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Dr. Bob is Robert Hsiung, MD,
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Posted by jrbecker76 on October 25, 2009, at 10:44:54
http://www.eurekalert.org/pub_releases/2009-10/nu-wad102309.php
Why antidepressants don't work for so manyNorthwestern research finds drugs aim at wrong target
CHICAGO --- More than half the people who take antidepressants for depression never get relief.
Why? Because the cause of depression has been oversimplified and drugs designed to treat it aim at the wrong target, according to new research from the Northwestern University Feinberg School of Medicine. The medications are like arrows shot at the outer rings of a bull's eye instead of the center.
A study from the laboratory of long-time depression researcher Eva Redei, presented at the Neuroscience 2009 conference in Chicago this week, appears to topple two strongly held beliefs about depression. One is that stressful life events are a major cause of depression. The other is that an imbalance in neurotransmitters in the brain triggers depressive symptoms.
Both findings are significant because these beliefs were the basis for developing drugs currently used to treat depression.
Redei, the David Lawrence Stein Professor of Psychiatry at Northwestern's Feinberg School, found powerful molecular evidence that quashes the long-held dogma that stress is generally a major cause of depression. Her new research reveals that there is almost no overlap between stress-related genes and depression-related genes.
"This is a huge study and statistically powerful," Redei said. "This research opens up new routes to develop new antidepressants that may be more effective. There hasn't been an antidepressant based on a novel concept in 20 years."
Her findings are based on extensive studies with a model of severely depressed rats that mirror many behavioral and physiological abnormalities found in patients with major depression. The rats, after decades of development, are believed to be the most depressed in the world.
Little Overlap Between Stress and Depression Genes
Redei used microarray technology to isolate and identify the specific genes related to depression in these animals. She examined the genes in the brain regions -- the hippocampus and amygdala -- commonly associated with depression in rats and humans.
Then she took four genetically different strains of rats and exposed them to chronic stress for two weeks. Afterwards, she identified the genes that had consistently increased or decreased in response to the stress in all four strains in the same brain regions.
Redei now had one set of depression-related genes that came out of an animal model of depression and one set of stress-related genes that came our of her chronic stress study.
Next she compared the two sets of genes to see if there were any similarities. "If the 'stress causes depression theory' was correct, there should have been a significant overlap between these two sets of genes," she said. "There weren't."
Out of a total of over 30,000 genes on the microarray, she discovered approximately 254 genes related to stress and 1275 genes related to depression, with an overlap of only five genes between the two.
"This overlap is insignificant, a very small percentage," Redei said. "This finding is clear evidence that at least in an animal model, chronic stress does not cause the same molecular changes as depression does."
Antidepressants Treat Stress Not Depression
Most animal models that are used by scientists to test antidepressants are based on the hypothesis that stress causes depression. "They stress the animals and look at their behavior," she said. "Then they manipulate the animals' behavior with drugs and say, 'OK, these are going to be good anti-depressants.' But they are not treating depression; they are treating stress."
That is one key reason why current antidepressants aren't doing a great job, Redei noted. She is now looking at the genes that differ in the depressed rat to narrow down targets for drug development.
She said another reason current antidepressants are often ineffective is that they aim to boost neurotransmitters based on the popular molecular explanation of depression, which is that it's the result of decreased levels of the neurotransmitters serotonin, norepinephrine and dopamine. But that's wrong, Redei said.
Drugs Aim at Wrong Molecular Target
In the second part of the study, Redei found strong indications that depression actually begins further up in the chain of events in the brain. The biochemical events that ultimately result in depression actually start in the development and functioning of neurons.
"The medications have been focusing on the effect, not the cause," she said. "That's why it takes so long for them to work and why they aren't effective for so many people."
Her animal model of depression did not show dramatic differences in the levels of genes controlling neurotransmitters functions. "If depression was related to neurotransmitter activity, we would have seen that," she said.
Similarities Between Human and Rodent Brains
Her findings in depressed rats, she said, are very likely applicable to humans.
"The similarities between these regions of the human and rodent brain are remarkable," Redei explained. "The hippocampus and amygdala are part of the so-called ancient lizard brain that controls survival and are the same in even primitive organisms."
