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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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« Fishing Around for Biomarkers | Main | Retractions: Why The Secrecy? »

January 17, 2011

Reboxetine Doesn't Work. But That's Not the Real Problem.

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Posted by Derek

Some time ago, I took nominations for Least Useful Animal Models. There were a number of good candidates, many of them from the CNS field. A recent report makes me think that these are even stronger contenders than I thought.

The antidepressant reboxetine (not approved in the US, but sold in a number of other countries by Pfizer) was recently characterized by a German meta-analysis of the clinical data as "ineffective and potentially harmful". Its benefits versus placebo (and SSRI drugs) have been overestimated, and its potential for harm underestimated. It was approved in Europe in 1997, and provisionally by the FDA in 1999, although that was later rolled back when more studies came in that showed lack of efficacy.

Much has been made of the fact that Pfizer had not published many of the studies they conducted on the drug. These do seem, however, to have been available to regulatory authorities, and were the basis for the FDA's decision not to grant full approval. As that BMJ link discusses, though, there's often not a clear pathway, especially in the EU, for a regulatory agency to go back and re-examine a previous decision based on efficacy (as opposed to safety).

So the European regulatory agencies can be faulted for not revisiting their decision on this drug in a better (and quicker) fashion, and Pfizer can certainly be faulted for letting things stand (in the face of evidence that the drug was not effective). All this is worrisome, but these are problems that are being dealt with. Since 2007, for example, trials for the FDA have been required to be posted at clinicaltrials.gov, although the nontranparency of older data can make it hard to compare newer and older treatments in the same area.

What's not being dealt with as well is an underlying scientific problem. As this piece over at Scientific American makes plain, reboxetine, although clinically ineffective, works just fine in all the animal models:

And this is a rough moment for scientists studying depression. Why? Because reboxetine works beautifully in our animal models. It’s practically a poster-child antidepressant. It produces acute effects in tests such as forced-swim tests and tail-suspension tests (which use changes in struggle as a measure of antidepressant efficacy). It produces neurogenesis in the hippocampus, which is thought to be correlated with antidepressant effects. When behavioral pharmacologists are doing comparisons between older antidepressants and newer ones, reboxetine is often used as a positive control, a drug known to have an effect in the behavioral test of choice.

But it doesn’t work in patients. And patients are what matters. Now, scientists are stuck with a difficult question: What went wrong?

A very good question, and one without any very good answers. And this certainly isn't the first CNS drug to show animal model efficacy but do little good in people. So, how much is the state of the art advancing? Are we getting anywhere, or just doing the same old thing?

Comments (49) + TrackBacks (0) | Category: Animal Testing | Clinical Trials | Regulatory Affairs | The Central Nervous System | The Dark Side


COMMENTS

1. NoreppyGuy on January 17, 2011 1:47 PM writes...

Reboxetine likely works in a small subset of people but given the huge placebo effect and the inability to identify that subset ex ante, it is going to fail more than it wins. In this regard, the SSRIs are better but far from perfect - some have argued that they do not work either and have used similar analysis to suggest so but for many, they truly do work and for that I have no doubt. If you take an SSRI and add a norepinephrine reuptake inhbitor such as reboxetine, you will tend to see a slight increase in efficacy and of course, doing this with one compound is what works for venlafaxine (effexor) and duloxetine (cymbalta). Lilly's drug stattera (atomoxetine) is in the same class as reboxetine being a selective norepinephrine reuptake inhibitor and it has some efficacy for ADD. Hopefully reboxetine will not be pulled from Europe - If you take a person with mild ADD, they may also have depression type issues due to the social difficulties as well as self esteem issues they might suffer from due to their inability to focus the way they would like to. A drug that has a modest anti-ADD effect through norepinephrine may give them enough to help their ADD. Lilly's drug has liver issues and it would be a shame if reboxetine will not be avialable because it will be one less option available to the small subset population that is quite familiar with its off label uses.

