# Molecular Factors Behind Stress Response



## Guest (Sep 8, 2011)

I continue to have hope that further brain research will help us understand anxiety, which is innate and necessary for survival. If we can underestand this better, this should lead to further understanding of DP/DR ... perhaps. There is clearly a connection one way or the other. At least I see it in myself.

This is in a sense "old news" but we are getting to the molecular level here. There are some great diagrams.
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"An organism's response to stress is one of the key strategies essential to its survival in dealing with environmental factors. Many patients with anxiety disorders and depression display an altered hormonal stress response and have increased volumes of CRH in the brain."

*Control of Fear in the Brain Decoded: Emotional Balance Is Regulated by Molecular Factors Behind Stress Response, Study Finds*

*ScienceDaily (Sep. 7, 2011)* - When healthy people are faced with threatening situations, they react with a suitable behavioural response and do not descend into a state of either panic or indifference, as is the case, for example, with patients who suffer from anxiety.

http://www.sciencedaily.com/releases/2011/09/110906085220.htm

"With the help of genetic studies on mice, scientists from the Max Planck Institute of Psychiatry have discovered two opposing neuronal regulatory circuits for the generation and elimination of fear. Both are controlled by the stress-inducing messenger substance corticotropin-releasing hormone (CRH) and its type 1 receptor (CRHR1).

The availability of these factors in neurons that release glutamate in brain areas of the limbic system activates a neuronal network which causes anxiety behaviour.

Conversely, in dopamine-releasing neurons in the mid-brain, these factors give rise to behaviour that reduces fear. Because disorders of the stress factors may be observed in many patients with affective illnesses, the scientists suspect that the pathological alteration of the CRHR1-dependent regulatory circuits may be at the root of such emotional maladies."


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## Quarter Pounder (Jun 17, 2011)

That's interesting. Does that mean that DP/DR could be an hormonal problem like, I don't know, hypothiroidism, and could be solved by taking CRH?
Too bad I don't have any anxiety nor fear, so I don't really relate to the article...


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## Jayden (Feb 9, 2011)

Quarter Pounder said:


> That's interesting. Does that mean that DP/DR could be an hormonal problem like, I don't know, hypothiroidism, and could be solved by taking CRH?
> Too bad I don't have any anxiety nor fear, so I don't really relate to the article...


I've been tested for hypothyroidism because my mom has some thyroid problem and I was perfectly fine. But I still think it could be hormonal


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## RamonX (Feb 10, 2011)

Hi Dreamer,
Again a very interesting post. Thank you.
It also underlines the need for better ways of testing and designing trials for the effectiveness of drugs.

I think it is à bloody shame that there still isn't any good anxiolytic drug available that works specific and does not cause tolerance. 
Together with pain it is one of essential causes of deep human suffering. It accounts for a lot of misery among people with psychiatric disorders.

In the last two decades a lot of research has been put into the quest for better anxiolytics. There are many different compounds and different classes of drugs that in animal research have clear anxiolytic potential. But at the moment there is very little left in the pipelines of pharmaceutical companies, and many of them have even thrown out all research for psychiatric drugs from their port folio's.

Why did all these compounds fail to reach the market? 
A lot of them failed to show superiority over placebo in final phase III stages. (this is the last stage before the Federal Drug Administration, or its European( or whatever other country's) counterpart can decide to give permission for registration. Other ones were dropped because the companies did not want to take the risk of having to finance expensive phase III trials without any guarantees. So they chose to market drugs that were just variations on older medications with no new mechanisms of action. Safe and much cheaper, but not at all likely to offer any advantage over older meds.

I have read about researchers who were shocked and very dissapointed that à medication that they worked on, and that was very promisng was just dropped orsold to another company that did nothing with it. 
I am not saying the big pharmaceuticals are the only ones to blame, in the end they just do what is to be expected of big companies, they try to make as much money as they possibly can with as little risk as possible. 
It is the whole system that prevents real breakthroughs. Everywhere in the world publicly financed research has been diminished, and everything is ruled by patents, so once a company decides to drop a substance, nobody else kan develop it further.

