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Carmine Pariante's MRC research award-Persistent fatigue induced by interferon-alpha

Discussion in 'General ME/CFS News' started by Dolphin, Dec 21, 2011.

  1. Dolphin

    Dolphin Senior Member

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    I thought I'd give this it's own thread:
     
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  2. Dolphin

    Dolphin Senior Member

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    I can't say I know much about her. But this paper with Simon Wessely was highlighted on another forum:

    If it does "go wrong", one plus is that any psychological speculation or lack of association with fatigue, etc they find will be to do with Hep C, so will undermine us less.
     
  3. Dolphin

    Dolphin Senior Member

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    (Junk?) 2 more loose connections with Simon Wessely

    Somebody posted these on another forum. How much they prove, I'm not sure.

    Max Pemberton wrote a very annoying column in a UK paper soon after this. I get the impression the meeting might have been a bit biased.


     
  4. Enid

    Enid Senior Member

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    Don't tell me this lot are on it and grinding through their own ignorance at our expense. Clever lot the psychos just about latching on to real pathologies ? - to save their bacon. We do not have to watch their growing up now - science left far behind and the whole international community knows.
     
  5. Dolphin

    Dolphin Senior Member

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    The CDC CFS program has funded research into the effects of alpha-interferon

    The CDC CFS program has funded research into the effects of alpha-interferon - article added Dec 2011

    http://www.cdc.gov/cfs/news/features/cytokines-and-cfs-symptoms.html

     
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  6. Dolphin

    Dolphin Senior Member

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    Links to pages on the CDC CFS website about interferon-alpha studies it has supported

    Links to pages on the CDC CFS website about interferon-alpha studies it has supported:

     
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  7. oceanblue

    oceanblue Senior Member

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    Thanks for posting all that info, Dolphin. I'm going to post stuff here as I read through the papers.

    First, here's a rationale of why IFNa is used as a model:
    Though I'm not sure the studies themselves are that compelling. Here's the one on
    Association of Exaggerated HPA Axis Response to the Initial Injection of Interferon-Alpha with Development of Depression During Interferon-alpha Therapy:

    Half of patients developed major depression and these patients had higher levels of ACTH and cortisol after IFNa administration, but with n=14 I'm not sure we can rely on this finding. Hopefully Pariante will have a decent sample size.
     
  8. oceanblue

    oceanblue Senior Member

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    Key study: how the effects of IFN-alpha on fatigue and depression are different

    Neurobehavioral Effects of Interferon-A in Cancer Patients: Phenomenology and Paroxetine Responsiveness of Symptom Dimensions, 2002

    One of the problems of using Interferon-alpha (IFN-a) treatment as a model of CFS is that IFN-a often causes depression too, which causes fatigue - and that takes us back to the problems of confusing depression with CFS/fatigue. This study, on cancer patients undergoing IFN-a treatment, shows that fatigue appears within the first 2 weeks of IFN-therapy starting, while depression can take a couple of months to develop. And crucially, treating patients with paroxetine (an antidepressant) before starting the IFN-a therapy largely blocks depression but has only a very limited effect on fatigue. This suggests that fatigue after IFN-a develops largely independently of depression, so probably occurs via a different mechansim:
    The authors note the similarity with CFS:
    and, interestingly, with cancer patients undergoing chemotherapy:
    Nb the study was quite small with initially 20 each in the antidepressant group and placebo group, and quite a high attrition rate (approx 35%) so it would have been nice to see the study replicated.

    The challenge for the new MRC study will be "to define the biological changes that occur in relation to the development of fatigue" without confusing them with the biological changes linked to depression, given that up to half of Hepatitis C patients treated wtih IFN-a develop depression.
     
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  9. Dolphin

    Dolphin Senior Member

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    Thanks for that - interesting. We will have to see what happens with your last paragraph. If Simon Wessely and/or others from the "chronic fatigue" team in KCL (big CBT and CBT-model fans) are involved, I'm not sure we should be confident about it. They haven't been particularly interested in biological changes that they can not explain by the CBT model (deconditioning, etc.).
     