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2. John on January 17, 2011 2:14 PM writes...

Methylphenidate, ketamine, and perhaps bupropion are the only true antidepressants on the market, I believe. Trying to find antidepressants while ignoring mu-opioid neurotransmission seems a hard row to hoe.

Too bad primate models are so expensive.

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3. NoreppyGuy on January 17, 2011 2:42 PM writes...

I had never heard that ketamine was an antidepressant, I always thought it was an NMDA antagonist that was used as a dissasociative anesthetic in animals primarily though I know it is used (abused) by folks. when you say it is an antidepressant, do you mean at sub-anesthesia type doses?

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4. Unix Ronin on January 17, 2011 3:20 PM writes...

One questions what conclusions one can draw about a rat's state of depression from how much it struggles when suspended by its tail or forced to swim until exhausted. It would appear to me that the hypothesis that this can be used to accurately read the rat's mental state is neither provable nor falsifiable. It's a little like making assertions about the meaning of a letter written in an unknown language, contained within a sealed envelope, after feeling the envelope to see what the folded paper within feels like and holding it up against the light to see if one can discern any marks.

Physiological factors such as drug toxicity or antobiotic efficacy can be objectively and unequivocally tested for in animal models (although even then, a drug that is safe in rats may be toxic to rats or dogs, or vice versa). The drug combats the infection, or it does not. The animal suffers drug-related toxicity, or it does not. But how can we assert that it is meaningful to study the effects of a drug upon the state of mind of an animal with which we cannot communicate to clearly elucidate its state of mind? It's a hit-and-miss process even between humans who speak the same language.

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5. SteveM on January 17, 2011 3:47 PM writes...

Re: All this is worrisome, but these are problems that are being dealt with. Since 2007, for example, trials for the FDA have been required to be posted at clinicaltrials.gov, although the nontranparency of older data can make it hard to compare newer and older treatments in the same area.

Derek, not quite. Clinical Trials are required to be posted, but results are not!

For example, Eli-Lilly has sponsored and fully completed 84 clinical trials of its toxic brain-bomb Cymbalta (Duloxetine). Of the 84 studies, 20 had results reported out, 64 did not. Meanwhile, anecdotes of Cymbalta induced iatrogenic car wrecks continue to pile up right and left at WebMD and other self-report sites.

Nobody knows what is happening behind the Clincal Trial curtain except the Pharma company. If reporting trial outcomes can be gamed, registering a trial in the first place becomes almost meaningless since the Pharma company will only show results it wants the regulators and public to see.

So much for transparency.

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6. John on January 17, 2011 3:50 PM writes...

@4: See http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2726824/

for an overview. This is a fairly active area of research.

NIH was using a single intravenous subanesthetic dose of ketamine (0.5 mg/kg for 40 minutes).
http://www.ncbi.nlm.nih.gov/pubmed/16894061

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7. NoreppyGuy on January 17, 2011 4:38 PM writes...

Duloxetine and car wrecks? LOL Are you sure they weren't driving Toyotas or using Retin A? I guess if you have to come up with an excuse, that duloxetine is as good as any.

"Nobody knows what is happening behind the Clincal Trial curtain except the Pharma company.

If reporting trial outcomes can be gamed, registering a trial in the first place becomes almost meaningless since the Pharma company will only show results it wants the regulators and public to see."

I was under the impression that when a manufacturer submits the NDA that all of their clinical studies are reported to the fda for that drug. At least that is what the clinical folks I know have explained to me. Where did you get this information?

I can't understand why if it is so easy to "game" the system, we are seeing so many spectacular, billion dollar failures in phase 3 studies. For example, why did Pfizer discontinue its study of its HDL elevator after investing so much money? Why did Merck just announce the failure of the clot inhibitor in stroke patients? Why do less than 1 in 10 drugs that enter clinical trials make it through?

