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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 21 of 21. This is the beginning of the thread.
Posted by linkadge on April 30, 2006, at 17:29:53
The study below compared the effects on swimming of mice lacking either SERT, NET or DAT.
Interestingly, the SERT knockout mice displayed the *least* mobility (ie little antidepressant effect), the NET knockout mice lasted a little longer, but the DAT knockout mice were the least depressed of the bunch.
I think DAT inhibitors would make well for antidepressants, but we'll never see them cause they might be abused.
http://www.ibnshomepage.org/FullAbstract.asp?ID=131
Linkadge
Posted by SLS on May 1, 2006, at 8:33:15
In reply to DAT knockout mice less depressed that SERT knock, posted by linkadge on April 30, 2006, at 17:29:53
> I think DAT inhibitors would make well for antidepressants, but we'll never see them cause they might be abused.
Nomifensine (Merital) was a reuptake inhibitor at DA and NE, but never displayed a tendency towards abuse. I hope this is true of the newer triple reuptake inhibitors as well.
- Scott
Posted by linkadge on May 1, 2006, at 15:46:53
In reply to Re: DAT knockout mice less depressed that SERT kno, posted by SLS on May 1, 2006, at 8:33:15
I don't really know why we have not persued other DAT inhibitors as antidepressants. I guess we just assumed that serotonin was the main culprit.
I remember reading that SSRI's were only very weakly active in forced swim tests in mice.
Linkadge
Posted by zeugma on May 1, 2006, at 16:12:28
In reply to Re: DAT knockout mice less depressed that SERT kno, posted by linkadge on May 1, 2006, at 15:46:53
> I don't really know why we have not persued other DAT inhibitors as antidepressants. I guess we just assumed that serotonin was the main culprit.
>
> I remember reading that SSRI's were only very weakly active in forced swim tests in mice.
>
> Linkadgethat is true, and is in fact one of the reasons Lilly took so long to develop fluoxetine as an AD. for a while, those that considered them, in fact, AD's thought they were 'false negatives' in the FST.
SSRI's are active in such tests but rats display different behavior: on TCA's or other NE potentiating meds the rats try to climb out of the glass cylinder, while on fluoxetine etc. they swim.
amphetamine has long been known as a 'false positive' in the test. so has atropine. i believe both produce climbing, behavior more typical of NE than 5HT meds.
-z
Posted by ed_uk on May 1, 2006, at 16:36:15
In reply to Re: DAT knockout mice less depressed that SERT kno » linkadge, posted by zeugma on May 1, 2006, at 16:12:28
Hi everyone
>forced swim test
I'm not convinced of the value of these 'animal models of depression'. I think they're very silly actually. Interesting, but silly. Honestly, who comes up with these ideas! Human depression is a complex phenomenon which cannot be replicated in a rat. The sooner scientists realise that animal experiments are *not* very useful the better. Large well-designed clinical trials in *humans* are the only studies which are really valuable in determining drug efficacy. Such trials are expensive but immensely useful.
Regards
Ed
Posted by zeugma on May 1, 2006, at 16:55:07
In reply to Animal models of psychiatric illness, posted by ed_uk on May 1, 2006, at 16:36:15
I'm not convinced of the value of these 'animal models of depression'. >>
it's a good thing to be skeptical :-)
I think they're very silly actually. Interesting, but silly.>>
they were a practical necessity early in the history of psychotropic drug development, before neural 'targets' were identified. and the targets were identified on the basis of compounds that were either discovered by accident (e.g. imipramine) or by means of behavioral tests (e.g. modafinil- they still don't know what its neural 'targets' are). so our knowledge is still shreds in a sea of ignorance. i would not dismiss the animal models, because they have given rise to all the DAT KO and null orexin mice, which have, in fact, given us insights into the etiology of disease states. not that much insight, but then we are working blind anyway when it comes to CNS disorders.
