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DaveW
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The following article outlines ongoing studies of the link between inflammation and depression.

Scientists Build On Case Connecting Inflammatory Disease and Depression
http://tinyurl.com/b3wdv

I suspect that Dr Marshall's work may provide a few missing pieces of the puzzle for these researchers (regarding the role of 1,25-D in the immune cascade, and how the inflammation can be reduced with an Angiotensin Receptor Blocker).

Perhaps ARB's will become the newest class of antidepressants?

DaveW
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Here is yet another independent research article connecting depression to cytokines and inflammation:

Scientists build on case connecting inflammatory disease and depression
http://tinyurl.com/7fkhv

The article notes that immunotherapy (which activates the immune system) has a high incidence of also causing depression. It also goes on to describe research in mice that tracks some of the actual chemical and hormone changes responsible for depression in the presence of inflammation. This research is not yet conclusive on all of the exact mechanisms yet, but they have identified some of the players (and they are not done yet).

On another forum, I saw an interesting response to this article (presumably by a patient), which effectively said;

After years of trying to explain this into the deaf ears of doctors and psychiatrists, it has finally been shown that it is not being depressed that makes us sick - it is being sick that makes us depressed.

- DaveW

drvikki
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Thank you all so much for links and information. It's very helpful.

Vikki

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I had read a recent Discover Magazine article on infectious causes of psychiatric illness and Brian Fallon mentioned the ability of inflammation associated with Lyme Disease to cause tryptophan degradation into kynurenine instead of being made into serotonin. 

At times, during the modified Phase II, and particularly during food sensitivity withdrawal reactions, I have had trouble with moderate depression.

I had testing done a couple years ago, showing that I was quite low in serotonin, and tried 5-htp (a tryptophan relative) and did perhaps have a slight benefit. I had thought about trying larger amounts of tryptophan, until I read the following article (free full text at: http://tinyurl.com/d6f7l )

Interferon-gamma-induced tryptophan degradation: Neuropsychicatric and immunological consequences.

They conclude that interferon induced tryptophan degradation may explain depression and contribute to other neurological disorders to some degree ( including Alz, Huntington’s, Parkinsons, schizophrenia, SLE, Tourettes, MS, major depression).

I guess this article is talking about the same sort of cytokine effect mentioned in the link provided above, but I picked up a couple other things from reading the article I found that suggested to me what might be better for me to try to use next.

This article questions the use of tryptophan supplementation, because some of the byproducts of the abnormal tryptophan degradation are neurotoxic, and more tryptophan would increase these byproducts, most probably.

They seem more positive about SSRIs, but also mention that anti-inflammatories, including tylenol and COX inhibitors (like aspirin or NSAIDS) help block the tryptophan degradation through their anti-inflammatory effects.

So, I decided when I began to feel depressed from a food reaction (which I think also elevates interferon gamma) to take a tylenol, even though I would not have done so normally, since my pain was minimal. It may be too early to be certain, but it did seem to alleviate my depression, (I used just one extended release tylenol yesterday and another this morning).

So, I just thought I would share this, in case others want to give it a try, when they are feeling depression related to Herx. I’d like to know if anyone else thinks it helps their depressive symptoms.

Joyce Waterhouse, Ph.D.

shamutooth
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Joyce, Pre-MP I had used Tylenol to help my insomnia, and wondered why it helped. Maybe this is the reason. Sam

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Hello,

My mood improved seriously when I started wearing NoIRs, the most powerful antidepressivum I ever used. Did not start the benicar yet.

SSRI did not have much effect on me, tried lots of them.

As I understand, they slow down the deactivation of serotonin, keeping serotonin receptors switched on. Could SSRI be useless if there is only very few serotonin in the brain? Because of the weak or none effect of the SSRI, I suspected having a lack of serotonin long before knowing about the MP.

The antidepressive effect of avoiding bright light is an impressive proof for 1,25D being involved in depression.

Nightshade

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I think on the whole, things like reducing D and Benicar should help if they reduce inflammation. And it’s great when someone is helped in that way, like Nightshade (of course the modified Phase II might be a different story, when many of us get hit with depression)

Here are a few more thoughts I wrote in response to someone who I was corresponding with offline:

<<Of course, it may not work for everyone. And I do think my food sensitivity reduction helps a lot with symptoms too.