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8. luysii on January 17, 2011 5:12 PM writes...

Episodes like this are nothing new to neurologists treating stroke (unfortunately)

The following article is old but authoritative. [ Stroke vol. 21 p. 1 - 3 '90 ] Of 25 different compounds of proven efficacy for treating focal and global brain ischemia (e.g. stroke) in animal models over the past 10 years based on published articles in refereed journals, NONE has proven efficacious in clinical trials in man, nor are any in general use today.

By '95 I stopped reading the animal stroke literature without noticeable harm to my patients. By the time I retired in 2000, the number of failed trials of treatments of stroke that had worked in animals was 65 (as I recall).

I still don't think we have anything useful for stroke (including TPA, the evidence for which was never really good even up to 2000). But don't quote me as I've not been reading the literature for the past 10 years (but if we did have something it's likely that we'd have all heard about it).

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9. Starlet on January 17, 2011 5:37 PM writes...

>> So much for transparency

The FDA, soon to be as laughable as the SEC.

>> Are we getting anywhere, ...

yes, closer to insolvency being widely recognized by the ignorant masses.

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10. SteveM on January 17, 2011 6:00 PM writes...

Re: #6 NoreppyGuy

"I was under the impression that when a manufacturer submits the NDA that all of their clinical studies are reported to the fda for that drug.

I queried the FDA regarding the reporting requirement of completed studies and the scientific rationale for withholding a report. This statement was included in their response to me:

"No, there is no scientific rationale for companies not having to publish results. Until a product is approved by FDA, the clinical trial results are proprietary and it is up to the sponsor whether or not they wish to release them.

The vast majority of Lilly sponsored Cymbalta clinical studies were conducted after approval. Lilly picks and chooses which studies it will report out. And that is fine with the FDA. Not so much with the patients who get hammered by Duloxetine.

BTW, I said iatrogenic car wrecks. It's in the dictionary...

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11. NoreppyGuy on January 17, 2011 6:17 PM writes...

SteveM - I'm still confused. The fda response to you says that if a drug is approved, the sponsor has to report the results of any clinical trials to the fda. Conversely, if a drug is not approved, why would the company have to publish the results? If it is not approved, who will take it? However, for the NDA, the FDA will request all the clinical data material. Wouldn't it be kind of crazy if a company could run 11 studies, find one that worked and then only submit that to the FDA and tell the fda they don't need to worry about the others. Does that make sense? Still not sure what you are trying to say here. Likewise, I did look up iatrogenic and got this: "induced inadvertantly by a physician or a medical treatment". Sorry, I just don't follow your point.

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12. milkshake on January 17, 2011 6:46 PM writes...

The lack of clinical efficacy or roboxetine for depression should not come as a surprise. Very closely related norepinephrine reuptake inhibitor tomoxetine (aka Stattera) was also originally developed for depression and failed for lack of efficacy/unfavorable side effect profile at high dose. It seems Eli Lilly did not publish the data from the failed depression trials and instead chose to re-developed the compound as a stimulant for attention-deficit disorder.

So, the rodent models of depression are not as informative and serendipity plays a big role in drug discovery (much like it was with discovery of tricyclic antidepressants more than half century ago). One has to wonder about false negative - good compounds that were thrown out based on these models.

A funny anecdote about serendipity: Origins of Zoloft are in discontinued norepinephrine reuptake inhibitor project that was cancelled at Pfizer because of undesired stimulant effects (which we now know are common to all epinephrine reuptake inhibitors). People working on the project were unhappy about the cancellation and revived the series in a submarine fashion and made few new analogs. When the collection of compounds got screened for serotonin reuptake, one compound stood out. It then transpired that the unwanted minor cis isomer present from reductive amination was responsible...

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13. SteveM on January 17, 2011 7:06 PM writes...

Re: #10 NoreppyGuy

No matter how you read the FDA, instruction, out of 84 Lilly sponsored studies, results are not available from 64 of them. Related to reporting, de facto sure ain't de jure...