>>Honestly, who comes up with these ideas! Human depression is a complex phenomenon which cannot be replicated in a rat. The sooner scientists realise that animal experiments are *not* very useful the better. Large well-designed clinical trials in *humans* are the only studies which are really valuable in determining drug efficacy. Such trials are expensive but immensely useful.>>
they are useful but how 'well-designed' are industry-sponsored trials? well-designed to demonstrate that the new drug is as efficacious as amitriptyline without causing constipation.
i'll make an exception for studies in which both comparotors are off patent. one can be sure of freedom from industry bias there. unfortunately, such studies are necessarily smaller because no corporation backs these.
on the other hand rats are cheap and don't respond to placebo (we assume).
-z
Posted by linkadge on May 1, 2006, at 19:14:32
In reply to Animal models of psychiatric illness, posted by ed_uk on May 1, 2006, at 16:36:15
I agree in some sences. It makes me feel bad to be compared to a rat.
In other sences though, many of the drugs that are active in the forced swim test seem to correspond to human efficacy.
For instance, ECT is effective in animal models, as is rTMS. Even access to wheel running is active. Brain growth factor injections are active, and so are CRH antagonists etc, NMDA antagonists, dopamine agonists, SJW, SAMe, etc.
Agents that induce the greatest increase in BDNF in certain areas of the brain seem to confer the most effect in the forced swim test.
Triple uptake inhibitors seem to also be much more active than either SSRI's or TCA's, at least from some of the preliminary reports.
I think imipramine is superior to SSRI's in the forced swim test, and in human depression it is arguably superior to SSRI's as well.
I think in some ways we are rats. I think we respond to pain and pleasure the same ways.
Yeah, I know, its controversial.
Linkadge
Posted by linkadge on May 1, 2006, at 19:33:37
In reply to Re: Animal models of psychiatric illness » ed_uk, posted by zeugma on May 1, 2006, at 16:55:07
I don't know. I personally think that SSRI's are so widespread and commonplace simply due to the fact that they're basically serentics. Nobody is going to object to a class of drugs that shuts people up. Its basically "SOMA" or whatever from Brave New World.
A lot of depressed people respond quickly to things like stimulants. Granted the effect is short lived. I don't know, SSRI's never really gave me much of a desire to live.
I think we need to do more to get people "actually feeling better", be more agressive.
I have a hunch that there are probably a number of extrordinarily effective agents that were dismissed because of potential for abuse.Linkadge
Posted by linkadge on May 1, 2006, at 20:05:02
In reply to Re: Animal models of psychiatric illness, posted by linkadge on May 1, 2006, at 19:33:37
According to:
http://www.acnp.org/g4/GN401000093/CH.html
Amineptine, which is a relatively selective DA uptake inhibitor, was more efficaceous than clomipramine, and had a faster onset of antidepressant action, in a double-blind trial in retarded patients; another dopaminomimetic agent, minaprine, was also more effective than clomipramine in retarded patients [88].
Linkadge
Posted by zeugma on May 2, 2006, at 5:42:14
In reply to Re: Animal models of psychiatric illness, posted by linkadge on May 1, 2006, at 19:33:37
I don't know. I personally think that SSRI's are so widespread and commonplace simply due to the fact that they're basically serentics. Nobody is going to object to a class of drugs that shuts people up. Its basically "SOMA" or whatever from Brave New World.
A lot of depressed people respond quickly to things like stimulants. Granted the effect is short lived. I don't know, SSRI's never really gave me much of a desire to live.
I think we need to do more to get people "actually feeling better", be more agressive. >>
I would not draw the conclusion, from the serenic effect of SSRI's, that SSRI's are not effective antidepressants.
The problem I think is that AD's have differential effectiveness (ie what works for one won't work for another) but that trials of patented drugs (which are the majority) obscure this due to industry sponsorship, not necessarily malign but it introduces subtle biases into studies that make it seem that AD response is random because all AD's are the same.
If you look at diligent investigators, using OFF-PATENT drugs, a different pattern emerges:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=search&DB=pubmed
One has to persevere through blind alleys to find patterns, eg:
These authors impress me tremendously because they actually admit to study failures:
Being able to be wrong is the cardinal feature of scientific endeavor. Rats don't give a rat's a** about the investigator's biases, which is why animal studies are helpful, and also since the patterns are difficult to detect (how many times have I read that AD selection is a random process because they all have 'equal efficacy') one can see patterns more clearly in another species than we can in ourselves oftentimes.
