Dr. Enlander tackles a poor paper "Fear of movement and avoidance behaviour..."

[Richie]

Alex
You may be right but I am suspicious of categorical statements! And serotonin is not the same as serotonergic systems.
What would you say about positive responses to HTP, 5HTP? It could be argued on your lines of "serotonin and sth else" that e.g. they work on depression because they raise niacin or sth. too. We don't know.

Also since serotonin is neurochemically active is it not possible that in some patients raising serotonin will directly improve mood. Or indeed worsen it?

I agree that the SSRI's work by rasing serotonin line is simplistic and I don't think the informed advocates of these drugs would maintain this. But interfering with serotonin systems does seem to affect mood. In Europe (not here in the UK) there is at least one SSREnhancer, (tianeptine) with an opposite action from SSRI's but effective in depression.

 

[alex3619]

My point earlier was there were a large number of drugs that raised serotonin very selectively, some of them much better than current drugs, and NONE of them affected depression.

I only make categorical statements in the negative, or try to, not in the positive. The onus is on a scientific hypothesis to be tested and succeed, and then tested in a robust fashion repeatedly. Any hypothesis that fails is to be rejected until it does not fail. Thats critical rationalism, the basis of modern science (at least in physics, chemistry, etc.) Furthermore all categorical statements are subject to revision on better evidence. Under current evidence serotonin boosting drugs fail, period. Its the ones that are so non-specific that they can interact with lots of things that work, at least with SSRis. Rejecting hypotheses that fail repeated testing is the basis of science.

 

[Richie]

OK, Alex. I do feel that your statement
It was disproved in the 1980s that serotonin corrects depression. I mean categorically disproved
is more seeping than you later statements.

Do you have any links to papers on serotonin selective drugs not affecting depression?

A question I would have immediately is what "selective" means? Is it selective relative to other neurochemicals, selective at one or other or anumber of receptors or what? A drug might only raise serotonin but if it acted on one receptor it might have quite different effects from if it acted at another.

For my part i believe serotonin systems are involved in mood and altering them can alter mood - for better and worse.

 

[MeSci]

OK, Alex. I do feel that your statement
It was disproved in the 1980s that serotonin corrects depression. I mean categorically disproved
is more seeping than you later statements.

Do you have any links to papers on serotonin selective drugs not affecting depression?

A question I would have immediately is what "selective" means? Is it selective relative to other neurochemicals, selective at one or other or anumber of receptors or what? A drug might only raise serotonin but if it acted on one receptor it might have quite different effects from if it acted at another.

For my part I believe serotonin systems are involved in mood and altering them can alter mood - for better and worse.

I don't have much knowledge about the biochemistry of depression, but I do know that drugs very often turn out to be a lot less selective than initially claimed. Vioxx was a stark and catastrophic example. I was actually studying medical science at the time that Cox-2 inhibitors were being developed, and was shocked by the sloppiness of some of the research, in particular a paper that purported to demonstrate exquisite specificity right down to the level of where it bound to the target. But instead of using human Cox-2 they were using Cox-2 from other species! Biological molecules vary a great deal between species - a major reason why drugs turn out to have unexpected results when they reach clinical trials.

New uses are continually being found for existing drugs because they are found to act on more than one target. This often happens by chance. I believe that Viagra was initially designed to be a heart drug. The sedating antihistamines are also anticholinergic, so reduce anxiety, muscle tension and nausea.

 

[MeSci]

Richie

Yes, we use the term "mind" for convenience. The brain is a complicated organ, orders of magnitude more complicated than most things we study in science, and so the term has pragmatic value. Its just that the term is used in very out of date ways in psychiatry.

The sometimes usefulness of psycho-therapeutic actions shows people can adapt, not that they reverse the underlying pathology. Nobody has been able to distinguish between the two, they just presume the answer.

I consider it highly likely that no psychological factors can cause these disorders, its the wrong paradigm. I do think they can modify responses, and also exacerbate symptoms. So there are therapies, but will never be cures using psychological strategies. The pathetic cure rates in psychiatry support this. The generalizability of these strategies just means that brains are adaptive in my view, we can learn to cope.

Psychological factors can have significant and long-term effects on the brain and body, for example the immune system, the cardiovascular system and the endocrine system. People caring for dementia sufferers have been found to have impaired wound healing. Stress increases the permeability of the blood-brain barrier, so can allow substances to enter the brain which would not normally. The same applies to the gut wall. So stress could well play a part in the development of ME and other autoimmune conditions. Many people find that psychological stress exacerbates ME, which could be due to increasing lactic acid production in the brain and/or body.

