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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 17 of 17. This is the beginning of the thread.
Posted by SLS on March 1, 2006, at 7:30:46
http://www.nih.gov/news/pr/feb2006/nimh-28.htmDepression Model Leaves Mice with Molecular Scar
In addition to triggering a depression (http://www.nimh.nih.gov/healthinformation/depressionmenu.cfm)-like social withdrawal syndrome, repeated defeat (http://www.nimh.nih.gov/press/bdnfknockdown.cfm) by dominant animals leaves a mouse with an enduring molecular scar in its brain that could help to explain why depression is so difficult to cure, suggest researchers funded by National Institutes of Health’s (NIH) National Institute of Mental Health (NIMH).
In mice exposed to this animal model of depression, silencer molecules turned off a gene for a key protein in the brain’s hippocampus. By activating a compensatory mechanism, an antidepressant temporarily restored the animals’ sociability and the protein’s expression, but it failed to remove the silencers. A true cure for depression would likely have to target this persistent stress-induced scar, say the researchers, led by Eric Nestler, M.D., The University of Texas Southwestern Medical Center, who report on their findings online in Nature Neuroscience during the week of February 26, 2005.
“Our study provides insight into how chronic stress triggers changes in the brain that are much more long-lived than the effects of existing antidepressants,” explained Nestler.
In the study, mice exposed to aggression by a different dominant mouse daily for 10 days became socially defeated; they vigorously avoided other mice, even weeks later. Expression of a representative gene in the hippocampus, a memory hub implicated in depression, plummeted three-fold and remained suppressed for weeks. However, chronic treatment with an antidepressant (the tricyclic imipramine) restored expression of the gene for brain derived neurotrophic factor (BDNF) to normal levels and reversed the social withdrawal behavior. BDNF in the hippocampus has been linked to memory (http://www.nimh.nih.gov/press/prbdnf.cfm), learning and depression, but Nestler said social defeat stress probably similarly affects other genes there as well.
The researchers pinpointed how social defeat changes the BDNF gene’s internal machinery. They traced the gene expression changes to long-lasting modifications in histones, proteins that regulate the turning on-and-off of genes via a process called methylation. Methyl groups, the silencer molecules, attach themselves to the histones, turning off the gene. Notably, imipramine was unable to remove these silencer molecules, suggesting that they remained a latent source of vulnerability to future depression-like responses to stress.
Imipramine reversed the suppressed BDNF gene expression by triggering a compensatory mechanism, acetylation, in which molecular activators attach themselves to the gene and overcome the silencer molecules. Imipramine turned off an enzyme (Hdac5) that degrades the activators, allowing them to accumulate.
“The molecular scar induced by chronic stress in the hippocampus, and perhaps elsewhere in the brain, can’t be easily reversed,” said Nestler. “To really cure depression, we probably need to find new treatments that can remove the silencer molecules.”
Posted by linkadge on March 1, 2006, at 15:08:07
In reply to Depression and hippocampal scarring - BDNF, posted by SLS on March 1, 2006, at 7:30:46
That is really interesting. I am ignorant of course, but I am hearing a bit about methylation lately, DNA methylation. Does that bear any links to the kind of methylation involved with SAMe?
Very interesting work. I certainly feel a scar.
BTW. F*ck the dominant mice.
Linkadge
Posted by theo on March 1, 2006, at 16:27:10
In reply to Depression and hippocampal scarring - BDNF, posted by SLS on March 1, 2006, at 7:30:46
Very interesting. By the way, are you going to break down and try the EmSam patch?
Posted by SLS on March 1, 2006, at 16:54:40
In reply to Re: Depression and hippocampal scarring - BDNF, posted by linkadge on March 1, 2006, at 15:08:07
Posted by SLS on March 1, 2006, at 17:10:47
In reply to Re: Depression and hippocampal scarring - BDNF » SLS, posted by theo on March 1, 2006, at 16:27:10
> Very interesting. By the way, are you going to break down and try the EmSam patch?
Actually, I have spent the last couple of weeks tapering and discontinuing Parnate. At this point, my doctor would like to see how I do on a combination of Lamictal and Wellbutrin. I am not very optimistic. In the past, Wellbutrin has made my depression worse, not better. It produced quite a bit of dysphoria the last time I tried it. In any event, that seems to be the next thing on the list.
I have never been a big believer in the capacity of selegiline to treat severe depression. I hope that I am wrong. I get the feeling that a great many people will migrate over to the EmSam patch. We will get a good idea as to the success rate of this drug early. Of course, we will not get a good idea of how valuable this drug is in mainstream psychiatry by looking at how many people improve on it here on PB. We tend to be a treatment-resistant population. No drug looks good here.
- Scott
Posted by linkadge on March 1, 2006, at 17:27:18
In reply to Re: Depression and hippocampal scarring - BDNF » theo, posted by SLS on March 1, 2006, at 17:10:47
There is a group of people who have kind of like a combination of cigarette additiction/depression/ADD. Perhaps there will be some application here.
Linkadge
Posted by linkadge on March 1, 2006, at 18:48:43
In reply to Re: Depression and hippocampal scarring - BDNF, posted by linkadge on March 1, 2006, at 17:27:18
The article said that imipramine turned off a gene called HDAC5 ? Isn't valproate a HDAC inhibitors ?
Linkadge
Posted by linkadge on March 1, 2006, at 19:05:26
In reply to Re: Depression and hippocampal scarring - BDNF, posted by linkadge on March 1, 2006, at 18:48:43
Now I am going on a search for agents that might be able to modify HDAC.
