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Created in 2008, Phoenix Rising is the largest and oldest forum dedicated to furthering the understanding of, and finding treatments for, complex chronic illnesses such as chronic fatigue syndrome (ME/CFS), fibromyalgia, long COVID, postural orthostatic tachycardia syndrome (POTS), mast cell activation syndrome (MCAS), and allied diseases.
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Thank you Cort for this comprehensive report on ongoing NIH funded trials.
I am confused about how Dr. Natelson goes about dividing the patient groups as ones with depression and those without. Furthermore, saying that biological abnormalities only show up in the group without depression.
Is he talking about primary depression and fatigue without true ME/CFS?
My problem with this is that you can have patient x who is severely affected by ME/CFS. Patient x did not manifest with depression at outset of the illness but, as the illness progresses an grows in intensity, the patient develops adaptive depression. Is Dr. Natelson saying that patient x, in the beginning, before he manifested with depression symptoms, would have a positive biological (extra proteins in spinal fluid) outcome yet, later when his illness is more severe and he becomes depressed because of it, these proteins will disappear?
I really hope that he is not of the school of thinking that depressed people are being diagnosed with ME/CFS!
It is a very confusing area and an intriguing one. My understanding is that he has found that people with ME/CFS with depression have different study findings - actually lower levels of the brain abnormalities that he is testing for - than people with ME/CFS without depression.
He's not talking about depressed people without ME/CFS at all and we know that depression is, in fact, quite different from ME/CFS; cortisol readings are bumped up (not down), they don't experience post-exertional fatigue, the metabolic abnormalities are not present; in most studies - CFS patients test differently than people with major depression....so people with ME/CFS and depression are quite different from people with major depression.
There are similariites as well...though. Learning that antidepressants can work quite well with chronic pain patients (who are not depressed) was kind of a revelation for me....These are really complex systems. It makes me wonder if these depression.....pain.....fatigue...... etc. fields all kind of weaves in and out of each other in ways that we don't understand. Researchers are now, for instance, really beginning to get excited about immune processes in the central nervous system that effect or cause depression. Of course they are interested in them in ME/CFS as well...
I can see how this could work.....there could be a depression prone subset of ME/CFS who are different, for some reason, than people with ME/CFS who do not become depressed.
You bring up a good point though about people who start off with CFS who are not depressed but later become depressed...It could be that Natelson has a group of patients who have been ill long enough that those people who are going to get depressed do so (?)
Thanks for your reply Cort,
I still have a problem though with the term "depression prone ME/CFS". Who in their right mind would have a debilitating illness that leaves them house/bedbound for ten years, be in pain most of the time and NOT BE SOMEWHAT DEPRESSED! He is kind of saying (from my understanding) that if someone is in this position and is not depressed = they are truly sick but the same person with the same circumstances who doesn't get depressed at all, well then - he is really sick.
Am I reading this all wrong?
In addition, he is looking at the neurological component of the illness. This makes sense since he is a neurologist. He can only test those that if on neurological meds, have to come off them for two weeks prior to testing. I don't know what neurological meds one is on (because they need it for their neurological problems) can just come off them for two weeks?
I was always perplexed about who is really being studied here but, I guess the same can be said about all studies. The most severe/bedbound patients can't participate and therefore are not represented in any of these studies.
Results Thus Far Several papers have come out of this long study. Biaggioni has documented angiotensin abnormalities in some POTS patients and found that low doses of the beta blocker propranolol significantly reduced the racing heartbeats and symptoms found in POTS patients, while high doses may make some POTS patients worse. The big news were waiting for is whether Biaggionis theory that reduced NO levels are at heart of this disorder causing sympathetic nervous system over-activation, low blood volume, cardiovascular problems, POTS, etc. is correct.
Among them were six statins and, intriguingly, three of them -- fluvastatin (Lescol), lovastatin (Altoprev), and simvastatin (Zocor) -- caused ATP levels to fall and production of free radicals to increase, Dr. Mootha and colleagues reported.