Regarding iatrogenic, Cymbalta has really shitty side effect and discontinuation profiles that most patients are not warned about. Is a blown out liver, or metabolic dysfunction or cognitive impairment from Duloxetine iatrogenic? You tell me. The side-effect info is usually obscured by the sales reps when they market to docs. So you have this slimy synergy between the clinical study people and sales and marketing. Nice.

Take that factual info and you can infer less than good things in the clinical study reports that Lilly has not released.

I'm confident the Lilly-Duloxetine reporting strategy is common across the Pharma spectrum. And that sorta stinks...

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14. lynn on January 17, 2011 10:47 PM writes...

SteveM and Noreppyguy - please note the difference between reporting of results to the FDA (which is done with all trials when submitting an NDA) and PUBLISHING the results (as the results are proprietary). I am still not clear, however, on whether that FDA answer (#9) that "Until a product is approved by FDA, the clinical trial results are proprietary and it is up to the sponsor whether or not they wish to release them." implies that once the drug IS approved, the study results should be released. Anyone know?

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15. willia_A_Nelson on January 18, 2011 3:31 AM writes...

Depression is such an ill-defined disease (e.g., what lab test helps bolster the psychiatrists' depression diagnosis?) that it seems almost absurd to claim that any drug can be labeled as an antidepressant. The pharmaceutical industry has pulled the wool over people's eyes for many years and succeeded with the aid of heavy marketing to help the "nonscientific profession of psychiatry" become "Scientific" by allowing them to distribute their drugs. P T Barnum was right, "there's a sucker born every minute".

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16. partial agonist on January 18, 2011 8:59 AM writes...

A long time ago I heard the quote, not sure from where, "No animal models are real; some are useful"

For CNS only a few seem useful, though there are no in vitro methods that give even as much assurance. At least if it DOES SOMETHING and you detect the compound in the right tissues then it has the potential to do something you want in the real world.

I used to doubt the usefulness of antidepressants, but I have seen close-up some loved ones gain enormous, life-transforming benefits, so I have become a believer in judicious use od SSRIs.

Any CNS disorder is a clinical trial crapshoot though and probably always will be. As the grave yard of obesity drugs, anti-addiction drugs, and (as someone above noted) stroke drugs shows us, the human brain is a lot more complex and redundantly-circuited than any animal model.

The only animal model I have had a lot of confidence in was way back when I was in antiinfectives and we could give animals a raging infection with a strain of pathogen that also affects humans. Even then lots of the data had to be taken with a grain of salt- duration of action, distribution, absorption, etc., but it was clear whether the compound had the POTENTIAL to work even if we were impanting an infection and dumping compound right on it at a specified, artificial time (the pharmacologists called it a furry petri dish experiment)

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17. g on January 18, 2011 9:34 AM writes...

#3-Noreppy

Ketamine is probably the only drug that is quickly effective in reducing depressive symptoms (ie-30 min-1 h), unlike common therapies which take 6-8 weeks. It is a sub-anesthetic dose and it only lasts for a few hours. However, because of side-effects (dec. respiration, lowered blood pressure, nausea, etc) it will likely never be used outside of experimental conditions with highly drug-resistant depression.

On the same note, sleep deprivation (not chronic sleep deprivation though) is also effective in reducing depressive symptoms in patients with treatment resistant depression.

No one really knows how these two treatments are effective in those with the hardest to treat depression. And we definitely do not have animal models of these effects.

A big issue is that the forced-swim and tail suspension tests only have predictive validity while the hippocampal neurogenesis model has construct validity. The learned helplessness model has the most face validity of the bunch.

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18. NoreppyGuy on January 18, 2011 9:47 AM writes...

StevenM - "Is a blown out liver, or metabolic dysfunction or cognitive impairment from Duloxetine iatrogenic"? I'd say no given they are all specifically warned about on the label.