  10. oceanblue

    oceanblue Senior Member

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    I think the goals of the new study are laudable but it will be hard to pull off, and the stable invovled doesn't exactly inpsire confidence. More on the studies above:

    Anterior Cingulated Activation and Error Processing During Interferon-alpha Treatment, 2005
    (nb the CDC page with this title, above, discusses a completely different experiment).

    Hepatitis C (HCV) patients who were given IFNa were compared with HCV patients who were not - both groups were given visuospatial tasks to complete while undergoing functional MRI scans (fMRI).

    You can't help wondering if this is the same situation as for measuing CFS fatigue where the test is too short to detect fatigue (repeat testing would have been interesting). But it is a slightly bigger study than the one above, and I believe other studies have implicated the ACC in fatigue too. Full paper (pdf, and I haven't read it myself, my comments are mainly on the abstract).


    Depressive Symptoms and Viral Clearance in Patients Receiving Interferon-a and Ribavirin for Hepatitic C (2005)

    This study found that Hepatitis C patients who developed depression when treated with Interferon-alpha plus Ribavarin (an antiviral drug) were less likely to respond to the treatment than patients who did not develop depression. Overall, 56 patients (ex 102) were Hepatitis C negative after the treatment but the most depressed patients (30% of total) were more than 3x less likely to clear the virus than non-depressed patients. According to the authors:
    but the abstract doesn't mention fatigue and the authors descirbe their findings as 'preliminary'. I'm not sure this study tells us anything useful about how fatigue works.



    Interferon-alpha-induced Changes in Tryptophan Metabolism: Relationship to Depression and Paroxetine Treatment, 2003


    Uninspiring. This study found that IFN-alpha treatment led to greater reductions in tryptophan (a precursor of serotonin) in patients who developed depression than those that did not. Tells us nothing about fatigue pathways. And again it's rather small study: 13 in the paroxetine treated group and 13 in the placebo group; the authors then compared placebo patients who developed depression with placebo patients who did not, but n is getting very small at this stage
     
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  11. oceanblue

    oceanblue Senior Member

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    There's a slightly bigger 2010 study from some of the same authors that found a moderate correlation (approx 0.45) between cortisol patterns and fatigue after IFN-alpha administration. Changes in diurnal cortisol patterns are the sort of thing they get excited about at KCL, judging by their previous publications on CFS.
     
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  12. Snow Leopard

    Snow Leopard Senior Member

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  13. oceanblue

    oceanblue Senior Member

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    Thanks for that, Snow Leopard - interesting.

    More studies:

    Basal Ganglia Hypermetabolism and Symptoms of Fatigue During Interferon-a Therapy, Capuron 2007

    Researchers compared the metabolic map of patients' brains before and during IFN-alpha therapy (using PET) and found there was an increase of metabolic activity in the basal ganglia that correlated with IFN-alpha induced fatigue. Interesting: could this be the brain location of fatigue?

    Unfortunately I can't access the paywalled paper to see how big the study was, but such brain studies are usually quite small. The finding also contrasts with the study mentioned above that found activation in IFN-alpha-treated patients in a different brain area, the anterior cingulate cortex (ACC). However, the ACC finding came from a study using fMRI to look at performance during a visuospatial task, so is not directly comparable.


    Chronic Interferon-Alpha Administration Disrupts Sleep Continuity and Depth in Patients with Hepatitis C: Association with Fatigue, Motor Slowing, and Increased Evening Cortisol, Raison 2010 (full paper)

    IFN-alpha treatment can also disrupt sleep, and decreased sleep quality was associated with increased fatigue, though "Despite IFN-alpha-induced increases in fatigue, daytime sleepiness did not increase."

    This finding potentially raises the question of whether IFN-alpha directly affects fatigue or is a side effect of sleep problems. However, it appears from the literature that while most IFN-alpha-treated patients suffer fatigue, only a minority have sleep problems (80% with fatigue vs 35% in the only data I've seen, though n was small), suggesting the fatigue effect is independent of sleep effects, at least in some patients.

    It's also worth noting that in CFS, sleep disturbances are common yet by definition cannot alone explain the fatigue.
     