###
Contributors to the study from Redei's lab include Brian Andrus, Kristen Dennis and Daniel Schaffer, research assistants, and Pradeep Shukla, a postdoctoral fellow. Jelena Radulovic, M.D., Dunbar Scholar and associate professor in psychiatry and behavioral sciences at the Feinberg School, also contributed as did Peter Vedell, a postdoctoral associate in professor Gary Churchill's group at The Jackson Lab, Bar Harbor.
Posted by linkadge on October 25, 2009, at 10:08:29
In reply to Why antidepressants don't work for so many, posted by jrbecker76 on October 25, 2009, at 9:44:54
This is a *very excellent* article and an interesting new path of research. This article definately rings true with myself.
I hope the genes they do uncover ultimately produce better depression treatments.
The times in my life when I have been the most depressed and suicidal have been periods of remarkably little stress.
Linkadge
Posted by seldomseen on October 25, 2009, at 10:21:54
In reply to Why antidepressants don't work for so many, posted by jrbecker76 on October 25, 2009, at 9:44:54
This is certainly a provocative study, but I do wonder if it has been through peer-review yet. Most of the time, studies that are presented at meetings haven't been published.
Not that peer-review is the end all be all of scientific merit, but of course, the authors of the study are going to proclaim its merit.
It's also highly unusual for a scientist to be so strong in the interpretation and application of a rodent study - or any study for that matter. But the author of the release may be taking her quotes entirely out of context...
We'll just have to see what comes out of this.
Seldom.
Posted by Phillipa on October 25, 2009, at 11:14:41
In reply to Why antidepressants don't work for so many, posted by jrbecker76 on October 25, 2009, at 9:44:54
So does this mean if you have anxiety take an antipressant and if you have depression take neither? Where does that leave benzos and antianxiety meds? As ad's cause stress for me worse than before? Or did I interpret it wrong? Phillipa ps is this all classes of antidepressants? Where do mood stabalizers fit it. Is it only for unipolar depression and not bipolar?
Posted by floatingbridge on October 25, 2009, at 13:13:28
In reply to Why antidepressants don't work for so many, posted by jrbecker76 on October 25, 2009, at 9:44:54
I'm wondering if this is why some get relief from MAOI's w/ their scatter-shot approach?
fb
Posted by bulldog2 on October 25, 2009, at 13:25:03
In reply to Why antidepressants don't work for so many, posted by jrbecker76 on October 25, 2009, at 9:44:54
I have no idea how her study was done and it has to be go through a trial of review to see if her results are truely valid. My thoughts:
1. First she used gene analogy and I don't even understand that concept.
2. Yes rats have similar brains but the differences can be huge in the final result.Most drugs that have passed the rat testing phase do not make it through human testing and that number is well of 90%. Until this testing goes though dogs, champanzees and finally people you can't assume her results have any validity.
3. Peta wants to stop aninal testing based on their investigations that show a low correlation between rats and even higher animals to humans.
4. I believe there are tests that do correlate stress with depression! Autopsies on depressed people have shown enlarged andrenals which seem to indicate chronic stress.
5. In my situation chronic stress seems to almost always lead to depression. I know others who say that is true for them also and others like one of the posters above who don't have that correlation.
6. I still believe that depression is not a disease but a symptom of possibly many diseases. The flaw in the research that looks for drugs for this disease is that rearch in reality is looking for a drug that will control this symptom so you end up with drugs that help about somewhat over 60% of people.
7. Actually I believe maois in some studies (one on parmate) helped over 90% of people who remained. High dropout rate due to sides.
8. Rat studies at best are an indication to further study the new concept.
9. I noticed some in this thread have already excepted her concept as a proven truth. At this point it is a hypothesis.10. But I feel one point is important. Science needs to find the cause or causes of depression. Than pharm companies can find truley effective drugs. She's right about since ssris and snris we really haven't put anything novel out there
11. What is sad is that the most effective drugs (maois) for those that can endure the sides and restrictions and they are over 50 years old are the best drugs out there.
12. While these rat studies are interesting and may need further research please don't assume that that is now a proven true. IT'S A HYPOTHESIS FOR NOW.
Posted by floatingbridge on October 25, 2009, at 13:36:15
In reply to Re: Why antidepressants don't work for so many » jrbecker76, posted by bulldog2 on October 25, 2009, at 13:25:03
Well, I'm posting again to say that article really triggered me. I feel lost and afraid and angry and that I don't know what the heck I am doing. I see a shrink, I'm in therapy. I just feel lost at this moment. I know this feeling will pass, and then I feel this way again.
fb
And when I say triggered, I don't imply any inappropriateness of posting--it's not the article--it's my anxiety!
