Cognitive-behavioural therapy v. mirtazapine for chronic fatigue and neurasthenia: randomised placebo-controlled trial (2008) Stubhaug

inox

inox

Senior Member (Voting Rights)
This trial is from 2008, but paper was made available online 2 january 2018.

This is the trial that Stubhaug references as the "4 day mindfullness treatment" beeing based on:
https://www.s4me.info/threads/a-4-d...-one-year-follow-up-2018-stubhaug-et-al.7230/



Background
Single interventions in chronic fatigue syndrome have shown only limited effectiveness, with few studies of comprehensive treatment programmes.

Aims
To examine the effect of a comprehensive cognitive-behavioural treatment (CCBT) programme compared with placebo-controlled mirtazapine medication in patients with chronic fatigue, and to study the effect of combined medication and CCBT.

Method
A three-armed randomised clinical trial of mirtazapine, placebo and a CCBT programme was conducted to investigate treatment effect in a patient group (n=72) with chronic fatigue referred to a specialist clinic. The CCBT programme was compared with mirtazapine or placebo therapy for 12 weeks, followed by 12 weeks treatment with a mixed crossover-combination design. Assessments were done at 12 weeks and 24 weeks.

Results
By 12 weeks the treatment effect was significantly better in the group initially receiving CCBT, as assessed with the Fatigue Scale (P=0.014) and the Clinical Global Impression Scale (P=0.001). By 24 weeks the treatment group initially receiving CCBT for 12 weeks followed by mirtazapine for 12 weeks showed significant improvement compared with the other treatment groups on the Fatigue Scale (P < 0.001) and the Clinical Global Impression Scale (P=0.002). Secondary outcome measures showed overall improvement with no significant difference between treatment groups.

Conclusions
Multimodal interventions may have positive treatment effects in chronic fatigue syndrome. Sequence of interventions seem to be of importance.
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https://www.cambridge.org/core/jour...rolled-trial/816FEB91B785A52B1555584829D8FE32

https://www.ncbi.nlm.nih.gov/pubmed/18310583
 
Have not read it, can't access it?

Do wonder what they used as 'placebo therapy'.

"comprehensive cognitive-behavioural treatment (CCBT)" must in reality be the homemade mix of talking (to), walking, drawing, mindfullness described in the 4 day treatment?

Also, at the time I was not following the news, let alone research, so unsure how it was recived. But it can't have made much of an impact, since I haven't really heard it referenced until now, and looking a bit into Stubhaugs background with ME.
 
Esther12 said:
http://sci-hub.tw/https://www.ncbi.nlm.nih.gov/pubmed/18310583

Sci hub is amazing. Drives me crazy to think of the time I used to spend trying to access papers. Almost any paper available here: http://sci-hub.tw/
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Thank you! Haven't got around to make use of sci-hub yet :)


So, it's patients diagnsed by f48 - neurasthenia, that might explain why this paper isn't mentioned much.


The clinical study population consisted of 72 patients with chronic fatigue complaints, fulfilling ICD–10 research criteria for neurasthenia (code F48.0).1
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The criteria for chronic fatigue syndrome, specified by the Centers for Disease Control (CDC),4 and the Oxford group3 were also examined in this population: 65 of the 72 patients fulfilled case definition by the Oxford (British) criteria and 29 patients fulfilled the CDC (US) criteria.
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A comprehensive cognitive–behavioural treatment programme for 12 weeks, consisting of two 1.5 h sessions of group therapy per week (cognitive–behavioural therapy 1.5 h, body awareness therapy 1.5 h), combined with a selfmanaged exercise programme with individually set daily exercise goals (minimal to mild/moderate), using an exercise diary for planned and executed activity.
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(b) Medication (double-blind) for 12 weeks: mirtazapine (individually adjusted dosage to adverse events; standard dose 15– 45 mg, allowing lower dose) v. inactive placebo (medication was dispensed for 2-week periods from the hospital pharmacy; tablets taken by the patients were registered and the returned tablets counted by the pharmacist).
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Ah, so I was wrong, the CCBT is sort of a cbt/get-mix? and the placebo was for the mirtazapine.

This is kind of confusing, isn't it? So he is aware of the need to blind the medication to get a more reliable result, but yet there is only subjective measures for the therapy arm.
Edit: missed this - they actually had 'cardiorespiratory fitness', but only as a secondary measure.


Not able to read the whole paper now, but the overall feeling is that this is far better written than the '4 day' one.
 
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The criteria for chronic fatigue syndrome, specified by the Centers for Disease Control (CDC),4 and the Oxford group3 were also examined in this population: 65 of the 72 patients fulfilled case definition by the Oxford (British) criteria and 29 patients fulfilled the CDC (US) criteria.
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Interesting how there is nearly a total overlap between the neurasthenia and oxford criteria.
 
Jonathan Edwards said:
As far as I know nobody has suggested that mirtazepine is of value for CFS or neurasthenia.
So there are two negative pill type comparators, neither of which are meaningful controls for CCBT.
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It seems to be their own idea - here's the rationale:

We wanted to examine the possible effects of a comprehensive cognitive–behavioural treatment (CCBT) programme compared with medication, and also the effect of this programme combined with medication. We had found sleep disturbance and depressive symptoms to be prevalent comorbid symptoms in neurasthenia,7 as also reported in chronic fatigue.8 Mirtazapine was chosen as the trial medication because of its positive effect on normal sleep9,10 and positive effect on depressive symptoms.11–13 We have not found any previous study of mirtazapine in neurasthenia or chronic fatigue syndrome, but for fibromyalgia positive effects have been reported for pain, sleep complaints and depression.
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But - now I noticed this, it doesn't make sense at all...? Both groups actually had the same treatment - only in opposite order.....?

