With Help from Rats, NU Neuroscientist Closes In on Depression Treatment

AN UNLIKELY ALLY: At Northwestern University’s Feinberg School of Medicine, Eva Redei is making inroads in finding better ways to identify and treat depression. Her main test subjects? Rats!

An illustration by Richard Mia
The brain of a rat has “enough similarity to the human brain that you can start to make some discoveries,” Redei says.

Put a healthy rat into a tank of water and it keeps paddling and trying to get out. Depressed rats, even though they are naturally strong swimmers, will give up. “This phenomenon represents despair,” says the neuroscientist Eva Redei, who works with the most despondent rats in the world. Ultimately she wants to use her findings about biomarkers in the blood of those depressed rats to learn how to better diagnose and treat the 20 million Americans who each year struggle with depression—the world’s leading cause of disability. “We cannot imagine how horrible it is for them,” says Redei, a professor of psychiatry and behavioral science at Northwestern University’s Feinberg School of Medicine. “There is absolutely no sun, there is no hope, there is no way out.”

Redei’s work with rats started 23 years ago, when she met William Paré, a researcher (now retired) at the Perry Point VA Medical Center in Maryland, who was studying rats predisposed to developing stomach ulcers. “We launched into a whole research strategy to try to see what were the neurophysiological characteristics of this animal strain that set them apart from normal rats,” says Paré.

Today Redei works with descendants of a breed of albino rats first genetically engineered in Kyoto, Japan. They are smart mammals, though these particular rodents are depressed and huddle together in their plastic pen rather than exhibiting the frolicsome behavior of healthy rats. Still, “there is enough similarity to the human brain that you can start to make some discoveries,” Redei says. “We already know that some of those markers we found in the blood of the animals are good to determine who is depressed and who is not in humans. What we would like to do is see whether these markers are actually drug targets”—the long-term goal of Redei and her colleagues.

Currently there is no lab test or cure for depression, and only half of the patients treated with antidepressants get better. “A whole group of people don’t respond to antidepressants or behavioral treatment, or they seem to respond to one treatment but not to another,” says the psychologist David Mohr, a professor of preventive medicine at Feinberg. “We don’t know why. All we can do is trial and error.”

And the number of treatment options is limited: Since the FDA approved Prozac in 1987, says Redei, “there hasn’t been a medication based on a novel mechanism.”

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Redei has made some crucial advances. She has already identified five key biomarkers for depression in her rats, and they seem to correspond to biomarkers in humans. Her hope is that doctors will one day be able to draw blood from a patient, determine if some or all of the biomarkers are present, and, based on those results, prescribe an appropriate treatment. “To tell [patients] with high probability that [they] are depressed is not the primary goal,” says Redei. “The real goal is that we can say, ‘You’ve got five of these five, which means you have one type of depression.’” Depending on the combination of biomarkers, doctors would know which drugs would work best for a particular patient. “[Doctors could say,] ‘This is the treatment that this patient is most likely to respond to,’” says Mohr.

Kathleen Pajer, head of the Division of Child and Adolescent Psychiatry at Dalhousie University in Nova Scotia, is collaborating with Redei to help determine the potentially best pairing of drugs and patients. A person’s DNA is fixed, Pajer says. “The rest of the story is gene expression. I may have genes that code for me to have depression, but if certain things happen or don’t happen, they never get turned on or off.” It’s like a panel of light switches, she explains. “We know this particular panel has been associated with this sort of response to this list of medications and this type of psychotherapy.”

Redei is working with Mohr to better understand the relationship between depression, genetics, and psychotherapy. Mohr drew blood from 78 patients with depression both before and after they received 18 sessions of psychotherapy. Now Redei is analyzing those samples to see whether behavioral therapy changes the way the patients’ genes are expressed.

Biomarkers could also play a crucial role in identifying teens with depression. “[Depressed teens] are tricky to diagnose because their behavior is hard to distinguish from normal adolescence,” says Redei. “And they don’t necessarily want to talk about it.”

Identifiable biomarkers would mean that doctors could rely less on a teen’s self-disclosure. “Our diagnostic criteria for depression are completely dependent on patient reports,” Pajer says. Recently she shipped the blood from 28 teens (half with depression and half without) to Redei, who is looking for a “unique gene expression profile” for both groups, as well as for adolescents whose depression is accompanied by anxiety. (Kids exposed to more stressors in their lives seem more likely to develop depression with anxiety.)

Redei and other scientists also hope their work might help erase the stigma associated with depression. “When people have it, they can feel as though it’s a moral failing as opposed to a disease like diabetes or cardiovascular disease,” says Laurie Zoloth, the director of the Center for Bioethics, Science, and Society at Feinberg. “Having a clear biomarker in these cases would make it easier to understand depression as a category of illness and lead these patients to therapeutic intervention.”

In a separate project, Redei is experimenting with healthy rats to alleviate the effects of fetal alcohol syndrome. Despite warnings from the surgeon general, approximately 10 percent of U.S. women drink throughout their pregnancies. As a result, they put their newborns at an increased risk for mental retardation, abnormal heart structure, behavioral problems, and depression. Working with pregnant rats that have been given food mixed with alcohol, Redei has learned that she may be able to prevent some of these problems in humans, especially in the children of the most genetically vulnerable females. The secret: Alcohol can diminish thyroid hormone in the body. When rats consume the human equivalent of two glasses of wine a day, they give birth to babies on the fetal alcohol syndrome spectrum. But when Redei supplements the diets of pregnant alcohol-consuming rats with thyroid hormone, it lessens the impact on their babies.

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In her office off North Michigan Avenue, Redei is far from depressed. She smiles and laughs easily. Toy rats line her shelves. A student who was getting married gave her a rodent bride; another sent a happy-looking wooden pull-toy rat. “They’re not all depressed,” she jokes.

But Redei, who knows something about unhappiness—her parents met as prisoners in an Austrian concentration camp during World War II and were their families’ only survivors—is all business when it comes to improving the quality of life for people with depression. “We are aiming to help those who are paralyzed by their disease,” she says.

That doesn’t mean eliminating sadness and other emotions intrinsic to life. “What is the normal level of depression that an alert citizen should feel in a tragic world?” asks Zoloth. “To some extent, history moves forward because people are angry and depressed and willing to fight for change. It depends on what you do about that despair.” For millions of Americans, that can pose a nearly insoluble problem.

“The environment changed around us extremely fast, and evolution can’t keep up,” says Redei. “So there is this discrepancy between our own expectations of ourselves and society’s expectations of us. Evolution needs some help”—and she and her rats are ready to provide it.

 

Illustration: Richard Mia

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