Posted by bulldog2 on October 25, 2009, at 13:38:10
In reply to Re: Why antidepressants don't work for so many » jrbecker76, posted by floatingbridge on October 25, 2009, at 13:13:28
> I'm wondering if this is why some get relief from MAOI's w/ their scatter-shot approach?
>
> fbGood point. The old drugs (tcas and maois) are dirty and due a lot of things. Their success rate on the severly depressed is higher than the new ssris and snris.
Posted by floatingbridge on October 25, 2009, at 13:38:35
In reply to Re: Why antidepressants don't work for so many » jrbecker76, posted by bulldog2 on October 25, 2009, at 13:25:03
Thanks Bulldog, I just read your post, and I'm calming down--feel like crying, but calming down. I'm sorry. I wish I could take my post back.
fb
Posted by seldomseen on October 25, 2009, at 13:54:48
In reply to Re: Why antidepressants don't work for so many » bulldog2, posted by floatingbridge on October 25, 2009, at 13:38:35
IMO, one should never apologize for being honest. I imagine a lot of people might be upset or confused by this study.
It's okay. We don't even know if any of this will withstand the rigors of peer review, or if these result will translate to humans at all.
Again, it's too early to say anything. Like many studies of this type, I suspect not much will come of it, but that's just my opinion.
Take care.
Seldom
Posted by Fred23 on October 25, 2009, at 14:23:28
In reply to Why antidepressants don't work for so many, posted by jrbecker76 on October 25, 2009, at 9:44:54
> Antidepressants Treat Stress Not Depression
This may explain why I've had success with Lexapro and Klonopin being effective in relieving my general anxiety levels and preventing panic attacks.
Posted by bulldog2 on October 25, 2009, at 14:26:00
In reply to Why antidepressants don't work for so many, posted by jrbecker76 on October 25, 2009, at 9:44:54
You post this as if it is a proven theory. You have to prove this using people. You say rat brains are similar to human brains. That still does not prove anything.
The great majority of these animal studies never end up correlating in humans.
Posted by linkadge on October 25, 2009, at 15:03:57
In reply to Re: Why antidepressants don't work for so many » jrbecker76, posted by bulldog2 on October 25, 2009, at 13:25:03
>6. I still believe that depression is not a >disease but a symptom of possibly many diseases.
I think depression is a disease.
>The flaw in the research that looks for drugs >for this disease is that rearch in reality is >looking for a drug that will control this >symptom so you end up with drugs that help about >somewhat over 60% of people.
I think that number is still overinflated. I also think that if you want to help a person get *well* you need to uncover the mechanism of the disease.
Posted by linkadge on October 25, 2009, at 15:13:50
In reply to Re: This is a rat study!, posted by bulldog2 on October 25, 2009, at 14:26:00
I think this is good research because it is at least attempting to look for alternatives to monoamine based approaches.
I think it is also good because it casts the depressive illness in a better light.
With the stress induced depression theory, depressed patietns are just pathetic wimps who cannot control the stresses of everyday life very well.
At least this study says no, there is something more fundamentally wrong with depressed patients than just people succumming to the stresses of everyday life.
I'm sure stress, like pain can induce depression.
But, I still think there is something more fundamentally wrong.I don't know if the finding of increased adrenal weight has been confirmed in other studies.
I just know with me, the anxiety and depression are for the most part two separate entities.
Linkadge
Posted by bulldog2 on October 25, 2009, at 15:44:29
In reply to Re: This is a rat study!, posted by linkadge on October 25, 2009, at 15:13:50
> I think this is good research because it is at least attempting to look for alternatives to monoamine based approaches.
>
> I think it is also good because it casts the depressive illness in a better light.
>
> With the stress induced depression theory, depressed patietns are just pathetic wimps who cannot control the stresses of everyday life very well.
>
> At least this study says no, there is something more fundamentally wrong with depressed patients than just people succumming to the stresses of everyday life.
>
> I'm sure stress, like pain can induce depression.
> But, I still think there is something more fundamentally wrong.
>
> I don't know if the finding of increased adrenal weight has been confirmed in other studies.
>
> I just know with me, the anxiety and depression are for the most part two separate entities.
>
> LinkadgeRegardless of what you think of the study it is still a rat study. Until the results are duplicated in people that is all it is.