Several brain area's and mechanisms have been elucidated that play an important role in anxiety behaviour. For most psychoactive substances have been found that can influence them. But probably genetic differences and other factors make these compounds behave differently in subgroups of people. (as is the case with older medications as well). This can make trials unreliable. If 100 people with panic attacks take à new substance and only 20 respond to it, chances are that the whole group effect won't reach à significant percentage over à placebo control group, although for the responders this medication could turn out very beneficial.

Recently in Holland there has been a lot of media attention for two little boys which Duchennes Muscular Dystrophy who were selected for à trial of 
à new med. For the boys the results were spectacular, and clearly not caused by a placebo effect. The group result of the whole trial was not sufficiënt though, and the boys were denied further treatment with this med. Soon they relapsed completely and the med won't be developed further. 
This was a big issue overhere, but actually it happens all the time. 
Well more about this later, because I have to go to bed now


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## Visual (Oct 13, 2010)

Thanks for the interesting article.

Noticed that dopamine is used to reduce anxiety - this has been my experience with dopamine agonists. In my case, it provides fuel for 'stuck' circuits, giving me a choice/ability to choose my response. Likely there are other mechanisms at work as well.

Neuroscience is working to understand why some people have a strong anxiety response to a situation where others do not. Thankfully there is so much plasticity in the brain to retrain stress response so that emotions assist us instead of rule us.

It is very important to resolve chronic anxiety since, not only does it make life difficult, but the "prolonged glucocorticoid exposure" actually kills neurons in the hippocampus. So it makes sense that "the use of CRH-receptor 1 antagonists" could prove very helpful. One should never feel discouraged or shame in trying medications to help resolve anxiety.

It will be neat to see how research with this develops


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## RamonX (Feb 10, 2011)

> Noticed that dopamine is used to reduce anxiety - this has been my experience with dopamine agonists. In my case, it provides fuel for 'stuck' circuits, giving me a choice/ability to choose my response. Likely there are other mechanisms at work as well.


Yes this is interesting, I never dared try a dopamine enhancing med. I fear that I might have psychotic symptoms (although I never had any before), and apart from that I am very sensitive to stimulating substances like caffeine and ventolin. But maybe I should try a low dose of ritalin once, see what it does.

I also wonder what this means for people that take anti-psychotics. They are promoted more and more for everything from real psychosis to the common cold







. But nervousness and agitation is a prominent adverse effect with them.

Alas CRH-1 antagonists have not yet fullfilled their promise although they have been in development for quite some time. Hopefully research projects like the one Dreamer mentioned can renew interest in them. This abstract shows another big trial that failed to show à CRH blocker superior to placebo. Luckily the researchers mention the possibility of genetic subgroups that might respond:

*Depress Anxiety. 2010 May; vol. 27(5) pp. 417-25
Multicenter, randomized, double-blind, active comparator and placebo-controlled trial of a corticotropin-releasing factor receptor-1 antagonist in generalized anxiety disorder.
Coric V, Feldman HH, Oren DA, Shekhar A, Pultz J, Dockens RC, Wu X, Gentile KA, Huang SP, Emison E, Delmonte T, D'Souza BB, Zimbroff DL, Grebb JA, Goddard AW, Stock EG
Pexacerfont did not demonstrate efficacy compared to placebo for the treatment of GAD. Whether these findings are generalizable to this class of 
agents remains to be determined. Our preliminary genetic finding of an association between a SNP for the gene encoding plexin A2 and an anxiety phenotype in this study merits further exploration. The trial was registered at clinicaltrials.gov (NCT00481325) before enrollment.
Affiliation: Bristol-Myers Squibb Company, Neuroscience Global Clinical Research, Wallingford, Connecticut 06492, USA. [email protected]
*



> It is very important to resolve chronic anxiety since, not only does it make life difficult, but the "prolonged glucocorticoid exposure" actually kills neurons in the hippocampus. So it makes sense that "the use of CRH-receptor 1 antagonists" could prove very helpful. One should never feel
> discouraged or shame in trying medications to help resolve anxiety.