1st, regarding car crashes and DIRECTLY from the Cymbalta label(which to Derek's original point, are really hard to test for in rats):

"Cymbalta may cause sleepiness and dizziness. Until you know how Cymbalta affects you, you should not drive a car or operate hazardous machinery."

2nd - Since you now mention liver effects, here is also DIRECTLY from the label: "Hepatotoxicity
There have been reports of hepatic failure, sometimes fatal, in patients treated with Cymbalta. These cases have presented as hepatitis with abdominal pain, hepatomegaly, and elevation of transaminase levels to more than twenty times the upper limit of normal with or without jaundice, reflecting a mixed or hepatocellular pattern of liver injury. Cymbalta should be discontinued in patients who develop jaundice or other evidence of clinically significant liver dysfunction and should not be resumed unless another cause can be established.
Cases of cholestatic jaundice with minimal elevation of transaminase levels have also been reported. Other postmarketing reports indicate that elevated transaminases, bilirubin, and alkaline phosphatase have occurred in patients with chronic liver disease or cirrhosis.
Cymbalta increased the risk of elevation of serum transaminase levels in development program clinical trials. Liver transaminase elevations resulted in the discontinuation of 0.3% (89/29,435) of Cymbalta-treated patients. In most patients, the median time to detection of the transaminase elevation was about two months. In placebo-controlled trials in any indication, for patients with normal and abnormal baseline ALT values, elevation of ALT >3 times the upper limit of normal occurred in 1.37% (132/9611) of Cymbalta-treated patients compared to 0.49% (35/7182) of placebo-treated patients. In placebo-controlled studies using a fixed dose design, there was evidence of a dose response relationship for ALT and AST elevation of >3 times the upper limit of normal and >5 times the upper limit of normal, respectively.
Because it is possible that duloxetine and alcohol may interact to cause liver injury or that duloxetine may aggravate pre-existing liver disease, Cymbalta should not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease." What else should they say?

3rd - Since you mention metabolic disorder, this is also striaght from the label: "Glucose Control in Diabetes: In diabetic peripheral neuropathic pain patients, small increases in fasting blood glucose, HbA1c, and total cholesterol have been observed (5.12)."

You are upset that not all the studies are published but have you even read the duloxetine label?


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19. Texute on January 18, 2011 10:52 AM writes...

The basic truth is that CNS diseases are not well simulated at all by the available animal models. This is particularly true in the case of psychiatric diseases. Acute anxiety can be induced in animals, but not much else. Genetic models of Alzheimer's have been around for a long time, but not much has come out of this research. The list goes on- it's a very difficult situation.

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20. Boghog on January 18, 2011 11:00 AM writes...

@partial agonist:
the quote sounds like a variation of:

all models are wrong, but some are useful

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21. SteveM on January 18, 2011 11:18 AM writes...

Re: #18 NoreppyGuy

Here's a common Cymbalta self-report from WebMD:

"This medication, like many other meds out on the market, is like a gamble to your body mind and spirit. I took this medicine for 3 years. Not only has my weight been hard to manage, I have not slept at all , had horrible muscle problems, my blood pressure has sky rocketed, but worst of all I have had some anger and irritability that scares me. When I decided I had enough I told my doc I was going off it. He advised me to wean off for the last 3 months. Every month I went down 30 mg, until today i am on none. The withdrawals have been HELL- I do not say that lightly. I know this stuff is poison, i have had the most vivid scary nightmares a person could have. I also have had some rage that freaks me out. Please do yourself a favor do not take this crap…"

Look, connect the dots. Cymbalta has a really crummy side effect profile but is heavily DTC marketed as a first line treatment for every tenuous indication Lilly can sink its teeth into.

Meanwhile the anecdotes (thousands) indicate that neither doctors nor patients are being made aware of the severity of the Duloxetine risk profile. (Expecting an average patient to read and interpret a PI is ridiculous.)