Linkadge
Posted by Phillipa on March 1, 2006, at 20:23:07
In reply to Re: Depression and hippocampal scarring - BDNF » theo, posted by SLS on March 1, 2006, at 17:10:47
Scott my exact reason for wanting to create a med board for mainstream people who have a positive response to meds. What do you think of this? Thanks Phillipa
Posted by theo on March 1, 2006, at 23:06:52
In reply to Re: Depression and hippocampal scarring - BDNF » theo, posted by SLS on March 1, 2006, at 17:10:47
At this point, my doctor would like to see how I do on a combination of Lamictal and Wellbutrin. >
> - ScottAre you keeping Abilify on board or stopping it for the Lamictal and Wellbutrin combo?
Posted by SLS on March 2, 2006, at 7:30:12
In reply to Re: Depression and hippocampal scarring - BDNF » SLS, posted by theo on March 1, 2006, at 23:06:52
> At this point, my doctor would like to see how I do on a combination of Lamictal and Wellbutrin. >
> > - Scott
>
> Are you keeping Abilify on board or stopping it for the Lamictal and Wellbutrin combo?
>
>
I will end up taking:nortriptyline 100mg
Wellbutrin 300mg
Lamictal 100mg
Keppra 1000mgI really don't know what I will do if this treatment fails, but I have a few weeks to think about it.
- Scott
Posted by SLS on March 2, 2006, at 7:56:26
In reply to Re: Depression and hippocampal scarring - BDNF » SLS, posted by Phillipa on March 1, 2006, at 20:23:07
> Scott my exact reason for wanting to create a med board for mainstream people who have a positive response to meds. What do you think of this? Thanks Phillipa
That's a tough one.
I think it is important to give people hope. SSRIs and SNRIs do work. So does Wellbutrin and Remeron. Unfortunately, they don't work for everybody. They also don't continue to work for many people in a consistent manner. It would be nice to see more success stories submitted to this forum, but there may be reasons why this is not the case.
What are the statistics? I guess that depends on who you ask.
It seems to me that for any single antidepressant, approximately 30% will achieve remission, and another 35% will experience a significant, although partial improvement. Of the 35% of people who do not respond to the first drug tried, approximately 65% will go on to respond to at least one antidepressant treatment. What remains frustrating is that it takes so much time to investigate different drugs and drug combinations. That leaves about 15% of the original cohort who will remain treatment-resistant using current therapies. Some people are more optimistic than I am. They state that no more than 5% of people are truly refractory to treatment.
I still believe that Psycho-Babble attracts people who have encountered problems with their treatment. Because of this, it appears that treatments are less effective than they really are in the general population.
My concern is that a separation of boards might cause the non-responders to grow to resent the responders. It might also add to the feelings of hopelessness of the non-responders rather than to inject them with more positive energy.
- Scott
Posted by Phillipa on March 2, 2006, at 18:32:31
In reply to Re: Depression and hippocampal scarring - BDNF » Phillipa, posted by SLS on March 2, 2006, at 7:56:26
Scott I see your point but what about a Newbie who sees a lot of discouraging posts. Why not keep the main board and then one for the positive responders so if a newbie has start up or side effects they will know that things do get better. Or is someone is having a really bad day they could go to that board to maybe feel more hopeful. But keep this one too. Don't get rid of it. I know some days all I want to hear is someone is better because a med worked for them. Love Phillipa
Posted by linkadge on March 2, 2006, at 19:09:40
In reply to Re: Depression and hippocampal scarring - BDNF » SLS, posted by Phillipa on March 2, 2006, at 18:32:31
Life is all about discouraging posts. We need to know the good and the bad. Trying to paint an unrealistically rosey picture about medications will only make things hard for people in the future.
What about the newbie? What if a newbie read about a negative experience somebody had with effexor, and that information helped them when they experienced the same bad thing? So you see, even negative posts can be helpfull under certain circumstances.
Linkadge
Posted by cecilia on March 3, 2006, at 0:53:35
In reply to Re: Depression and hippocampal scarring - BDNF » Phillipa, posted by SLS on March 2, 2006, at 7:56:26
I agree with Scott, as a non-responder it's hard sometimes not to resent the responders. Especially when they claim hugely inflated success rates for whatever happens to work for them. Or when they complain about side effects that seem trivial to non-responders. Cecilia
Posted by theo on March 3, 2006, at 11:17:55
In reply to Re: Depression and hippocampal scarring - BDNF, posted by SLS on March 2, 2006, at 7:30:12
>
> I will end up taking:
>
> nortriptyline 100mg
> Wellbutrin 300mg
> Lamictal 100mg
> Keppra 1000mg
>
> I really don't know what I will do if this treatment fails, but I have a few weeks to think about it.
>
>
> - ScottWhy did you drop the Abilify? Side Effects, poop out?
Posted by SLS on March 5, 2006, at 6:48:22
In reply to Re: Depression and hippocampal scarring - BDNF » SLS, posted by theo on March 3, 2006, at 11:17:55
> >
> > I will end up taking:
> >
> > nortriptyline 100mg
> > Wellbutrin 300mg
> > Lamictal 100mg
> > Keppra 1000mg
> >
> > I really don't know what I will do if this treatment fails, but I have a few weeks to think about it.
> >
> >
> > - Scott
>
> Why did you drop the Abilify? Side Effects, poop out?
You know my drugs better than my doctor does!Yes, I am still taking Abilify 10mg. I think it helps with energy and motivation, and might even be an anti-suicide drug.
- Scott
This is the end of the thread.
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