There is some very interesting stuff about the effects of stress here:

http://www.fi.edu/learn/brain/stress.html

 

[alex3619]

I agree that stress, which is a physiological response, can have an impact. I also agree that what people think about situations can alter their psychological stress. This is not the same as showing that thoughts can cause disease though. I don't disagree that we can have better thinking processes to modify disease response. Its improvement of coping strategies, which can include thought, that lead to better management. Nobody has yet proven its curative of anything. I would expect that better psychological coping might assist recovery though. Yet stress management is not what a lot of these therapies are about.

Is it possible that psychological stress alone, based on inappropriate thoughts, can cause disease? Yes, as an unproven hypothesis, and possibly nonscientific. Yet what is not clear is how much organic factors contribute to this. If it might be psychological then it might also be organic, or both. We need science to figure it all out, and not guesswork. The problem is these unproven hypotheses are treated as sound, when at best they are highly experimental medicine.

 

[alex3619]

On serotonin affecting drugs failing to alter depresson, I do not have any papers. This is from personal discussions, and mainstream biochemistry lectures, back in 2002. Most of this was never published. Failures don't get published. Yet the pharmocology professors knew about it, and so did the serotonin experts. These drugs never make it to market, and hence they never get anything published about them. This was all personal discussions with people who know a lot more about serotonin than most psychiatrists, and many of whom were in drug development.

 

[Richie]

An interesting discussion. Thanks to all.

 

[biophile]

It was disproved in the 1980s that serotonin corrects depression. I mean categorically disproved, which any serotonin pharmacologist could tell you. Yet nobody has a better idea as to why these drugs appear to work.

IIRC, there are newer hypotheses relating to immunomodulation and increased neuronal growth. I agree that the current methods and understanding are incredibly crude compared to how it probably really works. If only professionals admitted ignorance more often instead of pretending that psychiatry isn't several decades behind other fields of medicine.

I know that many mental health care professionals are not happy with the current state of the art for the treatment of psychiatric diagnoses, but one thing which has annoyed me with the biopsychosocial approach to ME/CFS is that the proposed mechanisms are as what Richie described as rather simplistic. The attitude and language used by proponents has often come across as something like: "Yes, we could know more about CFS, but we are pretty proud of the insights we have now on the disorder and we have the basics nailed". Whereas the actual reality may be as far removed from their current understanding as a few sloppy brushstorkes is to a masterpiece of surreal art.

On serotonin affecting drugs failing to alter depresson, I do not have any papers.

No need! AFAIK, SSRIs significantly raise serotonin levels within hours, but the effects on depression, if any, takes weeks. This coincides with the neuronal growth hypothesis, although I vaguely remember that the increased serotonin levels is still playing a role. I also recall that ketamine and perhaps a few other psychopharmacological agents or even novel substances just discovered under study have shown recent promise for almost instant benefits on depression (my guess is that these are a temporary fix, not a solution, but may provide further clues into what depression is on a biological level).

 

[Richie]

I would be surprised if raising serotonin is not involved in some way - e.g. enabling neuronal growth to occur., Altered receptor sensitivity is also a big area it seems and antidepressant treatment is claimed to enhance the serotonergic system at some receptors and turn it down at others.

Personally I can get a hit from serotonin raising drugs very quickly - not necessarily, but including sometimes an a-d effect. I would suppose that raising serotonin does have very immediate biological effects in some of us.

 

[alex3619]

Hi biophile , yes the serotonin response to SSRIs is about six hours, and the depression response can be two weeks. This does not disprove the serotonin hypethesis, but its not explained either. I do know many researchers are trying hard to build other models. Its the drug companies that have promoted the serotonin hypothesis over the last several decades, and I think if they had something better it would be used. This is begging for better research, but drug companies do not spend a lot of time on basic research. It costs too much.

 

[Enid]

Not good at relating to "fear of movement" - the muscles gone completely unresponsive it seemed (poss neurological infections) some muscles never recovered - where is the research to find what it is they call lightly post polio syndrome.

 

[Bob]

Re Serotonin for depression... It's a red herring... Serotonin levels might be indirectly related to mood, but they are not the cause of depression, as far as I understand... Anti-depressants with many other (non-serotinergic) mechanisms are on the market... Some increase dopamine levels, some increase noradrenaline levels, and Ketamine affects another neurotransmitter (GABA or Glutamate?).