Tack onto that, the possibility that Lilly non-reports trial outcomes because the efficacy of Cymbalta over placebo or safer alternatives may be marginal at best. So Lilly is shot-gunning Cymbalta at everything under the sun hoping the hyper-ambiguous “statistically significant� label will stick. And withholding scientifically valid data that may damage the brand.

BTW, Lilly is running a Duloxetine pediatric clinical trial right now. Do you think the parents who signed their kids up were fully informed? Would you allow your kid to take that stuff? If not, ask yourself what that says about Eli Lilly.

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22. NoreppyGuy on January 18, 2011 12:44 PM writes...

Steve M - I appreciate your points - I confess to not having a direct experience with this drug. Clearly some drugs are better tolerated than others and if my memory serves me, duloxetine took a long time to get to market so perhaps that is representative of a problematic development. I do know that dual action (serotonin and norep) antidepressants are in general more prone to side effects because there is a tradeoff between the extra efficacy some folks perceive from the dual action (some would say dirtier profile). The liver stuff is of course another matter. One thing though, I would say, is that reading patient testimonials regarding CNS drugs is especially tricky because everybody reacts differently. A drug that works great for one person could be pretty bad for another, that is the reality of psychiatric drugs and I know of no exception to that rule. Also, even in double blind clinical studies, the placebo treated folks often report many side effects as well. That is why individual testimonials should also be read with caution. But you could be right, maybe duloxetine is being taken by many people whom should not be taking it but I reckon they need to work that out with their Doctor. Cheers!

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23. luysii on January 18, 2011 2:33 PM writes...

If you want to study possible treatments of congestive heart failure, you can make an animal hypertensive by constricting blood flow to it's kidneys and then start throwing drugs at it. Ditto for studying hypertension. If you want to study cirrhosis and its treatment, there are all sorts of ways to make an animal cirrhotic. Streptozotocin kills the beta cells of the pancreas allowing you to study diabetes. The list goes on and on.

This all works because those organs are little different between animals and us. The brain is what sets us apart. Even so, we've done pretty well finding anticonvulsants using animal models.

The higher reaches of brain function is what (presumably) sets us apart. No wonder the animal models are crude and don't reflect what's going on. Still, it's the only game in town, so cut the animal modelers some slack.

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24. milkshake on January 18, 2011 4:05 PM writes...

duloxetine liver problems - thats what you get when you put napthalene and thiophene in the same molecule, and more so when these pieces with known liability have electron-donating substitution such as here. You are practically begging to get electrophilic metabolites from CYP oxidation. Also if I remember the original dose for which it was developed showed no efficacy in clinic, so they cranked up the dose several fold in later trials

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25. anon on January 19, 2011 9:21 AM writes...

Re #16: You might be thinking of this:
"All models are wrong, some are useful"

Its an old tox saying.

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26. MolecularGeek on January 19, 2011 12:04 PM writes...

25: Also a key mantra for the molecular modeling crowd.

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27. chris on January 19, 2011 5:25 PM writes...

It can be argued that many CNS animal models mimic some symptoms of the disease, others are simply in vivo biochemical assays that reflect part of the pharmacology of a known therapeutic agent. Perhaps the answer can only be found out in patients but antidepressant clinical trials are also notorious for giving high placebo effects.

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28. Anthony Bishop on January 19, 2011 9:54 PM writes...

Animal models of psychiatric disease is a tricky field. Investors (internal at pharma and VCs for biotechs) want to see the 'standard models'. Regulatory conservatism is valuable, but again promotes standard models. Advancing the state of the art is a difficult but a worthy endeavor - especially if you suffer from the myriad of serious CNS disorders.

I propose we keep focused and try as a group to be better at discovering and developing new drugs.

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29. Trottelreiner on January 20, 2011 2:58 AM writes...

