New Type of Antidepressant Works Quickly in Mice

A compound known as CGP3466B shows promise in quickly treating depression in mice in hours, versus weeks or months of typical antidepressants. Researchers at Johns Hopkins University School of Medicine (JHU) recently published their findings in Molecular Psychiatry.

Maged Harraz, study first author and a JHU researcher, first learned of CGP3466B, a drug created by Novartis, while reading about research done by Yale scientists on ketamine, an anesthetic with origins in veterinary medicine. CGP3466B works on the same network of proteins as ketamine, which targets NMDA receptors in the brain, blocking their activity and lowering symptoms of cognitive impairments, including depression.

Ketamine has fast-acting antidepressant properties, has shown promise as a potential treatment for blocking cocaine cravings, and is nontoxic to humans. But it's also addictive, abused recreationally (commonly known as Special K, among other names), and comes with schizophrenia-like side effects with prolonged use. So it is rarely used more than in single doses to accompany surgery.

Harraz wanted to understand ketamine’s signaling pathways, to see if there were other links in the molecular chain that could lead to drugs that work as effectively as ketamine, without the side effects.

They discovered that ketamine stimulates the creation of proteins called GAPDH and Rheb. When they applied the CGP3466B compound to mouse nerve cells, it prevented GAPDH from interacting with Rheb, thus breaking the signaling pathway, ostensibly creating an anti-depressant effect.

“Most antidepressants work mainly on serotonin, dopamine, or norepinephrine, which are neurotransmitters in the brain,” Harraz tells mental_floss. “Our compound does not work on these neurotransmitters but instead on the proteins that work with ketamine—particularly glutamate.” Glutamate is a neurotransmitter that is involved in almost all neuron functions. “Our protein works downstream of the receptors, so it doesn’t have the side effects of ketamine.”

Of course, depression is not something that can be easily measured in mice. “There are two research tools that are used as an antidepressant index in mice,” says Harraz. “One is the forced swimming test—a despair test. Mice are put into a water container where they have to swim to keep floating. Then, they try to escape. Most mice will try to escape for two minutes, and after that they realize they can’t, so they just float on the surface of the water. Antidepressants will make them try harder to escape after two minutes. Our compound made the mice try harder, so it’s suggestive that it has an anti-depressant effect.”

The other test is known as a “suppressed feeding test.” The mice are allowed water but not food overnight to make them hungry. “Then we put them in open fields where there is only one pellet of food in the middle,” Harraz describes. Because mice are usually not comfortable going into the open in an unfamiliar place due to fear of predators, most of them won’t go after the food. “Antidepressants will usually make them brave the middle and eat the food, so we use that as another index,” he says.

They use quantitative measures on the time it takes them to go to the middle and eat the food. “Our compound was really suggestive for antidepressant activity in this test as well,” Harraz says.

More startling than that, whereas typical antidepressants, like fluoxetine (brand name: Prozac) take as long as three weeks to provide this effect, CGP3466B worked in half an hour. “It was surprising that it worked as well as it did,” says Harraz. “Often times you build a theory and then things don’t work the way you thought. This is one of the few times that it worked.”

It is their hope that this research will lead to a drug that is better than ketamine. “Now we have strong evidence that CGP3466B is a candidate for an antidepressant,” he says.