Well all they did is discard all the results that showed it didn't work in order to make billions in profit while causing life threatening side effects. No harm, no foul.
Not as bad as that guy Wakefield, who mentioned that one of the patients had an odd formed head, but didn't make enough of a deal about it.
This isn't being taken lightly as you seem to imply, the scientists responsible for this are a bit screwed career wise. Wakefield got more attention because of the massive damaging effect he and his ilk had on immunization rates.
the scientists responsible for this are a bit screwed career wise
What, the companies they worked for are just going to hang them out to dry? Not likely, not if they want scientists to keep distorting results for them. The scientists responsible for this might not have the admiration of their peers, but they'll be securely employed.
You still need to convince a number of government bodies and the wider medical community that your results are kosher. If you've been shown to put your name on papers that falsify results it is going to be very difficult for you to convince these groups of the quality of your work.
In addition to Kirsch's book, I'd also recommend Anatomy of an Epidemic. It does a really good job explaining the biological reasons why SSRI's can't work. (Plus it also outlines all of the different reasons why the science behind them is fraudulent, same as Kirsch.)
* Can/should we be testing anti-depressants on animals at all?
* Is it possible that depression in animals is different than depression in humans? (i.e. animal tests are useless)
* Is it possible that lab conditions affect the psychology of the animal? (i.e. who won't be depressed spending your life in a cage, especially for larger animals like chimps, but also for social animals like rats which are undoubtedly caged individually)
Some of these are fundamental questions that call into question the validity of any tests, yet it seems like the community in question is more concerned with 'finding the right tests' within a framework that they assume to be correct.
> "Can/should we be testing anti-depressants on animals at all?"
Yes, of course. We can test a bunch of mice, rats, and monkeys, and then chop up their brains afterwords and actually look at what happened inside. It's not as good as experimenting on people, but it does tell us something.
> "Is it possible that depression in animals is different than depression in humans?"
This is exactly the question being asked. From the article: "Are we in fact modeling the right things? Do the tail-suspension test and forced-swim test detect antidepressant activity after all?" ie, that is, in fact, exactly the question being asked.
> "Is it possible that lab conditions affect the psychology of the animal?"
Lab conditions absolutely affect the psychology of the animal. In these tests, ideally, what they do is they have two populations of animals. Let's say group-A rats get injected with drug XYZ, and group-B rats get injected with saline (placebo). You then look for differences between the two populations. Ideally, the technicians don't know which rat is getting the drug or not, all they know is that rat#1 gets injection#1, rat#2 gets injection#2. So both populations of rats get the exact same treatment, and you look for differences between the two populations of rats.
(Also, some animals don't mind being in cages, but some do. For example, there's lots of experiments with rats and macaque monkeys, because they don't mind cages or people. Whereas chimps would rather rip your arms off than be caged up or experimented on.)
> Can/should we be testing anti-depressants on animals at all?
Would you prefer we test these things on humans? Scientists must put everything pass an ethics committee, testing on animals isn't ideal but the alternatives are far worse.
I have a vegetarian friend who works on vaccines, he doesn't like it but every now and again he injects a couple of hundred mice with something and a period of time later does them in for testing. He does it for the greater good, and it is done as humanly as possible.
This whole thing has been done to death (pardon the pun) and there isn't an alternative. If we want to save human lives we have to accept sometimes some small furry creature is going to lose it's squeak.
Cosmetics on the other hand . . .
> Is it possible that depression in animals is different than depression in humans?
Mentioned in the article that the tests on animal models of depression need re-evaluating.
> Is it possible that lab conditions affect the psychology of the animal?
Yes. I would prefer we test all drugs on humans as soon as volunteers can be found and the researcher thinks it would be beneficial.
I am assuming a volunteer free from political or even financial pressure, doing it out of desire to help. And possessing great and detailed knowledge of the side effects and both the known and potential dangers. I admit this is a bit of a straw man.
There are two reasons I want this.
1. Political. I am a libertarian and and thus think that if an adult wants to jump off a bridge they should be fully within their right to do that. The same goes if they want to test completely unproven or even fully known to be unsafe drugs.
2. Practical. This would speed up research tremendously, it would speed things up by years. We would save more lives.
I feel like the problem is even deeper. The animal tests actually confirmed expected findings based on changes in brain chemistry. The changes in brain chemistry happened in humans, too, if I'm not mistaken. Yet, humans showed no changes in depression, and the article made it sound like that the change in brain chemistry should have had some effect based on that alone. It seems to point to a flaw in part of the modeling of the brain itself.