Do I need more coffee....? :bored:

After the initial 12 weeks, treatment was continued in a combined crossover and treatment-combination design. Patients on medication (mirtazapine or placebo) received the CCBT programme for the next 12 weeks; patients having completed the CCBT programme received medication (mirtazapine or placebo) for the following 12 weeks
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Bjarte Stubhaug and ME-criteria in the 2008 thesis, Link to thesis: http://bora.uib.no/handle/1956/3221

i.e. p; 49 - 52:

"The clinical study population were 72 patients with chronic fatigue complaints, fulfilling ICD-10-research criteria of Neurasthenia, F48.0. Illness definition was operationalized [mhjcom: by Stubhaug him self w/ DSM-manual. As you all know, ICD-10 do not create criteria, so the loosly inaccurate term "ICD-10 criteria" do not exist, and If G93.3 is fullfilled you can not give F48 NB! important] by examining ICD-10 criteria. The included patients satisfied the ICD-10-criteria, allowing for mild depressive or anxiety symptoms clinically evaluated to be independent of or secondary to fatigue symptoms.

The criteria for Chronic Fatigue Syndrome, using CDC-criteria and British/Oxford-criteria, were also examined in the included patient population of neurasthenia (n=72). 65/72 patients fulfilled case definition by British/ Oxford criteria; 29 patients fulfilled CDCcasedefinition." which gives "CFS-Oxford non-CDC (n=34)" [mhjcom: ok, one page to another and the number differ...the dude is :banghead:)

Anyway, Stubhaugs F48 use gives

The clinical study population were 72 patients with chronic fatigue complaints,
fulfilling ICD-10-research criteria of Neurasthenia, F48.0.
62 patients from the study population fulfilling CFS case definitions of CFS- Oxford or CFS-CDC (excluding patients with neurasthenia non-CFS)
CFS-CDC (n=28) and CFS-Oxford non-CDC (n=34)

Stubhaugs F48 n=72 cohort 2008
13,9 % ~ 14% no ME at all
38,9 % ~ 39% fullfilled CDC-1994 fakuda
47,2 % ~ 47% fullfilled Oxford - 1991
[mhjcom: my "math-brain-calculus" is Lost to the "sea or space", so number could be fault]

so lets face it; with a dude with chronical neurasthenia lust 2 dust...
 
Both the Mirtazapine + CCBT and CCBT + Mirtazapine groups, as well as the Placebo + CCBT and CCBT + Placebo should have similar results at 24 weeks unless the study suffers from short term biases.

The reductions in the Fatigue Scale (Chalder) score at 12 weeks were small and not of clinical significance.

But instead it seems they don't understand the point of the crossover design and prefer just to cherry pick the results that suit their preconcieved conclusion, rather than just accept that this study had null results...
 
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We have not found any previous study of mirtazapine in neurasthenia or chronic fatigue syndrome, but for fibromyalgia positive effects have been reported for pain, sleep complaints and depression.
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So is this a good enough reason to use mirtazapine? Sounds to me like they're just making it up as they're going along. Of course they don't even use CFS, they just say "chronic fatigue". It's a complete muddle.
 
Sid said:
Mirtazapine is one of the most fatiguing antidepressants. Possibly the most fatiguing there is.
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Really? What do you mean by that, Sid? My caree's GP has just upped her dose of it to try and improve things, so I'm rather concerned.
 
FWIW Mirtazapine helped me POTS symptoms significantly when they were real bad. The day after I started taking it I noticed I could stand longer. I speculate this is due to Mirtazapine increasing adrenaline levels (by blocking aA2) and thus vasoconstriction.
 
sb4 said:
FWIW Mirtazapine helped me POTS symptoms significantly when they were real bad. The day after I started taking it I noticed I could stand longer. I speculate this is due to Mirtazapine increasing adrenaline levels (by blocking aA2) and thus vasoconstriction.
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Does it really do that, sb4? I can't see increased adrenaline levels being compatible with restful sleep. Now I come to think of it, my caree has been complaining about feeling as though she's got more adrenaline/cortisol or something in her system since she went on to the increased dose of mirtazapine.

Jonathan Edwards said:
As far as I know nobody has suggested that mirtazepine is of value for CFS or neurasthenia.
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Oh dear. Makes me wonder what my caree's doing on it, then :( GP was suggesting that we reconsider her medication, but now's not a particularly good time.
 
Wits_End said:
Does it really do that, sb4? I can't see increased adrenaline levels being compatible with restful sleep. Now I come to think of it, my caree has been complaining about feeling as though she's got more adrenaline/cortisol or something in her system since she went on to the increased dose of mirtazapine.



Oh dear. Makes me wonder what my caree's doing on it, then :( GP was suggesting that we reconsider her medication, but now's not a particularly good time.
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Yeah according to wikipedia it increased adrenaline. It makes you tired because it also is an antihistamine.
 
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