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Comment by pyre | Hacker News Reader

Questions I don't see being asked:

* 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.

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> "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?

See above.

Would you prefer we test these things on humans?

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.

And possessing great and detailed knowledge of the side effects and both the known and potential dangers.

How, precisely, would you propose that the participants in the first ever test of a drug obtain such knowledge?

Just assume there is a 99.9999% chance it will kill you. Many people would still take the chance to make a difference.

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.

> 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)

Yes, although that view seems both controversial, and very poorly funded. The landmark experiment here was http://en.wikipedia.org/wiki/Rat_Park

This isn't an issue with testing this is an issue of scientific fraud.

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