As to the Benicar, I don’t know that it would necessarily inhibit the enzyme that does the degradation, although for some it should reduce the IFN-gamma that induces the enzyme (called IDO). Besides, for some, Benicar increases the Herx which increases the inflammation. Different substances do different things, and that is why perhaps some people benefit from adding quercetin also, rather than just further increasing Benicar, and an NSAID or tylenol might help others.

Problem that developed with tryptophan use might be due to immune sensitivity to it that developed over long term use or to the increase in toxic byproducts perhaps due to the tryptophan degradation being increased.

I feel one has to watch for immune sensitivities to everything. My mom has to switch anti-inflammatories for her arthritis, as they seem to stop working after a while (and I suspect a sensitivity has developed). I developed a sensitivity to naprosyn at one point-- so far tylenol has been O.K., but if I were to use it constantly at a higher dose, I might also become sensitive to it and then I suppose I would switch. So, to avoid this, one might compare different ones and perhaps not stick with anyone too long.

I just read that this IDO enzyme (that does the IFN-gamma induced degradation) also breaks down serotonin, not just tryptophan.

As to the time course, I wouldn’t judge by the usual observations about anti depressants taking weeks. I think some do work more quickly (like Paxil, or SAMe), and I have read their understanding of the mechanism is not that great. Also, it may take time to break negative thinking patterns for some and that might contribute to the time it takes in some cases. And it might depend on the level of depression.

But perhaps some people would need to take the anti-inflammatories a while for an effect if, for instance, some alterations in brain circuits are needed due to long-term depression.

The Sayama paper cited in the Widner article (ref #24), at least shows that the effect of the enzyme on the IDO enzyme seems to occur within a day or two. They compare various amounts of various anti-inflammatories in Fig. 2 (they have free text version available of this paper).

Indomethacin (I think it’s prescription) and aspirin seemed to work pretty well in their in vitro mouse study (Sayama)--I don’t think this paper studied tylenol, but the other reference cited (#23) was on humans and the abstract mentions tylenol.

I think with tryptophan reduction, I read of cases where people quickly became depressed when given something that depleted their tryptophan. Perhaps that occurs to me when I get a sudden depression related to a food withdrawal reaction suddenly increasing the IFN gamma.

There is also the advantage that I’m pretty sure other people have done fine on the MP while taking anti-inflammatories for pain.

Anyway, it may be worth a try and I need to test it further myself. I also find that on days when I have a tendency toward depression, I also need to stay active to a certain degree (with periodic rests of course, when needed) and ignore a tendency to not feel like doing much (it often feels like a total lack of motivation and a level of indecisiveness--which I just try to ignore--and stay active anyway). When I rest too much on these days, I tend to feel worse (I think the activity may increase the epinephrine and dopamine, which are also important against depression). Novelty increases dopamine, so I tend to switch tasks frequently on those days. The amino acid tyrosine is thought to help for those neurotransmitters. These strategies may still be important even if the tylenol or NSAID helps on the tryptophan/serotonin front.

Depressions may differ. Mine tends to vary from day to day (usually with my food reactions and Herx). The one period lately when it set in more steadily was during a certain part of my modified Phase II. I have also had other periods of a few months on a few occasions over the years (pre-MP), when I was also prone to depression and/or anxiety, often associated with acute infections (more inflammation, probably, with higher IFN-gamma), but sometimes due to external circumstances (losing hope or self-confidence for a while, but of course, even these "psychological" things were also connected to my illness in multiple ways--but I find attitude does make a difference at least sometimes and to some degree).

Joyce Waterhouse, Ph.D.

Mary
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Thanks for the link to the article on depression. My husband and daughter have suffered from depression. My concern is that they have been exposed to me and the infections I carry....

Mary

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We just had our 4th child about 10 days ago; our 1st child since we all went D free a couple of years ago.I am overjoyed to share that this is the first time my wife has not had severe post-partum depression.Fact of the matter is,my wife is extremely happy and has adjusted very  well. Our newborn never cries unless he's hungry,and is completely relaxed and laid back.This is so unlike our other kids who had terrible fussiness from the day they were born.Coincidence? Maybe,but I am thinking otherwise...