Problem is, IMHO some of the diagnostic labels used are often syndromes compromising different symptoms of likely to contain multiple subgroups; this might explain part of the problems of animal models, e.g. amphetamine psychosis, the model used to develop haloperidol, might be a useful model for the paranoid subtype of psychosis, it might be of limited use in kinds of psychosis that are more related to social deficits. On the same lines, apathy and like are symptoms of depression, and it may be the animal models used are biased toward this, since one can easily observe it. Problem is, in humans with depression it is only part of the picture.

On another level, even targeting just one receptor or closely related ones can have wildly opposing effects, e.g. beta antagonists may lead to depression, but then, they might also be useful in PTSD, which has some relations to depression.

Concerning duloxetine, well, we now know the SSRIs have problems in discontinuation and like, but then, I would still call their side effects profile relatively beningn, especially after having witnessed their effects and those of some nice cardiocascular drugs. But then, the logic why we needed another arylpropanolamine RI eludes me, and likely did the FDA...

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30. maor on January 20, 2011 6:53 AM writes...

"Ketamine is probably the only drug that is quickly effective in reducing depressive symptoms (ie-30 min-1 h)"

If you're going to count drugs that are easily abused, I'll note that in my experience, ethanol is highly effective and is even quicker.

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31. John on January 20, 2011 10:13 AM writes...

@30: You've given a single dose of ethanol to people with major depression and seen remission lasting at least a week?

I'll never understand why people comment on science blogs when they haven't bothered to read the work under discussion.

We're interested in ketamine because it illuminates a mechanism we'd like to understand and target with new drugs, not because anyone plans to start handing out needles to patients.

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32. Karen on February 3, 2011 5:29 AM writes...

Hi

I am neither a pharmacologist or scientist. I have been taking Reboxetine on and off for 7 years now. I am in the UK. My depressions main symptom is that of extreme lethargy, tiredness, reclusiveness and despondency, as well as negative/irrational thinking. When taking Reboxetine I am alert, do not feel tired, feel quite creative, am able to enjoy others company and the negative thoughts are diminished. I stopped taking the drug after reading so much on the internet about it being a stimulant and wonder that it operates as a stimulant rather than an antidepressant? I fear the long term effect of being on a stimulant drug - it reduces my sleep hours quite dramatically. But I perform better on Reboxetine and the quality of life is better.
I don't fully understand the mechanics of antidepressants and how they operate on the brain but for depression where the main symptoms are extreme tiredness, Reboxetine does help but as a stimulant that 'awakens' parts of the brain.

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33. Joy on March 27, 2011 10:18 PM writes...

My doctor want to try me on Reboxetine and am apprehensive after reading all your comments. Karen most importantly did it help you. I have had horrific experience with others and no improvement with my depression. BUT a quality of life is what I need.

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34. Dudley Warman on July 17, 2011 8:56 AM writes...

I don't know if this is appropriate for a scientific blog. Like Karen I am in the UK and neither a pharmacologist nor is the fifth a scientist This is just my personal anecdotal experience.
Reboxetine has been very helpful in lifting depression over several years and counteracted the retardant effects of an SSRI. BUT it seems to have overstimulated me into something like a mini-stroke and later exacerbation of a CNS disease. I still take it because it leaves me alert, clear, decisive, less reclusive, creative. But I keep the dosage down (4 mg per day). My guess is that it acts as a brain stimulant.

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35. Dudley Warman on July 17, 2011 8:56 AM writes...

I don't know if this is appropriate for a scientific blog. Like Karen I am in the UK and neither a pharmacologist nor is the fifth a scientist This is just my personal anecdotal experience.
Reboxetine has been very helpful in lifting depression over several years and counteracted the retardant effects of an SSRI. BUT it seems to have overstimulated me into something like a mini-stroke and later exacerbation of a CNS disease. I still take it because it leaves me alert, clear, decisive, less reclusive, creative. But I keep the dosage down (4 mg per day). My guess is that it acts as a brain stimulant.