As far as to wether it is a disease or a group of symptoms this was my point. Cancer is a called a disease also. But it is turning out to be a cluster of diseases. At this point it doesn't look like there will be a silver bullet that cures all cancers but each cancer may require a separate approach. Depression may turn out to be a cluster of diseases also and many approaches may be required.Some evidence of this is the fact that you said that anxiety has no part in your depression. For me anxiety had a big part and for many it does.
Maybe we agree on one thing. The cause or causes are needed before we find better cures. I don't mean hypothesis I mean proven facts.
That means studies done on people. Rat studies in the majority of cases will not be found true in people wether you like the study or not. Let this scientist now duplicate this study with people and it becomes credible.
I'm not interested in a long debate with you on this. As of today this is a hypothesis done with a group of rodents.You can love this hypothesis all you like but like most rat studies will burn and fizzle away like a broken rocket.
Posted by SLS on October 25, 2009, at 15:53:26
In reply to Re: Why antidepressants don't work for so many, posted by linkadge on October 25, 2009, at 15:03:57
Absolute crap.
- Scott
Posted by linkadge on October 25, 2009, at 17:11:04
In reply to Re: This is a rat study!, posted by bulldog2 on October 25, 2009, at 15:44:29
>Regardless of what you think of the study it is >still a rat study. Until the results are >duplicated in people that is all it is.
It won't be replicated in human studies as it would be unethical to expose humans to experimental stress sufficiant to alter gene expression.
>As far as to wether it is a disease or a group >of symptoms this was my point. Cancer is a >called a disease also. But it is turning out to >be a cluster of diseases.
Well, its the same end result regardless of the exact etiology. All I am saying is that I think there are a subgroup depressed patients for whom everyday stress is not the *cause*.
>Depression may turn out to be a cluster of >diseases also and many approaches may be >required.Some evidence of this is the fact that >you said that anxiety has no part in your >depression. For me anxiety had a big part and >for many it does.
BIG Note** this study does not say that anxiety is not associated with depression. All it says is that exposing rats to stress alone is insufficiant to create the same altered gene experession that exists in a disease model of depression.
It does not say that the disease model was not experiencing anxiety.
I think this is a very important study because it aims to verify the validity of a disease model of depression in animals. I.e. there is something different about the depressive line of rats than simply taking normal rats and exposing them to stress. The flinders sensitive line is appears to have similar neurobiological underpinnigs to human depression. They exhibit abormalities in sleep, feeding and neuroendocrine function in the absence of stress. They are also responsive to standard antidepressant treatments.
This is a key problem with the posted study. It does not indicate whether or not the disease model of depressive rats used responded to standard antdiepressant treatments. If they did, then (while it does not contradict the findings of the study) it does contradict the conclusions - ie. the reason why standard antidepressant treament is inneffective for many depressed patients.
For many patients with severe, chronic depression
there are evidently no identifyable environmental causes. Patients with bipolar disorder can be up when the world is down and down when the world is up. There is something out of sync. There brain is not responding properly to the environment.My siblings and I grew up in the same house, went to the same school, ate the same food. Yet one of us has sufferent chronic depression since adolecence. I was not subjected to any more stress them. How is my depression caused by stress?
>I'm not interested in a long debate with you on >this. As of today this is a hypothesis done with >a group of rodents.You can love this hypothesis >all you like but like most rat studies will burn >and fizzle away like a broken rocket.
Everything in psychiatry a hypothesis, what exactly are you getting at? Don't stomp on everything that is new and different just because it may not lead to immediate clinical application. I applaud people for thinking outside the box yet some babblers don't give a rats *ss (no punn indented).
Linkadge
Posted by linkadge on October 25, 2009, at 17:30:55
In reply to Re: Why antidepressants don't work for so many, posted by SLS on October 25, 2009, at 15:53:26
It is you of all people SLS that I would expect to produce such a narrowminded responce.
You have always held that there are true neurobiological underppinings to severe chronic depression that many people experience.
You know something about the biological and structural abnormalities that are evident in depression. You, on many occasions, have expressed uncertainty as to whether these are a cause of or response to depression/anxiety.
To call this study absolute crap is to basically say the contrapositive. That is, that all depression is caused by stress. In other words SLS, there is nothing fundamentally wrong with you. The only reason you are depressed is because you are unable to deal with stress effectively.
Yes, that is what you are concluding by saying this study is crap.