Sam

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CONGRATULATIONS, SAM!!!   Such good news....and interesting note about the contedness of mom and baby.  Enjoy!!

Sherry

Prof Trevor Marshall
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Congratulations Sam. Additionally, thanks for posting this. It is such a warm feeling to know that another aspect of my mathematical model (post-partum relapse) seems to be valid:):)
 

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http://en.wikipedia.org/wiki/Antidepressant#Anti-inflammatory_and_Immunomodulation

Anti-inflammatory and Immunomodulation Recent studies show pro-inflammatory cytokine processes take place during depression, mania and bipolar disease, and is possible that symptoms manifest in these psychiatric illnesses are being attenuated by pharmacological affect of antidepressants on the immune system.[33][34][35][36][37] Studies also show that the chronic secretion of stress hormones as a result of disease, including somatic infections or autoimmune syndromes may reduce the effect of neurotransmitters or other receptors in the brain by cell-mediated pro-inflammatory pathways, thereby leading to the dysregulation of neurohormones.[38] SSRIs, SNRIs and tricyclic antidepressants acting on serotonin, norepinephrine and dopamine receptors have been shown to be immunomodulatory and anti-inflammatory against pro-inflammatory cytokine processes, specifically on the regulation of Interferon-gamma (IFN-gamma) and Interleukin-10 (IL-10), as well as TNF-alpha and Interleukin-6 (IL-6). Antidepressants have also been shown to suppress TH1 upregulation.[39][40][41][42][43] Antidepressants, specifically TCAs and dual serotonergic-noradrenergic reuptake inhibition by dual SNRIs (or SSRI-NRI combinations), have also shown analgesic properties additionally.[44][45] These studies warrant investigation for antidepressants for use in both psychiatric and non-psychiatric illness and that a psycho-neuroimmunological approach may be required for optimal pharmacotherapy.[46] Future antidepressants may be made to specifically target the immune system by either blocking the actions of pro-inflammatory cytokines or increasing the production of anti-inflammatory cytokines.[47]
And now look at this this http://tinyurl.com/26ky5o which is 42 reference from above Since cyclic adenosine monophosphate (cAMP) production is stimulated by some antidepressants, and since cAMP inhibits IFN-γ and stimulates IL-10 production, we postulate that the negative immunoregulatory effects of antidepressants result from their effects on the cAMP-dependent protein kinase A (PKA) pathway.
Is not caffeine  http://en.wikipedia.org/wiki/Caffeine#Effects_on_the_heart
responasible for

Caffeine increases the levels of cAMP in the heart cells, mimicking the effects of epinephrine. cAMP diffuses through the cell and acts as a "secondary messenger," activating protein kinase A (PKA; cAMP- dependent Protein Kinase).

Last edited on Sat Jul 14th, 2007 14:37 by wrotek

wrotek
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Thx Meg, i wonder if antidepressants can be good or are bad always. And if caffeine can interfere this way into immunomodulation.

Last edited on Sat Jul 14th, 2007 14:42 by wrotek

Aussie Barb
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Wrotek
see FAQ How can I control my anxiety and depression?   and scroll thru information. anecdotal reports seem to indicate that as health returns, caffeine etc do not present the same problems as otherwise.
best, Barb ...

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Some folks need antidepressants to palliate intolerable depression while they are recovering on the MP. In this respect they are 'good'.

This study suggests caffeine affects 1,25(OH)(2)D(3) stimulated VDR protein expression and 1,25(OH)(2)D(3) mediated actions in human osteoblast cells.

Caffeine decreases vitamin D receptor protein expression and 1,25(OH)(2)D(3) stimulated alkaline phosphatase activity in human osteoblast cells.

wrotek
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but is not palliation an immunosupression in this case too?

Russ
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Over the last year or so there's been a lot of reporting, mostly within the sports media, about the controversy over the link between concussions players suffer in football and the depression and dementia that some of these players suffer from later in life. 

One study of 2,552 retired NFL players found that players who had suffered three or more concussions during their career were three times more likely to have a clinical diagnosis of depression than other players(http://tinyurl.com/yot97x).  Another study found that retired NFL players had a 37% higher risk of Alzheimer's than other U.S. males of the same age (http://tinyurl.com/ywk4cy).

