK
Thanks for the comments Simon.

I've got to repeat my earlier comment. The way that they're able to get a string of papers supporting their own prior position out of the FINE trial just shows how poorly our current systems for medical research are working.
Thanks, nice to know someone reads my drivel, some of the time.

And yes, it is a bit surprising they are producing more papers on a Trial that failed on its primary outcomes. I do have some sympathy for using the Likert (0,1,2,3) scoring system for Fatigue as it is probably more appropriate for measuring change per subject, but the effect was rather small and Physical Function did not improve.

But I think there is a difference too between scientists producing more papers from a study they have invested so much time in, and those papers actually persuading anyone in the NHS to spend money on Pragmatic Rehabilitation. I don't think it's going to happen.
 

Simon

Senior Member
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Location
Monmouth, UK
...
Younger age and shorter illness improve prospects
Across both the PR and treatment as usual group both age and illness duration were predictors of fatigue outcome. The regression coefficients (Table 5) were given as:
Age = -0.1
Illness duration= -0.01
I don't really know anything about how to interpret the size of these effects, and haven't been able to reach the authors yet for clarification, but those effects look rather small to me.
OK, I can now clarify the effect of age and illness duration on improvement in the Chader Fatigue scale, according to their model.:

For age, the "-0.1" means that for every year older a patient is, their Chalder Fatigue score will increase, on average by 0.1 less than the avearge - or, a patient ten years older would be expected to show an improvement of 1.0 Chalder points less than average. For the Treatment as usual group the mean improvement from baseline was +2.8 points, for Pragmatic Rehabilitation + 5.5 .

For illness duration, it's slightly different as illness duration was measured in months, so for every extra year a patient has been ill, there Chalder score would be expected to improve by 0.01x12= 0.12 Chalder points less than a patient of average illness duration.

Significance? Leaving aside the issue of whether or not the small gain in self-reported fatigue is meaningful... The illness duration coefficient was reasonably robust with p=0.008, while the age coefficient was hovering on the margins of significance with p=0.044, especially as there was no adjustment for multiple comparisons.
 

Dolphin

Senior Member
Messages
17,567
But I think there is a difference too between scientists producing more papers from a study they have invested so much time in, and those papers actually persuading anyone in the NHS to spend money on Pragmatic Rehabilitation. I don't think it's going to happen.
The Liverpool service is based on Pragmatic Rehabilitation.

Orla did a great critique of the programme in this thread: http://forums.phoenixrising.me/inde...liverpool-cf-cfs-clinic-patient-handout.3066/ . One should be able to download the manual oneself if anyone is interested.

As they say themselves This was a repeat of the Powell et al. (2001) study in the patients' homes: "Pragmatic
rehabilitation was originally developed and tested in a hospital setting,14" 14: http://www.ncbi.nlm.nih.gov/pubmed/11179154 .
Powell et al. also had a follow-up study: http://bjp.rcpsych.org/content/184/2/142.long .
The Powell et al. study is often included in reviews/meta-analyses of GET and CBT i.e. as evidence for them.
 

Enid

Senior Member
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3,309
Location
UK
What amazes me in all of this presented by psyches is that it is simply a study of depression in isolation - I could accept clinical depression at the stage one is barely functioning but as I recall nothing to do with the psychological depression - a world of difference.
 

Dolphin

Senior Member
Messages
17,567
How the authors describe Pragmatic Rehabilitation:
The treatment has elements in common with both
CBT and GET but differs from them in that it starts with the
explicit delivery of an explanatory model for patients’ symptoms.
The model focuses on factors that may be maintaining fatigue
and activity limitations, explaining the roles of cardiovascular
and muscular deconditioning, disturbed sleep–wake cycles,
hypothalamic–pituitary–adrenal axis dysregulation, and the
somatic manifestations of arousal. Patient and therapist then
collaborate to design a rehabilitation programme based on
addressing these factors.
As mentioned above, if interested in more info, follow link in my signature to see details from Liverpool manual.
 

Simon

Senior Member
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Location
Monmouth, UK
The Liverpool service is based on Pragmatic Rehabilitation.
Simon said:
But I think there is a difference too between scientists producing more papers from a study they have invested so much time in, and those papers actually persuading anyone in the NHS to spend money on Pragmatic Rehabilitation. I don't think it's going to happen.
Orla did a great critique of the programme in this thread: http://forums.phoenixrising.me/inde...liverpool-cf-cfs-clinic-patient-handout.3066/ . One should be able to download the manual oneself if anyone is interested.