Yes, i think prolongued stress is a critical factor in most psychiatric disorders, and even in à lot of somatic diseases. It would be such à big help to have meds that reliably can dampen stress.


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## Sleepwalker (Dec 4, 2008)

Visual said:


> Thanks for the interesting article.
> Noticed that dopamine is used to reduce anxiety - this has been my experience with dopamine agonists. In my case, it provides fuel for 'stuck' circuits, giving me a choice/ability to choose my response.


That's interesting 'dude.
Specifically which dopamine agonists do you take or are you familiar with?


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## Visual (Oct 13, 2010)

Sleepwalker said:


> That's interesting 'dude.
> Specifically which dopamine agonists do you take or are you familiar with?


The best I've used is Sinemet (carbidopa/levodopa). Others tried (with benefits) are: Requip, Selegiline, and Wellbutrin (this one can be rough - take only small doses).

Here is a curious article, http://en.wikipedia.org/wiki/Aniracetam Notice the method of action and then method of action of drugs that do the opposite of this one. However, haven't heard reports of lasting benefits of trying this for DP, DR, or HPPD.


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## Guest (Sep 28, 2011)

RamonX said:


> Why did all these compounds fail to reach the market?
> A lot of them failed to show superiority over placebo in final phase III stages. (this is the last stage before the Federal Drug Administration, or its European( or whatever other country's) counterpart can decide to give permission for registration. Other ones were dropped because the companies did not want to take the risk of having to finance expensive phase III trials without any guarantees. So they chose to market drugs that were just variations on older medications with no new mechanisms of action. Safe and much cheaper, but not at all likely to offer any advantage over older meds.


no depression-anxiety-DP-panic pill will EVER be able to beat placebo. accept it. they are only better in creating addictions and making one feel like a drunk zombie.


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## Sleepwalker (Dec 4, 2008)

Visual said:


> The best I've used is Sinemet (carbidopa/levodopa). Others tried (with benefits) are: Requip, Selegiline, and Wellbutrin (this one can be rough - take only small doses).
> 
> Here is a curious article, http://en.wikipedia....wiki/Aniracetam Notice the method of action and then method of action of drugs that do the opposite of this one. However, haven't heard reports of lasting benefits of trying this for DP, DR, or HPPD.


Visual, how do you get your sinemet; is it by prescription only? Is there a generic version?
I am excited to try it.


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## Visual (Oct 13, 2010)

Sleepwalker said:


> Visual, how do you get your sinemet; is it by prescription only? Is there a generic version?
> I am excited to try it.


Have a prescription for it (3 years now). Have only tried the generic. Always a matter of $$$. I get a discount though a state program so about $25.00 last about 3 months.


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## staples (Apr 1, 2009)

I've been thinking this all along. Not saying specifically CRH or CRHR1, but the fact that these amino acids sends the signal to your adrenal glands to release cortisol, DHEA and other hormones. I believed DP / DR has always been linked to a hormonal imbalance.

The problem is in western medication when we test for Hyper / Hypothyroid the normal levels to what a average doctor sees are so much different then what a holistic doctor sees. My doctor told me that one person who was only 22 had a "normal" thyroid level as someone in their 80s.

Another thing, normal doctors don't treat for adrenal fatigue. They only treat the EXTREME cases, which are; Cushing's and Addison's disease. Your body either produces too much cortisol to the point of danger, or not enough to the point of danger. In my eyes, anyone with anxiety has some sort of adrenal fatigue but we're always stuck in fight or flight mode. That puts a huge toll on your hormone levels.

Another thing, remember that anti-depressants don't make serotonin, it only helps keep it in the brain longer (long story short). If your body doesn't produce enough serotonin, then the SSRIs that are being taken can't do their job properly. A lot of people will still feel depressed, anxious, tired and the list goes on.