A neuropathologist has done some controversial work in which he examined the brains of a few of the cases of deceased former NFL players who had either committed suicide or showed signs of severe dementia or "punch-drunk syndrome" (http://tinyurl.com/2gtn5r).  There were no overt signs of brain injury but under the microscope he found the "telltale red flecks of abnormal protein".  He and others believe there is a definite connection between the head injuries these players suffered during their careers and the depression and/or dementia they later developed.  The NFL is obviously resistant to accepting that link.

I'm assuming that the TH1 bacteria are the root cause of the depression and dementia in these cases, and that head injuries somehow play a role by allowing a TH1 infection in the brain to proliferate more rapidly.  I actually had a head injury near the time when my health took a turn for the worse, so I'd be interested to hear thoughts on what role head injuries play in the development of TH1 disease and whether TH1 disease that was "accelerated" by a head injury would be any less likely to achieve recovery on the MP.

One other thing I found interesting is that the pathologist's theory is that the abnormal proteins appear when the brain is hit but then disappear as healthy brain cells devour them, leading to recovery.  But when the brain suffers too many blows, the brain cells can't keep up with the protein and "give up".  This sounds a bit like how a healthy immune system can clean up cancerous cells that develop whereas a dysfunctional immune system will not be able to "keep up" and the cancer will proliferate. 

Also had the thought that steroids and all the other anti-inflammatory drugs professional athletes use probably are a factor as well, though the findings of that first study (ex-NFL players who had concussions were more likely to suffer from depression than other ex-NFL players) seems to indicate that the head injuries do play role.

Anyways, thought I'd share this and I'd be interested to hear any thoughts on this.

 

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Russ wrote: I'm assuming that the TH1 bacteria are the root cause of the depression and dementia in these cases, and that head injuries somehow play a role by allowing a TH1 infection in the brain to proliferate more rapidly.
I have a basic theory. Whenever  the body receives an injury, the injured area becomes inflamed. From medterms.com, part of the definition of inflammation reads;

"In technical terms, the inflammatory response directs immune system components to the site of injury or infection and is manifest by increased blood supply and vascular permeability which, in technical terms, allows chemotactic peptides, neutrophils, and mononuclear cells to leave the intravascular compartment."

Which means that any immune cells sent to the site that are already infected with CWD bacteria are allowed to escape the bloodstream and get into the tissue, where the inflammation and abundance of other immune cells to infect would be a nice little incubator. And, no longer being in the bloodstream, they probably stick in that area, compounding the effects of 1,25 D production and the creation of inflammation. Any further injuries to the same area could bring in new species of bugs that have been picked up since the last injury, which would allow the bugs in that area to mutuate further and cause more damage, and/or become harder for the immune system to kill. I also suppose that when the cells containing the CWD bacteria die, the release of cytokines would do their damage to the tissue in the immediate area where they are located, which in this instance is the brain.

Of course, it's just my theory - it may need corrections. :cool:

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Indeed, it's just a theory :) And it doesn't paint the whole picture :)

The issue of healing is directly coupled with the innate immune system, as it is the phagocytes which have to clean up dead and damaged cell and tissue after an injury. If you have an intraphagocytic Th1 infection then those injuries will not heal as the phagocytes are not working at full effectiveness.

Your Th1 infection predated your injury. As Th1 syndromes are chronic they necessarily progress slowly and progressively, and the stress (physical to tissue, and emotional to brain) would probably have hastened that progression.

But you would almost certainly have wound up ill, even without injury to hasten the slide :)
 

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I don't know if this has been suggested before, but is it possible that brain herxes can cause depression due to the inflammation of the tissue resulting in an increase in histamine levels in the brain? I read up a bit about this and there seems to be a fair amount of research linking high histamine to depression and OCD, among other things. Apparently the histamine uses up the bodys methyl groups, and the body needs these methyl groups for the production of serotonin, dopamine and to do about a million other things. Therefore high histamine causes a shortage of good things. Histamine also functions directly as a neurotransmitter and can cause a variety of problems.

SAMe provides methyl groups so it can simultaneously lower histamine levels and aid the body in making "good" chemicals.

Obviously I'm not an authority on this so what I'm writing is my understanding of what could be going on here based on what I have read. It apparently has no side effects and simply helps the body with its natural processes.

Might it be feasable to use SAMe along with the MP meds?

