Unique Experimental Drug Shows Antidepressant Effects

Could lead to more effective treatment for depression

March 31, 2003

Public Affairs

Belmont, MA - Dynorphin, a brain chemical likened to the "evil cousin" of those that cause a runner's high, may be the key to future treatments for depression. Researchers at McLean Hospital have found a new drug that specifically targets dynorphin receptors, blocking the chemical and producing antidepressant effects in animals.

William Carlezon, PhD

William Carlezon

"This is exciting because we think we've figured out what's wrong with the brain and we've designed a drug to fix it--rather than finding something that seems to work and then working backwards to try to figure out what's wrong in the brain. We think we have a much more powerful strategy," says William Carlezon, PhD, director of McLean Hospital's Behavioral Genetics Laboratory, who led the team of researchers.

The study published in the April 1 issue of the Journal of Pharmacology and Experimental Therapeutics (abstract) shows 5-acetamindinoethylnaltrindole or ANTI when administered to rats, sustained their ability to swim for longer periods during a forced swim test. Without the drug, rats will consistently "give up" and float after about 10 minutes on their first test, but the next day when re-tested, they will give up in just two minutes. The new McLean Hospital study shows the animals that got doses of ANTI immediately after the first swim test as well as the next morning, kept swimming during their re-test that afternoon.

Carlezon explains, "They didn't give up as readily and the more time it takes them to give up the less we think they're depressed. That's what antidepressants do."

The success of this research may mark a new era in drug development, according to Carlezon. Antidepressant and other psychopharmacological drugs are usually discovered by accident, but here scientists knew the dynorphin pathway was involved in depression. Previous McLean Hospital studies showed that stress activates a chemical in the brain called CREB and that switching on CREB in key brain regions therefore mimicking stress made rats more sensitive to stressors and caused them to more quickly develop depressive-like symptoms. Researchers also found the rats had more dynorphin in the regions where CREB was activated. Given these findings, scientists theorized that if the action of dynorphin could be interrupted, it might lead to a potential new drug. Carlezon and his team then embarked on a mission to find that drug and now believe they have.

Researchers tested two other dynorphin blockers that had the same effects, however, they had to be administered directly into the brain. Because of its structure, ANTI could be injected peripherally with the same results.

"This is a good example of how modern techniques in molecular biology may lead to the development of totally new treatments for mood disorders such as depression," says Carlezon, also the director of the new Medication Development Laboratory at McLean, where the studies were conducted.

Carlezon hopes to begin a long-term study in animals and if all goes well, start testing the drug in humans in a few years.

"The goal is to develop a drug that is more effective, works faster, using a lower dose, with less side effects than treatments currently available. We hope that by narrowing in on what we think is actually triggering the symptoms of depression, we can start to realize some of those goals."

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