Animals In Print
The On-Line Newsletter
From 6 April 2004 Issue
Why Test Animals to Cure Human Depression?
By GINA KOLATA
You might think if questions were raised about whether antidepressant drugs can make patients suicidal during the first few weeks of treatment, that scientists would turn to animal testing for further investigation.
After all, suicides are rare enough that there are no firm human data on whether the drugs can cause them. But you can do experiments with animals - examining their brains, giving them high doses of drugs - that you could never do with people.
That might seem like a reasonable course of action, especially after the Food and Drug Administration announced last week that it was so concerned about a possible, though very slight, suicide risk that it wants antidepressant drugs to carry warnings on their labels. But it turns out that animal experiments are not an option.
The reason, said Dr. Alan Schatzberg, chairman of the department of psychiatry and behavioral science at Stanford University's School of Medicine, is that "we don't have an animal model of depression."
Instead, he and other experts say, the first generation of antidepressants was discovered by accident. Though a few came on the market based on clinical tests showing they could help patients, animal tests were later developed to speed the discovery of other drugs. The idea was for pharmaceutical companies to use animal testing to screen thousands of potential new compounds to pick out those most likely to work in clinical tests on depressed patients.
The problem, some researchers say, is that while the animal tests work fine for identifying promising new drugs, they do not mimic anything like human depression. For one thing, animals respond to the drugs within half an hour, while depressed patients need weeks before feeling their effects.
Another difference is that antidepressants affect different parts of the brain in animals and humans. "Depression has a strong emotional and cognitive component," Dr. Schatzberg said. "People feel sad, worthless, guilty."
Those symptoms, he noted, involve the prefrontal cortex, a brain area not highly developed in animals. So, he asked, "How do you model it in an animal?"
In one popular test, mice are placed in a pool of water and monitored to see how long they swim before giving up. If they are treated with an antidepressant, they swim longer.
Another experiment involves hanging mice by their tails; those given antidepressants struggle longer before giving up.
In a third test, mice are taught to avoid an electrical shock by pushing a lever. When the lever is inactivated, the mice continue to push it anyway, even though they still get shocked. Mice under the influence of antidepressants keep pushing it longer.
But Dr. Robert R. Ruffolo, president of research and development at Wyeth, said it was a mistake to assume that an animal test can reflect human behavior. "The first thing we do - and this is tough - is we don't try to relate the behavior in an animal to a human behavior," he said. Animals like mice, he added, "don't feel happy or sad."
"We didn't have someone in a lab thinking, 'Gee, if an animal swims longer, it won't be depressed,' " Dr. Ruffolo said. Instead, researchers found, by trial and error, that the same drugs that make a mouse swim longer are the ones that alleviate depression in humans. "It almost didn't matter what the behavior was," Dr. Ruffolo said.
Such tests, says Dr. Solomon Snyder, director of the department of neuroscience at Johns Hopkins University Medical School, are "very, very empirical." But, he added, there is a certain rationale at work. "What's notable about depressed people is that they are hopeless. That's sort of what they are trying to model."
Some psychologists say they can make animals exhibit signs of depression by putting them in situations where they feel helpless to control their fate. "All this stuff about animals don't feel sad or hopeless, that's some huge leap," said Dr. Martin Seligman, director of the Positive Psychology Center at the University of Pennsylvania. He said that the only sign of depression that could not be elicited in animals was suicide.
What if, by chance, researchers stumbled on an animal test that predicted whether an antidepressant drug might prompt suicide as a rare side effect in people?
"We would immediately go back and test all of our drugs," Dr. Ruffolo said. If the animal tests indicated that the drugs were linked to suicide, he added, the company would use the test to search for other drugs that were not.
Even so, animal research can be a trap, researchers say, because it forces companies to zero in on drugs that generate the same results in limited tests.
That cycle produces lots of me-too drugs but little insight into how to produce better antidepressants that could help more people and perhaps even make them more cheerful and optimistic. Maybe even drugs that could alleviate concerns that some patients might commit suicide when they first start taking them.
"Would you miss new classes of drugs that are antidepressants and work by completely different mechanisms?" Dr. Ruffolo asked. "The answer is absolutely yes."
Dr. Schatzberg of Stanford agrees, acknowledging that "We need new theories."
"We're getting closer but we're not there yet," he said.
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