It's not so much that the modeling of the brain is flawed; it's just that the chemistry of stress and recovery in our brains is complex and has multiple variables. There are lot of outstanding questions.
There are different kinds of depression that manifest themselves with different symptoms (manic depression, sluggishness, suicidal thoughts). What causes some but not others? The type of treatment can depend on this.
Serotonin plays a big role in depression, which helps explain why SSRIs are so effective. Dut is depression caused by not enough serotonin, or is it because the receptors aren't as sensitive to it? Norepinphrine is used by the locus coeruleus, and a lack of it has been linked with PTSD, panic disorders, and depression. Why doesn't this new medication make a difference? Are the low levels of norepineprine a cause or just a symptom? Dopamine signals the pleasure pathway. A lack of it means a lack of pleasure, which is definitely a part of depression.
Those are the big three chemicals, but there are so many other variables. There's a genetic component to depression as well. What genes are responsible for hereditary depression? Even if you inherit the gene, it may require some environmental stimulus to cause it to express itself. What sort of role does childhood trauma play with this?
If you're interested in this stuff, read "Why Zebras Don't Get Ulcers" by Robert Sapolsky. It's a really well-written, thoroughly researched book on stress and anxiety from a scientific perspective. The writing is approachable without pandering, and having a bit more insight into the science of our weird little happy/normal/sad system has given me some direction in managing stress in my life.
Regarding "Why Zebras Don't Get Ulcers", they ought to change the title of that book. The theory that ulcers are caused by stress has fallen into disrepute. Infection by helicobacter pylori is now believed to be the primary cause of peptic ulcers.
This is covered in the book FWIW. The argument that the author makes is that despite H. pylori being the primary cause of ulcers, it doesn't explain all cases. He argues that even controlling for lifestyle variables (drinking, smoking, etc) that stress it self still causes a two to threefold increase in risk ulcers.
I got the impression that the scientifically-relevant (e.g. non-ethical) questions you list would be asked. Having said that, the community should be more concerned with 'finding the right tests' - our "safe" method of testing drugs we suspect are okay is animal testing (whether that is ethically right or wrong), and animals are probably easier to test objectively in this situation, as well as possibly immune to the placebo effect.
I'm under the impression that questions like: "Is it possible that lab conditions affect the psychology of the animal?" aren't asked because:
* No one wants to know the answer if it means that we no longer have a test framework to experiment within. If tomorrow we found out that we couldn't use animals as test subjects because the validity of any such experiments was suspect, then how would 'we' generate grant money?
* Hand-wavy answers like, "It's impossible to know, so we'll just assume that the answer is no."
Wrong! Those are exactly the questions that are asked.
The tests use a group of control subjects vs test subjects which is standard throughout science. This means it takes out a factor such as what environment the animal is stored in by simply storing them all in the same type of environment. This is done every time a study is run to remove minor variations.
Science is all about controlling the variables, it is actually what scientists spend most of their time thinking about.
What really went wrong in this case is when they got to the point of testing humans they stopped doing "science" and started doing "business".
If they hadn't sweeped the bad data under the rug they could have published a lovely paper about how the standard tests for depression in animal models failed (in reboxetine's case, one goat a herd does not make, the tests could just be bad for reboxetine for some reason).
Then you have the wrong impression. That question is asked, and the answer is "yes." The followup questions are "by how much?" and "what can we do to minimize the effect on what we're studying?".
Validity tests are important because if you're going to blow $50,000,000 on research you want _something_ to help guide the way, and you don't want it messed up by having non-conducive lab conditions.
Searching the free access medical literature at NCBI I quickly found:
"Refining animal models in fracture research: seeking consensus in optimising both animal welfare and scientific validity for appropriate biomedical use"
"From Bedside to Bench and Back Again: Research Issues in Animal Models of Human Disease" with the abstract starting "To improve outcomes for patients with many serious clinical problems, multifactorial research approaches by nurse scientists, including the use of animal models, are necessary. Animal models serve as analogies for clinical problems seen in humans and must meet certain criteria, including validity and reliability, to be useful in moving research efforts forward. This article describes research considerations in the development of rodent models."
I'm certain that you'll easily be able to find others.
"Wait, and ponder how there is noting quite so cute as a mouse swimming..."