As they say themselves This was a repeat of the Powell et al. (2001) study in the patients' homes: "Pragmatic
rehabilitation was originally developed and tested in a hospital setting,14" 14: http://www.ncbi.nlm.nih.gov/pubmed/11179154 .
Powell et al. also had a follow-up study: http://bjp.rcpsych.org/content/184/2/142.long .
The Powell et al. study is often included in reviews/meta-analyses of GET and CBT i.e. as evidence for them.
I probably wasn't very clear: While Pragmatic Rehabilitation has been used in Liverpool for years, I don't see the results of this latest paper (based on the FINE trial)providing any new evidence that will help persuade NHS commissioners to invest in PR elsewhere. Since FINE was a much bigger trial than the original Powell 2001 study, its overall null result is a strong argument against PR, though I doubt they will close down the Liverpool unit on the basis of it.
 

Dolphin

Senior Member
Messages
17,567
I probably wasn't very clear: While Pragmatic Rehabilitation has been used in Liverpool for years, I don't see the results of this latest paper (based on the FINE trial)providing any new evidence that will help persuade NHS commissioners to invest in PR elsewhere. Since FINE was a much bigger trial than the original Powell 2001 study, its overall null result is a strong argument against PR, though I doubt they will close down the Liverpool unit on the basis of it.
Ye. I partly took it as an opportunity to plug the Liverpool thread.

I recall reading how initial small studies often show large improvements which often tend to get smaller with bigger studies - it is interesting how this has appeared to happen here and also in the PACE Trial (if one looks at earlier studies, the final SF-36 PF scores were often more impressive).
 

HowToEscape?

Senior Member
Messages
626
Hm. Part of this depends of which end of the telescope one looks though.

I find I have powerful changes in "mood" rigidly connected to changes in physical energy. e.g.; if I am only moderately tired and take an energizing substance such as caffeine, the increase in physical energy brings a sharp reduction in cognitive fog, the feeling of dullness, and brings on a better frame of mind. This is minutes after dizzyness, heavy eyes, blank mind, slow perceptions (I could accidentally bump someone on a busy street by not reacting fast enough). The same thing can happen spontaneously.
Mood is quoted because it's not exactly that, but I cannot think of a better word at the moment.

We have a disease that blanks out one's mind. It's pretty reasonable to think it would directly affect one's state of mind. Not being able to exercise, get some sun, have a career, go on a date (much less have a companion) just might cause a touch of depression, eh?

It's pretty obvious that depression is going to be found in any group of people with this disease. Any disease that prevents one from having even a slice of normal life is going to do that.
 
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We have a disease that blanks out one's mind. It's pretty reasonable to think it would directly affect one's state of mind. Not being able to exercise, get some sun, have a career, go on a date (much less have a companion) just might cause a touch of depression, eh?

Yup. But even with all of that (and diagnostic tools presuming you are physically capable of doing the things that depressed people don't want to do), depression in ME is generally borderline. If questionnaires were used which don't presume you are fully functional physically, I'm not convinced that we'd even be borderline depressed as a group.

Anyway, just because studies say we have depression, doesn't mean it's true. It's very important to examine the methods used to make the determination.
 

Simon

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Location
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I recall reading how initial small studies often show large improvements which often tend to get smaller with bigger studies - it is interesting how this has appeared to happen here and also in the PACE Trial (if one looks at earlier studies, the final SF-36 PF scores were often more impressive).
This is usually taken to be an example of publication bias. Lets say the 'true' effect of a therapy is real but small. A study with few participants might find a small 'effect', but the effect won't be statistically significant because small studies inevitably have large margins of error. Such a study would count as a 'null' result and is unlikely to be published eg as a) journals don't like null results and b) the authors might find the null result inconvenient so don't even try to publish. Consequently, most small studies that get published find large effects simply because studies that don't find large effects usually have 'unpublishable' null results.

By contrast, for large studies a small effect is likely to be statistically significant, even if clinically unimportant, so larger studies are more likely to be published (also because they represent more investment by researchers, and funders may demand publication regardless of results).
 

Dolphin

Senior Member
Messages
17,567
This is usually taken to be an example of publication bias. Lets say the 'true' effect of a therapy is real but small. A study with few participants might find a small 'effect', but the effect won't be statistically significant because small studies inevitably have large margins of error. Such a study would count as a 'null' result and is unlikely to be published eg as a) journals don't like null results and b) the authors might find the null result inconvenient so don't even try to publish. Consequently, most small studies that get published find large effects simply because studies that don't find large effects usually have 'unpublishable' null results.

By contrast, for large studies a small effect is likely to be statistically significant, even if clinically unimportant, so larger studies are more likely to be published (also because they represent more investment by researchers, and funders may demand publication regardless of results).
Thanks. Would be interesting to see funnel plots, although I'm not sure there is enough data yet, or data would have to be used from different outcome measures, which isn't ideal.