-z
Posted by zeugma on May 2, 2006, at 5:44:45
In reply to Re: Animal models of psychiatric illness, posted by zeugma on May 2, 2006, at 5:42:14
sorry:
Int J Neuropsychopharmacol. 2003 Dec;6(4):339-46. Related Articles, Links
Age-dependent antidepressant pharmacogenomics: polymorphisms of the serotonin transporter and G protein beta3 subunit as predictors of response to fluoxetine and nortriptyline.Joyce PR, Mulder RT, Luty SE, McKenzie JM, Miller AL, Rogers GR, Kennedy MA.
Department of Psychological Medicine, Christchurch School of Medicine and Health Sciences, P.O. Box 4345, Christchurch, New Zealand. peter.joyce@chmeds.ac.nz
In 169 depressed patients randomized to treatment with either fluoxetine or nortriptyline, we examined whether polymorphisms of the serotonin transporter and the G protein beta3 subunit influenced response to these antidepressants. For depressed patients under the age of 25 yr the T allele of the G protein beta3 subunit was associated with a markedly poorer response to nortriptyline, while serotonin transporter polymorphisms did not predict antidepressant response. However, in patients 25 yr or older, the G protein beta3 polymorphisms did not predict antidepressant response, while the s,s genotype of the serotonin transporter was associated with a poorer response to both fluoxetine and nortriptyline. These differential pharmacogenetic predictors of antidepressant response by age, may provide clues to understanding the discontinuities in pharmacological responsiveness of child/adolescent and adult depressive disorders.
-z
Posted by SLS on May 2, 2006, at 7:28:06
In reply to missing link » zeugma, posted by zeugma on May 2, 2006, at 5:44:45
Interesting. I wonder if tianeptine would a better choice for people who possess the s,s genotype for SERT.
- Scott
> Int J Neuropsychopharmacol. 2003 Dec;6(4):339-46. Related Articles, Links
>
>
> Age-dependent antidepressant pharmacogenomics: polymorphisms of the serotonin transporter and G protein beta3 subunit as predictors of response to fluoxetine and nortriptyline.
>
> Joyce PR, Mulder RT, Luty SE, McKenzie JM, Miller AL, Rogers GR, Kennedy MA.
>
> Department of Psychological Medicine, Christchurch School of Medicine and Health Sciences, P.O. Box 4345, Christchurch, New Zealand. peter.joyce@chmeds.ac.nz
>
> In 169 depressed patients randomized to treatment with either fluoxetine or nortriptyline, we examined whether polymorphisms of the serotonin transporter and the G protein beta3 subunit influenced response to these antidepressants. For depressed patients under the age of 25 yr the T allele of the G protein beta3 subunit was associated with a markedly poorer response to nortriptyline, while serotonin transporter polymorphisms did not predict antidepressant response. However, in patients 25 yr or older, the G protein beta3 polymorphisms did not predict antidepressant response, while the s,s genotype of the serotonin transporter was associated with a poorer response to both fluoxetine and nortriptyline. These differential pharmacogenetic predictors of antidepressant response by age, may provide clues to understanding the discontinuities in pharmacological responsiveness of child/adolescent and adult depressive disorders.
>
> -z
>
>
Posted by ed_uk on May 2, 2006, at 14:56:23
In reply to Re: Animal models of psychiatric illness » ed_uk, posted by zeugma on May 1, 2006, at 16:55:07
Hi Z
I imagine that numerous medications which may have been effective in humans have been discarded due to lack of efficacy in certain animal models of psychiatric illness.
Ed
Posted by linkadge on May 2, 2006, at 16:09:31
In reply to Re: Animal models of psychiatric illness, posted by zeugma on May 2, 2006, at 5:42:14
Thats tue. You're right rats don't care. They don't even know they're getting drugs.