It seems a little disturbing that the model for which drugs humans should receive should be "how well does it make animals seem to perform when we torture them"...
Although I know it's not at all -literally- why they are used (not to mention that they may not work), these tests seem to say something to me about our understanding of depression, right there.
It's kind of hard to ask a rat if he's feeling blue. While I agree that the tests are somewhat suspect, they're used because they provide an objective metric that isn't influenced by experimenter bias. We'll likely need to find something else that will work better.
In the end, I agree with you, but I'll add this: I think this is a triumphant moment for science. We ran tests, we thought we were getting one result, but we got another. Now, we'll reexamine our assumptions, and attack the problem with renewed vigor. The end result will be a much greater, and much better founded knowledge of depression.
I love that science always wins. Even, and especially, when it fails.
This is not directly related to the post. But gauging that this topic will attract readers knowledgable about antidepressants, I figured I might get an illuminating response.
I often read that a side-effect of a antidepressant is heightened suicidal feelings. That completely mystifies me. Isnt it exactly what it is supposed to be working against ?
Antidepressants motivate people to improve their lives.
One obvious way to do this is suicide. If your every moment of existence is painful, suicide is an immediate improvement.
It's the motivational aspect that seems to increase suicide - motivation turns people's lethargic depression into a more active form of depression where they find the will to carry out their desires.
A common desire among the depressed is the desire for death. Your typical depressed person however is too depressed to even exert the energy or thinking necessary to end his life.
This may be one explanation of the phenomena but there are others.
For example, some anti-depressants disrupt REM sleep, creating a phenomena akin to a waking dream and thus making individuals less sensitive to finality of their actions.
Also, the most dangerous time for suicide for a person on anti-depressant is when they suddenly stop taking them - as happened to a good friend of mine. It is hardly the motivational quality that gets people going at that point.
Edit: suicidal AND homicidal feelings are "rare" but all-too-common responses to anti-depressants and especially to withdrawal from anti-depressants. I've had friends who had both responses in fashions that are at least very unexpected. Anyone with loved-ones taking such drugs, be on your guard.
Seconding the sentiments on withdrawal. I went off Citalopram cold turkey due to an incompetent doctor (who incidentally had not informed me that it was a dependency forming drug). I have never, ever felt that shit in my entire life, and hope I never do again.
If you ever launch into a profanity-laden tirade at the top of your lungs in public because a car was inching forwards at a red light, you might also be going through withdrawal.
Tip for those who want to avoid this: Fluoxetine. Switch to it before quitting, it has a really long half-life so you can just stop taking it, and the levels in your body slowly tail off. Much nicer.
Speaking as someone who has been on a couple... they change everything. You think differently, about different things. For the most part I would summarise the changes as less emotional, cooler, more patient, slower to anger, but lots of the changes seemed completely random. If you randomly change someone's thoughts, they might think about suicide less often, or they may think about it more often. That's just my guess, which judging by this article is about as good as anything right now.
> Isnt it exactly what it is supposed to be working against ?
Not really. Depression and suicidal tendencies are two separate things. Anti-depressants treat depression, they aren't designed to reduce the risk of suicide.
> “Concluding simply that depression causes suicide and leaving it at that may be inadequate for several reasons,” he writes. “It is abundantly clear that most depressed people do not attempt suicide and that not all suicide attempters are clinically depressed.”
> I often read that a side-effect of a antidepressant is heightened suicidal feelings. That completely mystifies me. Isnt it exactly what it is supposed to be working against ?
That's ironic, but not odd. For example, treatments for stomach discomfort can have side effects that include... stomach discomfort.
Chemicals affect different people differently. Some people react in the opposite way than others.
You're joking - but that's actually an EXTREMELY interesting question.
Would humans on Reboxetine do better on a forced swim test? Because if they do, but they are still depressed then that's clear evidence that the forced swim test is worthless.
On the other hand if it has no effect, then humans are different from animals and don't react the same way to drugs, but the test may still be good.
Because if they do, but they are still depressed then that's clear evidence that the forced swim test is worthless.
Worthless for measuring antidepressants, maybe. But I'm sure you could find sponsors for a drug that causes someone to irrationally keep fighting, even if it has no effect on mood.
Forced-swim test was originally developed as an animal model for learned helplessness. So perhaps a subclass of humans whose depression arises from learned helplessness could benefit from reboxetine.