This "toxicity signature" wasn't seen with other statins, although it was seen with another drug often used by the same patients - the beta-blocker propranolol (Inderal).
In this study, they looked through their 2,940 compounds to see if any had the opposite effect. In essence, Dr. Mootha said, the work has produced a "look-up table" that can now be used to find compounds that have desired effects.
In this case, they found six compounds that increased gene expression and reduced free radicals and two of them are known -- at least anecdotally -- to have anti-diabetic effects.
One is mebendazole (Vermox), a benzimidazole used to treat infestations by worms."
In the 1990s, a research group at Karolinska Institutet demonstrated how the body can convert nitrate to NO, a molecule involved in many important bodily functions, such as blood pressure regulation, the immune defence and cell metabolism.
In this new study, the same team had healthy people take nitrate equivalent to 200-300g of spinach or lettuce for three days, after which they were given a cycling task to perform. The researchers then analysed samples from their thigh muscles and compared them with similar samples from the same subjects when they had taken a placebo instead. After nitrate ingestion, a significant improvement was seen in the efficiency of the mitochondria, which consumed less oxygen and produced more of the energy-rich substance ATP per consumed oxygen molecule.
Thanks for the summary Cort. This could be a very interesting year.
Anecdotally; when I was still working I really needed some help from my GP to cope with my symptoms one of which was being unable to control my temperature even in a normally heated office. Frankly I was constantly sweating like a pig and on the verge of passing out.
My GP must have assumed a SNS problem and prescribed propranolol 80mg, 1 per day. Did it work? Oh yes and then some. I can't remember the details now but I do remember having never felt so ill in my life and rather than overheated I felt like an ice cube. I had to quit them after a few days. So low and slow would be the way to go.
You may have heard of 'statin myopathy' that may occur in a small number of vulnerable people (including the elderly and those with a mitochondrial defect).
One study looked at the effects on mitochondria of nearly 3000 compounds, half of which were FDA approved drugs :
http://www.medpagetoday.com/Cardiology/Dyslipidemia/8489
http://forums.phoenixrising.me/show...ent-for-worms-has-helped-my-gut-a-bit-but-why
Perhaps I should 'eats all my spinach'
http://insciences.org/article.php?article_id=9838
Thanks Cort, interesting stuff, lets hope something useful comes of it all. As for the depression issue, i have (apart from post natal) never suffered from depression, other than some normal amount of grief due to losing out on the life i wanted for myself. But i do wonder why they dont study anxious patients alongside M.E patoients as so many M.E patients have severe anxiety rather than depression. This has never made sense to me, as there are many who (wrongly ) think of M.E as a type of anxiety disorder rather than a depressive disorder.
Justy.
He feels researchers missed the boat when they focused on depression (I imagine because fatigue is common in depression) and that if they focused on anything they should have focused on 'anxiety' and this is coming out in the science with findings suggesting that ME/CFS is associated with increased sympathetic nervous system (fight or flight) activity; ie increased arousal.
That's exactly what they have focused on for the last 20 or so years and it hasn't resulted in much. They talked about 'atypical depression' and anxiety in CFS patients as a potential causative factor.
See this conference report from 1993 (ignore the front cover which is currently the wrong image).
http://books.google.com.au/books?id=9cAa038ka1QC&printsec=frontcover#v=onepage&q&f=false
I still have a problem though with the term "depression prone ME/CFS". Who in their right mind would have a debilitating illness that leaves them house/bedbound for ten years, be in pain most of the time and NOT BE SOMEWHAT DEPRESSED! He is kind of saying (from my understanding) that if someone is in this position and is not depressed = they are truly sick but the same person with the same circumstances who doesn't get depressed at all, well then - he is really sick.
(...)
I was always perplexed about who is really being studied here but, I guess the same can be said about all studies. The most severe/bedbound patients can't participate and therefore are not represented in any of these studies.