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36. Dudley Warman on July 17, 2011 8:56 AM writes...

I don't know if this is appropriate for a scientific blog This is just my personal anecdotal experience.
Reboxetine has been very helpful in lifting depression over several years and counteracted the retardant effects of an SSRI. BUT it seems to have overstimulated me into something like a mini-stroke and later exacerbation of a CNS disease. I still take it because it leaves me alert, clear, decisive, less reclusive, creative. But I keep the dosage down (4 mg per day). My guess is that it acts as a brain stimulant.

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37. Dudley Warman on July 17, 2011 8:58 AM writes...

I don't know if this is appropriate for a scientific blog. Like Karen I am in the UK and neither a pharmacologist nor is the fifth a scientist This is just my personal anecdotal experience.
Reboxetine has been very helpful in lifting depression over several years and counteracted the retardant effects of an SSRI. BUT it seems to have overstimulated me into something like a mini-stroke and later exacerbation of a CNS disease. I still take it because it leaves me alert, clear, decisive, less reclusive, creative. But I keep the dosage down (4 mg per day). My guess is that it acts as a brain stimulant.

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38. John X on February 9, 2012 7:48 AM writes...

I feel amazed when I see that reboxetine is considered ineffective. For me and another of my friends it is the "only" anti-depressant drug. I had a very severe depression in 1975 which partially cleared up. So I would say I had major depression in partial remission, though I was clinically diagnosed as having dysthmia. In any case I have been depressed since 1975. I went to numerous psychiatrists and tried virtually every antidepressant drug with little effect. The SSRI's had little effect. The TCA drugs made me worse. When reboxetine came to australia about 2008 I tried reboxetine. From the first week I knew I was on to a winner. I have been on reboxetine for 3 yrs now and am nearly depression free. I still get a little better every day and am expecting to be in top form in another year.It's taken a long time but the depression was with me for over 30 years.
The only other drug that worked was tranylcypromine "Parnate" which seemed to work quite dramatically. However I only took it for 10 days.
I tried nardil another MAOI expecting it to work because Parnate did but it didn't. It also caused complete impotence and inhibition of ejaculation which is a rather frustrating problem given that these drugs increase libido.
They say reboxetine is less efficacious than SSRI's in clinical tests. This shows the problem in trusting these tests. If we get a large number of people say 100 with depression and compare reboxetine with fluoxetine ,say. Then I am prepared to believe reboxetine would perform no better. But individual humans are different in their neurochemistry there will allways be that one person (like me) who will respond much better to one drug than another.
So viva reboxetine . It has been a lifesaver for me.

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39. Tapioca on May 6, 2012 10:57 PM writes...

Ditto that last remark. I suffered from depression for at least fifteen years and tried all of the usual anti-depressants prescribed. Then a couple of years ago my illness became severe. I searched the internet and found out about Reboxetine - I read personal testimonies on several message boards and decided to ask my doctor to let me try it. Eventually I was given Reboxetine and, within a couple of weeks, I was back to being the real me again. I had forgotten what the real me was. It was an amazing transformation. So it obviously works for some people - I don't know what I'd do without it.

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40. Tapioca on May 7, 2012 2:21 AM writes...

MRHA UK Report September 2011

"• A European review of data has shown that reboxetine is an effective medicine for patients with severe clinical depression. These results are in line with current clinical guidance on antidepressant use
• The balance of benefits and risks for reboxetine in the treatment of depression remains positive

Reboxetine is an effective antidepressant. A comprehensive European review of data has shown it has a clear clinical benefit. The results of the review stratified by baseline disease severity show that reboxetine efficacy is greater in patients with severe depression and has not been shown in patients with mild/moderate disease, which is in line with current clinical guidance.
There are no safety data to suggest any change to the benefit-risk balance of reboxetine. Overall, it is considered the balance of risks and benefits of reboxetine remains favourable."