The real problem here is that the field of psychiatry is bandying about diagnoses like "depression" as if they actually mean something, when actually they reflect behavioral traits which could arise from a variety of etiologies.
Perhaps not a forced swim test, but having a human swim in place (or tread water) for as long as they can. In a swimming pool, with people around to rescue them if they stop swimming and start drowning, and being removed as soon as they give up by ... I don't know, going over and grabbing the edge of the pool? Or making some unambiguous hand gesture, or yelling a safe word, or whatever. I'm not entirely sure how valid the results from this would be, but there's also controversy over forced swim tests with rats and mice, so it would probably be just as accurate.
The test doesn't measure swimming, but rather how long before they give up.
So you could make a rigged test. For example:
Tell people you will pay them $200 if they can find the exit of a maze (either real or on the computer). But the maze is rigged, and has no exit. Then time how long it takes before they give up.
Ineffective modification of an existing drug as a means of extending the validity of a patent is a widespread practice. This was possibly not the case here. But given that we are tolerant of such practices and defend them, it comes as no surprise to me that an established drug on the market has no effect on the symptom that it was meant to address.
How does it follow that questionable patents derived by making small changes to existing drugs leads to drugs that have no effect? I think that's begging the question.
I think you got me wrong. I didnt say that questionable patents lead to drugs that have no effect. Infact if you read it again you will find that I explicitly pointed to that possible misinterpretation.
My point was that in an environment where it is possible to extend the duration of a patent by adding modifications to the parent molecule that are known to have no benefit, it does not surprise me that a marketed drug has no benefit either. My point was about my lack of surprise, not a cause and effect relation.
"Ineffective modification of an existing drug as a means of extending the validity of a patent is a widespread practice. This was possibly not the case here. But given that we are tolerant of such practices and defend them, it comes as no surprise to me that an established drug on the market has no effect on the symptom that it was meant to address."
I only see your explicit admission that the first situation (questionable patents derived by making small changes to existing drugs) might not even apply in this case. You do not "point" to a "possible interpretation", you were breezily suggesting a lazy and fallacious connection.
Privileges granted that you disagree with are a different matter than scientific dishonesty. We could remove the whole issue of chemical-tweak patents on drugs by allowing perpetual drug patents, or by ruling that new drugs must be chemically different to some particular degree to not be covered by a patent (expired or not), or by abolishing drug patents entirely, and none of those solutions would imply anything as to the efficacy of future drugs or the trustworthiness of drug research.
I still dont see where I made the connection that you ascribe to me. Nevertheless if such a connection is indeed visible in my comments, thats probably my lack of native english skills showing. Suspecting that my comment might be misinterpreted, I attemped to prempt that. Apparently not very effectively. So let me try again:
We are tolerant of, or inadequately vigilant of ineffective drugs. One such sign can be seen in a particular apect of the patent system I described. Given this environment, it does not surprise me that a particular drug was found to be ineffective.
Your downvotes came with an explanation, which is better than silent downvotes.
Well the article discusses a different issue - the drug passes objective animal-based anti-depression tests with flying colours but, for an unknown reason, is ineffective on people. This raises the question of how we should objectively measure anti-depression efficacy.
Thats not the full story though. The article mentions that the manufacturers were aware of the fact that it was ineffective on humans and hid that data. Discrepancy in animal and human efficacy isnt new by any means, thats why drugs go through a protracted human tests.
Fuck antidepressants. I was on 'em, and I went off 'em of my own volition because I knew they didn't bloody work (and made me tired besides).
Wanna cure your depression? There are two ways.
1) Change how you think. Most of the time it requires conscious effort on your part, sustained over months or years; although if being poor has you depressed and you win the Powerball, that can give you an instantaneous new outlook. Cognitive behavioral therapy has proven vastly more effective than any drug.
2) The route Bill Zeller took. For some people that's their only way out of misery and suffering, and the rest of us need to learn how to respect their choice on an individual and societal level.
> Whereas drugs like citalopram and fluoxetine primarily target the neurotransmitter serotonin, reboxetine targets the neurotransmitter norepinephrine.
I think I was prescribed Edronax in 1999 for a very short while. The side-effect was knocking me out and caused me to sleep for 20 hours a day... I stopped very soon with them.
Not as bad as that guy Wakefield, who mentioned that one of the patients had an odd formed head, but didn't make enough of a deal about it.