Psycho-Babble Medication Thread 847161

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Bipolar disorder and genetics. New data.

Posted by SLS on August 19, 2008, at 7:14:26

LARGEST STUDY OF ITS KIND IMPLICATES GENE ABNORMALITIES IN BIPOLAR DISORDER
Links Sodium, Calcium Imbalances to Manic Depressive Episodes

The largest genetic analysis of its kind to date for bipolar disorder <http://www.nimh.nih.gov/health/topics/bipolar-disorder/index.shtml>; has implicated machinery involved in the balance of sodium and calcium in brain cells. Researchers supported in part by the National Institute of Mental Health, part of the National Institutes of Health, found an association between the disorder and variation in two genes that make components of channels that manage the flow of the elements into and out of cells, including neurons.

"A neuron's excitability -- whether it will fire -- hinges on this delicate equilibrium," explained Pamela Sklar, M.D., Ph.D., of Massachusetts General Hospital (MGH) and the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard, who led the research. "Finding statistically robust associations linked to two proteins that may be involved in regulating such ion channels -- and that are also thought to be targets of drugs used to clinically to treat bipolar disorder -- is astonishing."

Although it's not yet known if or how the suspect genetic variation might affect the balance machinery, the results point to the possibility that bipolar disorder might stem, at least in part, from malfunction of ion channels.

Sklar, Shaun Purcell, Ph.D., also of MGH and the Stanley Center, and Nick Craddock, M.D., Ph.D., of Cardiff University and the Wellcome Trust Case Control Consortiuum in the United Kingdom and a large group of international collaborators report on their findings online Aug. 17 , 2008 in "Nature Genetics."

"Faced with little agreement among previous studies searching for the genomic hot spots in bipolar disorder, these researchers pooled their data for maximal statistical power and unearthed surprising results," said NIMH Director Thomas R. Insel, M.D. "Improved understanding of these abnormalities could lead to new hope for the millions of Americans affected by bipolar disorder."

In the first <http://www.nimh.nih.gov/science-news/2007/genetic-roots-of-bipolar-disorder-revealed-by-first-genome-wide-study-of-illness.shtml>; such genome-wide association study <http://www.genome.gov/20019523>; for bipolar disorder, NIMH researchers last fall reported the strongest signal associated with the illness in a gene that makes an enzyme involved the action of the anti-manic medication lithium. However, other chromosomal locations were most strongly associated with the disorder in two subsequent studies.

Since bipolar disorder is thought to involve many different gene variants, each exerting relatively small effects, researchers need large samples to detect relatively weak signals of illness association.

To boost their odds, Sklar and colleagues pooled data from the latter two previously published and one new study of their own. They also added additional samples from the STEP-BD <http://www.nimh.nih.gov/health/trials/practical/step-bd/index.shtml>; study and Scottish and Irish families, and controls from the NIMH Genetics Repository <http://nimhgenetics.org/>;. After examining about 1.8 million sites of genetic variation in 10,596 people -- including 4,387 with bipolar disorder -- the researchers found the two genes showing the strongest association among 14 disorder-associated chromosomal regions.

Variation in a gene called Ankyrin 3 (ANK3) showed the strongest association with bipolar disorder. The ANK3 protein is strategically located in the first part of neuronal extensions called axons and is part of the cellular machinery that decides whether a neuron will fire. Co-authors of the paper had shown last year in mouse brain that lithium, the most common medication for preventing bipolar disorder episodes, reduces expression of ANK3.

Variation in a calcium channel gene found in the brain showed the second strongest association with bipolar disorder. This CACNA1C protein similarly regulates the influx and outflow of calcium and is the site of interaction for a hypertension medication that has also been used in the treatment of bipolar disorder.

In addition to NIMH, the research was also funded by NARSAD (National Alliance for Research on Schizophrenia and Depression), the Wellcome Trust, Johnson & Johnson Pharmaceutical Research & Development, the Johnson & Johnson Foundation, the Sylvan C. Herman Foundation, the Stanley Medical Research Institute, the Dauten Family, the Merck Genome Research Institute, and the National Health and Medical Research Council of Australia.

 

Re: Bipolar disorder and genetics. New data. SLS

Posted by Marty on August 19, 2008, at 11:06:27

In reply to Bipolar disorder and genetics. New data., posted by SLS on August 19, 2008, at 7:14:26

Scott,

[PS: I know you don't quite fond of my LONGGGG post, but please read this one as I'd like your thoughts about the atypical effects CHELATED(only) Potassium has on me, a Bipolar type 2 and because I think it could interest you because of the potential link with the new study.]

Wow .. exciting stuff. Personalized/Genetic medecine can't come fast enough! Having more significant target get us closer to this day. Genetic therapy for mental illness has so much potential that if I wouldn't calm myself I think I would cry :P I wish the next step they would take is to find what's promote ANK3 expression and find ways to inhibit those promoters directly rather than indirectly.. reducing the biological events cascade between the drugs mechanism of action target and the reduced ANK3 expression.

