New antidepressant drug takes effect in hours, study shows

A compound showed antidepressant effects in mice in hours, compared to weeks or months needed for traditional antidepressants, according to a study published online January 12, 2016 in the journal Molecular Psychiatry.

The compound CGP3466B, which researchers had previously shown to inhibit cocaine addiction in mice, has already been tested for safety in humans.

“One of the promising things about CGP3466B is that it targets a new network of proteins,” says study author Solomon Snyder, MD, Professor of Neuroscience at the Johns Hopkins University School of Medicine, in Baltimore, MD. “That means it may work in patients who are unresponsive to other types of drugs, and it lays the foundation for the development of a new class of fast-acting antidepressants that target the same network.”

The researchers identified this new network of proteins when they investigated an old drug, ketamine. Although ketamine is known to be a fast-acting antidepressant at low doses, it’s also addictive and can produce schizophrenia-like symptoms, Dr. Snyder said. So the researchers sought to investigate ketamine’s mechanism of action in order to develop another fast-acting antidepressant, but a safe one.

Previous research described ketamine as a glutamate-NMDA receptor antagonist. In this investigation, first author Maged Harraz, PhD, a research associate in neuroscience at Johns Hopkins, and fellow researchers worked out the steps of the molecular chain reaction responsible for ketamine’s NMDA-blocking antidepressant effects. They performed biochemical tests on mouse nerve cells and found that ketamine stimulates the creation of proteins—GAPDH and Rheb—that help build certain connections between nerve cells.

The team’s prior research on blocking cocaine cravings had already found that the compound CGP3466B prevents nitric oxide from reacting with GAPDH. The researchers determined that this effect also blocks GAPDH from interacting with Rheb and continuing the chain reaction’s signaling.

“CGP3466B works on the same network of proteins as ketamine, but since it works later in the chain reaction, it has fewer side effects,” Dr. Harraz said.

To test whether CGP3466B worked like ketamine to produce antidepressant effects in mammals, the researchers performed two standard experiments in mice that can represent non-depressed behavior.

The first experiment tested how quickly mice gave up trying to escape from a pool of water. Mice given CGP3466B spent an average of an extra half a minute trying to escape compared with normal mice given no treatment. In the second experiment, treated mice were twice as fast to venture into a new environment to get a piece of food.

“In the second test, the drug worked in only half an hour,” Dr. Harraz says. “Other antidepressants tested in mice, like fluoxetine, can take 3 weeks to show similar results on the same test.”

CGP3466B looks promising as a novel antidepressant, the researchers noted, because it has already been shown to be non-toxic and non-addictive in phase I clinical trials for treatment of amyotrophic lateral sclerosis and Parkinson’s disease, although it was eventually proven ineffective in treating those conditions.