Off topic...
I think there is a reason that they have not produced better anti-depressants, with alternative mechanisms... It's because any really effective anti-depressants are addictive, and are therefore not allowed to go to market... If lab rats are shown to freely self-medicate any drug in development, then it doesn't go forwards into phase II or III trials, because it will become a banned substance. That's my understanding, anyway.

 

[Richie]

A brief surmise goes: Dopamine desire t
Norepinephrine energy Glutamate potential Serotonin gives the mood to start Histmaine the concentration

Even that will be a simplification.
Bob
Case in poin may have been http://en.wikipedia.org/wiki/Amineptine

 

[John H Wolfe]

My take on fear, inactivity, and pathophysiology:

1. One may reasonably associate fear of PEM/PENE with (greater subsequent) inactivity in some cases
2. Rowe associates inactivity with enhanced nerve sensitisation leading to enhanced central sensitisation and local inflammation
3. Dr Meirleir associates mild inflammation with increased vit D 1,25
4. Dr Meirleir associates increased vit D 1,25 with reactivation of herpesviridae
5. Many experts associate ME/CFS (onset) with acute viral infection e.g. by herpesviridae
6. Dr Meirleir observes higher than normal 'latent', but lower than acute infection, levels of herpesviridae activity in ME/CFS patients

Hopefully a quick run through this list will provide a fair indication as to why I too believe fear of activity, and the potential for resultant inactivity, are issues that should be addressed responsibly going forward

Smart rest and smart activity are, for me, the key to unlocking the illness as I believe neural hypersensitivity may lie at the heart of our illness and indirect/direct nerve mobilisation (which constitute activity) improves neural sensitisation, whereas relative inactivity only seems to worsen neuromuscular tension in those with the idiosyncratic structural profiles that put them at risk (I believe most PWME have these profiles e.g. dorsal defects/hypermobility)

Attempting exercise before neuromuscular and nerve detensioning has taken place and nerve glide is unimpeded and well tolerated is, however, clearly unwise if you subscribe to a theory like mine!

 

[Valentijn]

Hopefully a quick run through this list will provide a fair indication as to why I too believe fear of activity, and the potential for resultant inactivity, are issues that should be addressed responsibly going forward

There's no indication that a group of patients who are inappropriately fearful of activity actually exists. Thus it seems strange to devise a treatment based on a condition which is completely hypothetical.

 

[Sushi]

John H Wolfe

Hopefully a quick run through this list will provide a fair indication as to why I too believe fear of activity, and the potential for resultant inactivity, are issues that should be addressed responsibly going forward

I don't see any relationship to your points taken from the latest De Meirleir ME/CFS Alert video #45:

1. Dr Meirleir associates mild inflammation with increased vit D 1,25
2. Dr Meirleir associates increased vit D 1,25 with reactivation of herpesviridae
3. Dr Meirleir observes higher than normal 'latent', but lower than acute infection, levels of herpesviridae activity in ME/CFS patients

Dr. De Meirleir (not Meirleir which will not get you internet hits) believes that the inflammation he is finding has very different sources--not inactivity nor enhanced nerve sensitization. You are attempting to put together two very different models.

Sushi

 

[John H Wolfe]

There's no indication that a group of patients who are fearful of activity actually exists

Think we may already have discussed this point. You believe no-one with ME/CFS is fearful of activity, I know of people who are severely affected, and one girl who has comorbid FM, for whom fear of PEM/PENE does (understandably) play a role in their remaining relatively inactive. I guess we shall just have to agree to disagree

Dr. De Meirleir (not Meirleir which will not get you internet hits) believes that the inflammation he is finding has very different sources

Oh aye?

You are attempting to put together two very different models

I am indeed attempting to put together several different observations/theories, thinking somewhat 'out side the box'

 

[snowathlete]

I may well be mistaken but I thought De Meirleir was saying the viral levels were higher than acute infections too. Not lower. Anyone else watched it can confirm either way?
He also was talking about other viruses in this comment he made not just herpes viridae - he specifically mentioned Fifth disease (Parvo B19) as well.

 

[lansbergen]

I may well be mistaken but I thought De Meirleir was saying the viral titres were higher than acute infections too. Not lower. Anyone else watched it can confirm either way?

I think he said lower.