Last edited on Tue Aug 28th, 2007 22:35 by Marselle

jcwat101
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I am pretty sure the answer would be:

ATTENTION: Unnecessary dietary supplementation and OTC medications are to be avoided because we cannot know how they might interact with the medications on the Marshall Protocol, or how they might affect the immune system.

Also, using SAMe and related substances would be in the category of combining the MP with another protocol and there could be unknown effects on the efficacy of the MP.

See the links Meg and Barb posted, above, for the MP's views on dealing with depression, anxiety and mental illness.

Joyce Waterhouse

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Joyce is correct about unnecessary supplementation. But we take intolerable depression very seriously. We don't want members to endure a depression that could be dangerous. If your depression is intolerable to you, please take whatever medication that works to help you feel better (including SAM-e) providing your doctor approves. 

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Hi all,

I have been looking a little into serotonin and histamine. It seems a lot of anti-depressants and anti pschychotics work on these two.

What I found about serotonin was rather interesting.

It seems serotonin plays a role in oxidative stress. If serotonin binds to the 5-HTR 2 receptor it downregulates something called myeloperoxidase, thereby downregulating oxidative stress.

Now, the most interesting thing is that this receptor, which essentially is the serotonin 2 receptor (5-HTR is the chemical name), is expressed by the VDR... See the tables of Wang et al.

No, I am just a layman, so I hope someone with more knowledge can check the paper out to see if I am right.

This piece of information might be another reason why beni works wonder against pain. Simple explanation:  if VDR doens't work, the serotonin 2 receptor isn't expressed, leading to oxidative stress going haywire.

PMID: 18041649

Sincerely, Frans

PS  in the tables of wang et al one finds that a lot of serotonin receptors are expressed by the VDR (link to depression?), as are the histamine H1, 2 and 4 receptors (link to psychosis allergy?)

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Frans,

Funny thing that you should be reading up on this subject. I find it very interesting since everything with me started with the diagnosis of depression then many years later Fibromyalgia, Chronic Fatigue and Lyme disease (which we know now is all the same..different color cats but all are cats) The Marshall Protocol has put me in a place that is indescribable when it comes to my depression. I  had depression  (pre MP) to the point of wanting to commit suicide many times not to mention life was a struggle everyday.

Mood swings were something that was a part of daily life for me. My TH1 symptoms started as depression then came the pain, fatigue, and poor sleep, daytime sleepiness etc etc...Antidepressants saved me but never have they relieved/gotten rid of symptoms....like the MP. I am now starting to live a life I have never known. I am not the first member to note this but I am amazed at just how good things are.....Of course when I herx the depression, moods and sleep can worsen temporarily...but when I am not herxing WOW WOW WOW. I just cant say enough about it. I keep getting amazed when I see the progress I am making. It is like a dream come true....a life I have never known.

Jeannine

Frans
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Jeannine,

Well, the plot thickens.

As I mentoined, several histamine receptors are also probably transcribed by the VDR, namely H1, 2 and 4. See Wang et al.

One thing that stands out once one looks into the histamine receptors is their role in sleeping.

The histamine H1 receptor is mentioned as being the most important receptor in the so-called circadian rhythm. This is a fancy word for what we know as bio-rythm, sleeping at night and waking at day.

So, if the VDR doesn't work, it seems only logical that our sleeppatterns get disturbed, since the main receptor regulating our biorhythm isn't there.

Sincerely, Frans

Prof Trevor Marshall
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As the section on clinical studies in my new paper concludes:
"Surely we are being naive if we expect the exogenous modulation of a metabolism that is responsible for the expression of over a thousand genes to provide a simple go/no-go result?"
..Trevor..

Frans
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Hi all, I just found a paper confirming the Histamine H1 receptor as being transcribed by the VDR, see PMID 17547532.

This receptor is reported to be the most inportant in maintaining a normal circadian rythm, our biological clock.

So, sleepproblems are not really unexpected in these th1 diseases...

Sincerely, Frans

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Frans,

I truly appreciate your active investigation into these issues as I have been unable to sleep deeply without taking a small amount of an anti-histamine at bedtime.

Knowing that being on the MP is resolving the underlying cause of my sleep problems reassures me that I am on the right track.

Thanks!
~Joyful~



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