I guess the problem is that even though the rat may start to act more "normally" we still don't really know how they feel inside.
Kind of like with the SSRI's with me. I know that I may have been eating better, and sleeping a bit better, but thats a long way from actually reporting feeling better.
Another big flaw I see is that we don't test the drugs on animals for long enough. So a drug can keep an animal swimming a little longer in the short term, but how do we know that effect will last into the long term.
I'm not saying SSRI's don't work for certain people, I just don't think they have a terrably profound antidepressant effect overall.
I don't want to say cause I don't really know, but I have suspicion that there are a lot of good antidepressants like amineptine that get pulled because they have abuse potential, even though they *may* be arguably more reliable, fast acting, and robust.
Linkadge
Posted by zeugma on May 2, 2006, at 17:00:32
In reply to Re: Animal models of psychiatric illness » zeugma, posted by ed_uk on May 2, 2006, at 14:56:23
hi Ed.
>
> I imagine that numerous medications which may have been effective in humans have been discarded due to lack of efficacy in certain animal models of psychiatric illness.>>that's probably true. I would suggest that you study nehavioral pharmacology at school, so that you can design better models :-) except that i think you think the whole project is misguided.
unfortunately, the NK2 inhibitors, which are supposedly the next generation of AD's, got their initial credentials from gerbils :-)
i think animal models are important, because that is where the real (unbiased) science is done, in the lifespan of a drug. And then at the other end of a drug's lifespan one can study the drugs scientifically when pharma companies are not biassing the evidence.
-z
>
>
Posted by zeugma on May 2, 2006, at 17:14:21
In reply to Re: missing link, posted by SLS on May 2, 2006, at 7:28:06
Interesting. I wonder if tianeptine would a better choice for people who possess the s,s genotype for SERT.>>
it does suggest, doesn't it, that serotonin is the pathway to AD response.
i think better 5-HT1A agonists than buspirone have potential, too, unfortunately bringing these drugs to market is difficult despite their efficacy in animal studies. buspirone really seems like the least impressive of the lot, and I hope gepirone or something similar reaches US market in the near future.
i would recommend that you try gepirone ER if/when it reaches market, i feel comfortable with that recommendation of course only because it's not available now. both 5-HT1A agonists and tianeptine seem like ways of getting around 5-HT transporter-mediated treatment resistance (speaking generally). i think the makers of Remeron have done studies in this area too.
-z
Posted by ed_uk on May 2, 2006, at 17:23:02
In reply to Re: Animal models of psychiatric illness » ed_uk, posted by zeugma on May 2, 2006, at 17:00:32
Hi Z
> except that i think you think the whole project is misguided
Yep! People are not the same at rats. The findings of animal studies cannot be applied to humans, which is why I don't think much of them.
Ed
Posted by zeugma on May 2, 2006, at 17:34:43
In reply to Re: Animal models of psychiatric illness » zeugma, posted by linkadge on May 2, 2006, at 16:09:31
Another big flaw I see is that we don't test the drugs on animals for long enough. So a drug can keep an animal swimming a little longer in the short term, but how do we know that effect will last into the long term.>>
the FST is a model of AD action that gained credibilty because AD's demonstrated potency only after a day or two of administration. a day of a rat's life is about two weeks of a human's, so it was taken as providing convergent evidence considering it often takes two weeks to manifest an AD response in a human. there are longer term models as well. the problem is that the models are only as good as the theories behind them (very few human depressives have had their olfactory bulbs removed, yet this is considered a model of depression in the rat).
>>
I'm not saying SSRI's don't work for certain people, I just don't think they have a terrably profound antidepressant effect overall.>>I agree. The disorder they seem most effective for is OCD. dapoxetine, Lilly's new SSRI, is going to be marketed for premature ejaculation, and it may prove more efficacious for that indication than for any mood disorder. Which is frustrating, to say the least.
Since we really have no clues as to the underlying disorder in each person's case, doctors use SSRI's as the most innocuous choice, and the one that saves the labor of diagnosis. I wish more thought went into diagnosis, myself, but that study of 'teenage pre-psychotics' shows me where diagnostic skills go- into making money for pharma. It makes me despair. It really does.