Cort said:With grant success rates at less than 20%, grants are hard to come by. The NIH estimates that grant success rates of about 30% are about right; anything lower than that suggests the NIH has other priorities for its funds. First time grant success rates in the mid-late 2000s, for ME/CFS, however, were only around 8%. Nevertheless, the money, when they can get it, is so good thats its well worth the effort. The CFIDS Association, for instance, has been able to parley their recent small grant packages into millions of dollars of NIH funded studies.
In the last two years there were no new investigators in chronic fatigue syndrome that were reviewed. None. So that's a problem. I mean, it's a problem for the field that for some reason new investigators are not even submitting applications. I would urge you to encourage people to do that (http://www.youtube.com/watch?v=nf2yOxf74bE).
from earlier coments you reported from Alan Light, I had thought they felt they'd done enough and were moving on to drug testing.its first goal will be to validate the results of the old study with new patients
You write, Cort, that the first time grant success rates in the mid-late 2000s, for ME/CFS...were only around 8%. At the last CFSAC meeting, Dr. Cheryl Kitt, Deputy Director of the NIH/CSR, reported that recent success rates are really quite high in the CFS study section because the number of applications is low
Dr. Kitt says that what she's noticed, particularly in the past few years, is that if an individual is funded the first time, they tend to not come back in the second time, for some reason.... We're not getting competitive renewals very often. Overall, she says, We receive very few applications.... The NIH really can't fund applications it doesn't see. The success rate is pretty high for applications to be funded because the denominator is small. There aren't that many.
Dr. Kitt's report suggests, then, that these grants aren't so difficult to come by, after all. In an earlier article, you wrote, Researchers probably dont feel they can make progress in what they feel is a wastebasket disorder (http://forums.phoenixrising.me/content.php?526-Ottawa-IACFS-Conference-IV-CFS-and-the-Immune-System). Doesn't that assessment better account for our recent situation?
Hats off to you again, Cort, for another excellent review summarising a vast amount of very useful information.
I think the Fletcher Good Day/Bad Day study is very exciting and, as you say, could change the way research is done if it finds a real difference between the two. It could lead to far more consistent results than we currently see in biologial abnormalities research.
I was also delighted to see that the Lights will be trying to repicate their very interesting findingsfrom earlier coments you reported from Alan Light, I had thought they felt they'd done enough and were moving on to drug testing.
Thanks Cort, interesting stuff, lets hope something useful comes of it all. As for the depression issue, i have (apart from post natal) never suffered from depression, other than some normal amount of grief due to losing out on the life i wanted for myself. But i do wonder why they dont study anxious patients alongside M.E patoients as so many M.E patients have severe anxiety rather than depression. This has never made sense to me, as there are many who (wrongly ) think of M.E as a type of anxiety disorder rather than a depressive disorder.
Justy.
.The Beck Depression Inventory (BDI) is widely used to assess depression in chronic pain despite doubts about its structure and therefore its interpretation. This study used a large sample of 1947 patients entering chronic pain management to establish the structure of the BDI. The sample was randomly divided to conduct separate exploratory (EFA) and confirmatory factor analyses (CFA). EFA produced many satisfactory two-factor solutions. The series of CFA generated showed reasonable fit for ten of those solutions. All included a first factor identified as negative view of the self (items: failure, guilt, self-blame, self-dislike, punishment and body image change), and a second factor identified as somatic and physical function (items: work difficulty, loss of appetite, loss of libido, fatigability, insomnia and somatic preoccupation). The remaining items (suicidal ideation, social withdrawal, dissatisfaction, sadness, pessimism, crying, indecisiveness, weight loss, irritability) loaded infrequently or not at all in the CFA solutions. They did not form a coherent factor but comprised items associated with negative affect.
When compared with published data from samples of depressed patients drawn from mental health settings
the mean item scores for items reflecting the negative view of the self were consistently statistically lower that that observed in samples; there was no consistent difference between the samples on the items reflecting somatic and physical function; but the mean scores for the remaining affect items were significantly greater in the mental health samples. This version of depression is strikingly different from the psychiatric model of depression (e.g. DSM-IV or ICD-10), which is primarily defined by affective disturbance, and secondarily supported by cognitive and somatic symptoms