Look folks, this isn't rocket science. All this study really concluded is that a group of mice (that have a gene profile that results in tendencies towards depression) is still fundamentally different than a group of mice which have simply been exposed to stress. It actually helps to verify the notion that there is something fundamentally different about depressed people.
Sure, if you want to go on believing that the reason you're depressed is becuase you have a stressful life then be my guest. It really doesn't help plead your case to the lay person (who already things depressed people are just a bunch of people too weak to handle the pressures of everyday life).
Note**, this study does also *not* suggest that stress can't be the straw that breaks the camels back so to speak. Its not unreasonable to suggest that the mice with both the "disease model" gene profile and "stress induced" induced gene profile didn't feel worse than either alone.
All it is suggesting is that the mice who had the depression like behavior before the stress had something different about them.
Think back to your life. So, if it was stress that made you depressed, how was your life before that? Would you have considered yourself perfectly well up until the point that stress caused clinical depression??
Research in humans does seem to suggest that even in people who do have depression that was triggered by stress, there were subtle behavioral differences before the onset of the first episode.
Did people even read the study. Do people even realize what it found??? - or do they just read the headline and disagree with that???
Linakdge
Posted by Cecilia on October 25, 2009, at 18:10:00
In reply to Why antidepressants don't work for so many, posted by jrbecker76 on October 25, 2009, at 9:44:54
I don't get it. How do you even know if a rat is depressed? They certainly don't get depressed the way people do. They may have a few of the same physical symptoms that some humans get, but the worst symptoms, the feelings, the self hate and shame and hopelessness and despair and constant terrifying panic and loneliness and guilt-doubt rats get any of these, animals live in the moment, not in the past which equals depression or the future which equals anxiety. I suppose it's possible they do get some of these feelings but how would the researchers know. Cecilia
Posted by Phillipa on October 25, 2009, at 19:02:30
In reply to Re: Why antidepressants don't work for so many, posted by Cecilia on October 25, 2009, at 18:10:00
I know for me anxiety has always been my problem. Have to be on the go or involved in something. Is that depression? I don't cry. I fear the future. Phillipa
Posted by Sigismund on October 25, 2009, at 19:06:18
In reply to Re: Why antidepressants don't work for so many, posted by Cecilia on October 25, 2009, at 18:10:00
>I don't get it. How do you even know if a rat is depressed?
Exactly
>They certainly don't get depressed the way people do.How do you know?
>They may have a few of the same physical symptoms that some humans get, but the worst symptoms, the feelings, the self hate and shame and hopelessness and despair and constant terrifying panic and loneliness and guilt-doubt rats get any of these, animals live in the moment, not in the past which equals depression or the future which equals anxiety. I suppose it's possible they do get some of these feelings but how would the researchers know.I think it's as possible as it is impossible, which is to say I have no idea.
I feel sure that humans have had strange ideas about what animals do or do not feel.
Posted by TenMan on October 25, 2009, at 19:24:19
In reply to Re: Why antidepressants don't work for so many, posted by Sigismund on October 25, 2009, at 19:06:18
The monoamine hypothesis is a joke. I'm glad this study was conducted and I share linkadge's sentiments. Finally research is starting to look in other directions besides the stressed rat. Looking back, this could be groundbreaking.
Posted by psych chat on October 25, 2009, at 21:25:14
In reply to Why antidepressants don't work for so many, posted by jrbecker76 on October 25, 2009, at 9:44:54
Maybe the rats are observed to be depressed because they don't eat, they sleep all day, don't interact socially, don't mate, etc.
?
Posted by Sigismund on October 25, 2009, at 22:37:11
In reply to Re: Why antidepressants don't work for so many, posted by psych chat on October 25, 2009, at 21:25:14
They must mate, or maybe it was done by AI?
Posted by SLS on October 26, 2009, at 4:32:40
In reply to Re: Why antidepressants don't work for so many » SLS, posted by linkadge on October 25, 2009, at 18:30:55
Ok. You are right. You convinced me.
:-)
I was hasty in condemning the whole paper.
I guess the part that elicited a strong reaction in me was that in which the author of the paper proposed that antidepressants treat stress rather than depression. I interpreted it out of context. However, the rationale that there are few genes that overlap between stress and depression does little to refute the idea that one can trigger the other. Other than that, the paper offers some new perspectives that might require a change in rat study paradigms.
Poor, poor depressed rats. :-(
- Scott
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