The antidepressant reboxetine: A headdesk moment in science
scientificamerican.com
scientificamerican.com
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.
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.
http://www.huffingtonpost.com/irving-kirsch-phd/antidepressa...
(Apologies for linking to huffpo, but the article is by the guy who did the definitive survey of the research.)
You can check out some of the original scientific studies he cites on his website, though it of course makes more sense with his context http://robertwhitaker.org/robertwhitaker.org/Depression.html
* 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.
* 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."
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).
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.
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.)
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?
See above.
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.
How, precisely, would you propose that the participants in the first ever test of a drug obtain such knowledge?
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.
Yes, although that view seems both controversial, and very poorly funded. The landmark experiment here was http://en.wikipedia.org/wiki/Rat_Park
Forced Swimming Test http://en.wikipedia.org/wiki/Behavioural_despair_test
Tail Suspension Test http://www.stoeltingco.com/stoelting/productlist13c.aspx?cat...
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.
"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"...
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 ?
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.
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.
http://en.wikipedia.org/wiki/Antidepressant#REM_Sleep
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.
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.
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.
> 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.
This article might be interesting for you: http://www.scientificamerican.com/blog/post.cfm?id=being-sui...
> “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.”
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.
You'll have to go back to the earlier half of the 20th century to see research like that.
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.
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.
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.
The norepinephrine one isn't directly changing my mood, or reducing my fears, but it's definetly increasing my drive, in a kind waking me up.
Perhaps my depression isn't "typical", because it seems mostly originating from an affection of the pituitary.
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.
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.
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.
I'm curious if this might be effective as an ADHD drug. This is essentially what Strattera does: http://en.wikipedia.org/wiki/Atomoxetine