  14. WillowJ

    WillowJ Senior Member

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    thanks for all this; very interesting
     
  15. oceanblue

    oceanblue Senior Member

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    Comment on the planned study of Interferon-alpha induced Fatigue

    When the MRC grants were announced last week there was a lot of scepticism about the Pariente study of fatigue in Interferon-alpha treated Hepatitis C patients. First, it isn't actually studying CFS and second, Carmine Pariente is a psychiatrist from the Institute of Pschiatry, Kings College London, making him a stablemate of Simon Wessely, which understandably causes some suspicion.

    Points in favour of the study
    However, looking at some of the literature, I can see the case for using IFN-alpha treatment as a model of how fatigue is generated. IFN-alpha treatment rapidly induces fatigue in most patients, and quite often causes sleep disturbances, pain and cognitive dysfunction too, which are also common in CFS. While IFN-alpha often causes depression too, this usually takes much longer to develop than the fatigue, can be blocked by pre-treating patients with anti-depressants (unlike the fatigue) i.e. depression appears to be caused by a mechanism independent of fatigue.

    The brain imaging findings are intriguing too. The PET study found the basal ganglia of fatigued IFN-alpha-treated patients were more active than untreated patients, and another study found a correlation between fatigue and errors in another part of the brain during a demanding visuo-spatial task.

    And of course, cytokines have long been suspects in CFS research, though no one has really pinned down the role. The most interesting finding to date has come from the Dubbo studies of Post Viral Fatigue, which found a strong correlation between acute illness cytokines and illness severity, and later development of fatigue. The authors suggested that the intial high levels of cytokines in the body led to long-term cytokine production in the brain, causing fatigue and other symptoms of CFS.

    Unfortunately most of the work on biological changes associated with IFN-alpha treatment have been focused on the link with depression - in fact, it's widely used as a model of inflammation-linked depression. The link with fatigue has received relatively little attention.

    Issues for the study
    A confounding factor with this study is that depression and sleep problems, both of which can contribute to fatigue. Around 30% of IFN-alpha patients develop a Major Depressive Disorder, but more have lesser levels of depression. The study will need to control for this so will need to be quite big. As with CFS research, many of the findings in this field to date have been based on small samples with no attempts to replicate them. An MRC grant should provide the funds for a substantive study

    Of course, whatever the findings about the nature of fatigue in IFN-alpha-treated Hepatitis C patients, they won't automatically apply to CFS patients. But should the study make significant findings about the nature of fatigue in IFN-alpha-treated patients, it will provide a clear target for investigating fatigue in CFS. And there aren't too many of those currently.

    Whether or not Carmine Pariente will share Simon Wessely's preference for psychological explanations of fatigue remains to be seen. However, unlike Wessely, Pariente is Biological Pyschiatrist and by inclination biological psychiatrists tend to prefer biological explanations for things.
     
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  16. Enid

    Enid Senior Member

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    Let's hope so oceanblue - dodgy otherwise.
     
  17. Dolphin

    Dolphin Senior Member

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    Thanks oceanblue for researching it.

    Small point:

    He's a psychiatrist i.e. a qualified medical doctor who has gone on to specialise in psychiatry.

    --
    Another (small) point in its favour is that some ME/CFS clinicians such as Dr. John Chia have used the therapy [interferon-alpha] so its useful to know as much as possible about the treatment's effects.
     
  18. Enid

    Enid Senior Member

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    Is this psychiatry moving into the world of biology - well what do you know - there's some hope for all !

    (All psychiatrists are qualified Docs first - not specialists in medical fields so much to learn and rant I've seen too many ill caught up in their mumbo jumbo)
     
  19. Dolphin

    Dolphin Senior Member

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    Link to free full text of Wessely and Pariante Hep C study

    Wessely S, Pariante C. Fatigue, depression and chronic hepatitis C infection. Psychological Medicine 2002: 32: 1-10.
    is available for free at:
    hxxp://simonwessely.com/Downloads/Publications/CFS/142.pdf
     
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  20. oceanblue

    oceanblue Senior Member

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    Thanks.
    This ties in with the Interferon-alpha studies which show very low levels of fatigue for HCV patients at baseline, before interferon treatment. Which is just as well, really, because if they were fatigued before the treatment it would be much harder to interpret the results.
     

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