Btw Scott, did I ever told you how I get QUICKLY excited and my mood improve when I take even low dose of Protein-bounded Potassium supplement ? After I tried about 40 supplements I, in fact, consider Protein-bounded Potassium (with Chromium for 5-HT2 desensitivation/Insulin enhancer) my best discovery. My memory doesn't allow me to remember with confidence even the basics of 'Cell Membrane Potential' right now.. but I may want to revisit this story as Potassium works with Sodium in membrane potential. Interesting fact considering the finding of the new study! Not sure of the implication/mechanism of action at all because ONLY the protein-bounded form as this effect on me ! Possibilities:

PS: I just checked the bottle and I was wrong about the Potassium being protein-bounded: it's in fact bounded to some Peptides, Polypeptides and Amino acids. Even more interesting...

1. NaKATPase inhibition: the Potassium would bind to the transporter but would be unable to enter the cell because of the bounded-protein leading to NaKATPase inhibition by way of occupation. That would end up stabilizing the membrane potential.. considering the effect on me this is counter-intuitive and so would implicate other cascading biological events caused by that inhibition.

2. Enhanced Potassium availability/transport improving, when in depressive state, my defective bipolar neurons ability to fire at will.

3. Enhanced Potassium availability/transport leading some susceptible bipolar neurons to fire in a random fashion.

4. Interaction with Potassium ion channels. Antagonism or better 'Agonism' because of the chelation ?

What do you think Scott ? Any thoughts ? I wish some other Bipolar on the board would give the protein-bounded Potassium a try and report about it. Willing ? The Chelated Potassium is by 'Trophic'.. pretty cheap. Anyone willing to try should stick to this highly available brand for obvious reasons.

/\/\arty

 

Re: Bipolar disorder and genetics. New data. Marty

Posted by SLS on August 19, 2008, at 12:30:40

In reply to Re: Bipolar disorder and genetics. New data. SLS, posted by Marty on August 19, 2008, at 11:06:27

> [PS: I know you don't quite fond of my LONGGGG post, but please read this one as I'd like your thoughts about the atypical effects CHELATED(only) Potassium has on me, a Bipolar type 2 and because I think it could interest you because of the potential link with the new study.]

Another interesting observation is that calcium supplement makes me feel considerably worse with an hour. I don't mess around with calcium anymore. Maybe with magnesium? I don't know.

> Wow .. exciting stuff. Personalized/Genetic medecine can't come fast enough! Having more significant target get us closer to this day. Genetic therapy for mental illness has so much potential that if I wouldn't calm myself I think I would cry :P I wish the next step they would take is to find what's promote ANK3 expression and find ways to inhibit those promoters directly rather than indirectly.. reducing the biological events cascade between the drugs mechanism of action target and the reduced ANK3 expression.

I am not familiar with ANK3. However, I do agree with your premise regarding gene therapy being direct rather than indirect via second messenger cascades.

> 1. NaKATPase inhibition: the Potassium would bind to the transporter but would be unable to enter the cell because of the bounded-protein leading to NaKATPase inhibition by way of occupation. That would end up stabilizing the membrane potential.. considering the effect on me this is counter-intuitive and so would implicate other cascading biological events caused by that inhibition.
>
> 2. Enhanced Potassium availability/transport improving, when in depressive state, my defective bipolar neurons ability to fire at will.
>
> 3. Enhanced Potassium availability/transport leading some susceptible bipolar neurons to fire in a random fashion.
>
> 4. Interaction with Potassium ion channels. Antagonism or better 'Agonism' because of the chelation ?


I'm afraid I don't know enough about NaKATPase to be able to comment. I guess I have my next project. :-)


- Scott

 

Re: Bipolar disorder and genetics. New data. SLS

Posted by Marty on August 19, 2008, at 15:02:18

In reply to Re: Bipolar disorder and genetics. New data. Marty, posted by SLS on August 19, 2008, at 12:30:40

> Another interesting observation is that calcium supplement makes me feel considerably worse with an hour. I don't mess around with calcium anymore. Maybe with magnesium? I don't know.
---
Really? Me too! ..big time. I also feel way more anxious. Interesting. That's the kind of think I'd like to being able to make a Pool about on this board. If you're not sure about Magnesium, you should give it a good trial with a respectable dosage. I've found it to be pretty good.


> I am not familiar with ANK3. However, I do agree with your premise regarding gene therapy being direct rather than indirect via second messenger cascades.
---
Actually I never heard of ANK3 before reading your post, but from what I read in it Lithium would reduce ANK3 expression. So...

> I'm afraid I don't know enough about NaKATPase to be able to comment. I guess I have my next project. :-)
---
Ahah. Great.. keep me posted about your trial. Again I suggest you try the same brand/type of chelated potassium as me.

/\/\arty

 

Re: Bipolar disorder and calcium?

Posted by Amigan on October 13, 2008, at 11:12:50

In reply to Re: Bipolar disorder and genetics. New data. Marty, posted by SLS on August 19, 2008, at 12:30:40

> Another interesting observation is that calcium supplement makes me feel considerably worse with an hour. I don't mess around with calcium anymore.

http://www.dr-bob.org/cgi-bin/pb/mget.pl?post=/babble/alter/20081006/msgs/857183.html#857183

> Maybe with magnesium? I don't know.

Magnesium sounds very good in this case. Have you, or anyone else, tried it and had positive results?


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