I'm actually testing with my doctor a theory to see if dropping my anti-depressant below the recommended dose (60mg is recommended, but I'm dropping it to 30mg) and adding 5HTP to my regimen proves to be more beneficial then staying at a higher dose of my SSRI. That way I don't run the risk of having too much serotonin and getting serotonin syndrome.

I'm also going to be doing BHRT (bioidentical hormone replacement). These are natural hormones to try to balance me out and get me back on track.

I hope this makes some sense. I've been working all day and I'm tired as hell lol.


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## Sleepwalker (Dec 4, 2008)

Visual said:


> Have a prescription for it (3 years now). Have only tried the generic. Always a matter of $. I get a discount though a state program so about $25.00 last about 3 months.


Visual, I managed to get some Simenet without a prescription--25/100.
Could you tell me a little bit about your daily dose and and how you finally settled on the dose you're on , now?

I would imagine that for Parkinsons' the dosing would be much higher that for our use, here.
I plan to begin seeing a neurologist, but in the meantime, it would be nice to get some of your experience.


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## Visual (Oct 13, 2010)

Sleepwalker said:


> Visual, I managed to get some Simenet without a prescription--25/100.
> Could you tell me a little bit about your daily dose and and how you finally settled on the dose you're on , now?
> 
> I would imagine that for Parkinsons' the dosing would be much higher that for our use, here.
> I plan to begin seeing a neurologist, but in the meantime, it would be nice to get some of your experience.


You'll find some details in http://www.hppdonline.com

1/2 pill 2 or 3 times a day usually does the trick. Some notice it in a couple days. Others much shorter. One guy said in 30 minutes he began to cry because he could feel reality coming back into him after 5 years. Also, he could see ships out his window as fuzzy objects, now he can see them clearly and read the names on them.

As far as the dose you settle on, it generally is the minimum that works - this is the rule with PD (however, as you suggested, they take a LOT more when the disease advances). The standard formulation (not CR) seems to work best.

In general, you will find that you don't 'feel' you need more and taking more doesn't 'feel' right. So far with the people that try it, about half say it helps a lot. The others say it does nothing and they can't even tell they have taken it. It is gentle as far as these meds go (sounds like a laxative commercial) with very little side effects - especially on such a low dose. It is not addictive and, at this low dose, can be taken for life if one wishs.

What are your main symptoms?

Have you tried other meds?

Hope this helps and let us know how it goes...


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## Sleepwalker (Dec 4, 2008)

Visual said:


> You'll find some details in http://www.hppdonline.com
> 
> What are your main symptoms?
> 
> ...


-"Brain Fog": Confused and very disorganized thinking.
-Anxiety. (Probably GAD, since 1. My anxiety covers a wide range of things and 2. I have Mitral Valve Prolapse; associated with GAD).
-Constant neck tension. (interesting is the fact that when given a good massage, my DD lifts tremendously. However the effect does not last long - the tension soon returns).
-Mental fatigue; often exhaustion.
-Depression.
-Obsessiveness (thinking) and rumination.
-Almost total lack of focus and concentration.
-Very poor working memory.
-Inability to learn new things (forgetting old things, too.)
-Emotional flatness.
-Thoughts that seem to be outside my head; just hovering above it.
-Fell robotic; just going though the motions of life.
-Empty feeling in my head: to name some that come to mind.

At present, I'm on:

Lamotrigine 100mg X 2 daily
Clonazepam 2-2.5 mg/ day
Melatonin (lozenge) as needed.
Syndol (muscle relaxant) as needed.

My mainstay, really, is lamotrigine and clonazepam.

As for the sinemet, well, unfortunately, didn't seem to make much difference.

I'd would welcome your obsevations.

p.s. Recently I'd been looking into AD/HD, the inattentive type, co-morbid with anxiety (which, incidentally occurs at a rate of 40%), according to one source.


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