>>
I don't want to say cause I don't really know, but I have suspicion that there are a lot of good antidepressants like amineptine that get pulled because they have abuse potential, even though they *may* be arguably more reliable, fast acting, and robust.>>I would be curious to know why amineptine is a more effective AD than Ritalin, if it is. Just like I am curious as to why atomoxetine is less of an AD than desipramine, if it really is.
-z
Posted by linkadge on May 2, 2006, at 18:11:15
In reply to Re: missing link » SLS, posted by zeugma on May 2, 2006, at 17:14:21
I like the endocannabanoid deficiancy theory.
There are drugs like anandamide reuptake inhibitors in the pipelines. Anandamide binds to 5-ht1a like buspar, but it also antagonizes 5-ht2a. It acts at other receptor systems too. It has strong anxiolitic properties, and I believe it is neurotrophic.
In animal models of depression 5-ht1a agonists seem to be effective for both depression and anxiety.
I'd hate to think that the theraputic effect of SSRI's is reduced to their agonism at 5-ht1a, otherwise we're hitting a lot more receptors than necessary.
Yeah, thats a good question, as to how different serotonin genes would affect responces to SSRI's vs. tianeptine.
The interesting thing about tianeptine, is that it displays neuroprotective capacity far beyond the effects of SSRI's. Tianeptine seems to have a strong ability to block stress induced hipppocampal morphological (sp.) changes.
Linkadge
Posted by linkadge on May 2, 2006, at 18:31:07
In reply to Re: Animal models of psychiatric illness » linkadge, posted by zeugma on May 2, 2006, at 17:34:43
I think the animal models are valuble. I have to admit that some of the testing seems pretty sick to me. When I found out how they tested for potential new painkillers in animals I just about vomited. Thats not the way you treat something that moves and breaths.
Anyhow, so it goes.
>I agree. The disorder they seem most effective >for is OCD. dapoxetine, Lilly's new SSRI, is >going to be marketed for premature ejaculation, >and it may prove more efficacious for that >indication than for any mood disorder. Which is >frustrating, to say the least.
Thats exactly it. Zyprexa is probably a better weight gain pill than a antipsychotic. The best I could get from SSRI's was numb. Sure, they shut off certain circutry that I could do without, but they shut off a whole lot more.
Its hard to explain to a doctor how the drug makes you feel better, and yet *so* much worse all at the same time.
>Since we really have no clues as to the >underlying disorder in each person's case, >doctors use SSRI's as the most innocuous >choice, and the one that saves the labor of >diagnosis. I wish more thought went into >diagnosis, myself, but that study of 'teenage >pre-psychotics' shows me where diagnostic >skills go- into making money for pharma. It >makes me despair. It really does.
Its really pathetic. I just don't see how drug companies havn't changed their tactics yet. They don't think we can't see through these studies. Geez, I hope they've got represititives reading these boards. I don't know how some of these drug companies live with themselves. A good company would require all of its workers and drug reps to ingest the drug they push for 3 weeks and after that decide what is, and what is not an appropriate application.>I would be curious to know why amineptine is a >more effective AD than Ritalin, if it is. Just >like I am curious as to why atomoxetine is less >of an AD than desipramine, if it really is.
Some studies have found positive application of ritalin in depression:
http://biopsychiatry.com/methdep.htm
Yeah. I personally found that ritalin was an effective antidepresant. I had no compulsion to increase the dose. I found it helped my anhedonia, and I was able to get pleausure out of things I enjoyed doing, like playing the piano.
But you're right, it is strange that two drugs with similar mehanisms don't work the same.
Linkadge
Posted by linkadge on May 2, 2006, at 20:28:25
In reply to Re: Animal models of psychiatric illness, posted by linkadge on May 2, 2006, at 18:31:07
People with the SS genotype seem to have it rough.
I know its been asked before, but is this kind of testing available anywere?
I know it wouldn't conclude much, but it might be a more usefull piece of information in the future.
Linkadge
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