A potential new antidepressant could work in hours, not weeks or months, according to experiments with mice.
The drug used in the animal studies, CGP3466B, is known to be safe for humans. But more research is needed to determine if its rapid antidepressant action in mice will also appear in human patients, neuroscientists say.
Most currently available antidepressant drugs take a long time to have a noticeable effect on symptoms of clinical depression, such as prolonged sadness, feelings of emptiness or unworthiness, fatigue, insomnia, or a change in appetite or weight.
“One of the promising things about CGP3466B is that it targets a new network of proteins,” says Solomon Snyder, professor of neuroscience at Johns Hopkins University School of Medicine. “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 discovery came out of investigations into the workings of a different drug, ketamine, long used primarily at high doses to induce anesthesia during surgery but also known, at lower doses, to be a fast-acting antidepressant.
Unfortunately, ketamine is addictive and can produce schizophrenia-like symptoms, making it unsuitable for prolonged use. Researchers hoped, however, that it could shed light on how to make a better fast-acting antidepressant.
Scientists knew that ketamine interacts with excitatory NMDA receptors on nerve cells in the brain to block their activity. Using biochemical tests on mouse nerve cells, researchers worked out the steps of the molecular chain reaction responsible for ketamine’s NMDA-blocking antidepressant effects and found the drug stimulates the creation of proteins that help build certain connections between nerve cells.
“CGP3466B works on the same network of proteins as ketamine, but since it works later in the chain reaction, it has fewer side effects,” says Maged Harraz, a research associate in neuroscience and first author of the new paper that is published in the journal Molecular Psychiatry.
To see if CGP3466B, like ketamine, has antidepressant effects in mammals, the researchers used two standard behavioral tests on mice. The first tested how quickly mice give up trying to escape from a pool of water.
Compared to normal mice given no treatment, mice given CGP3466B spent an average of an extra half-minute working the problem. In the second test, treated mice were twice as fast to brave an unsheltered new environment to get a piece of food. Both behaviors in mice are considered surrogates for non-depressed behavior.
“In the second test, the drug worked in only half an hour,” Harraz says. “Other antidepressants tested in mice, like fluoxetine, can take three weeks to show similar results on the same test.” (Fluoxetine is also known by the brand name Prozac.)
The team is optimistic about CGP3466B; it has already been shown to be nontoxic and non-addictive in phase I clinical trials that explored its use for Lou Gehrig’s and Parkinson’s diseases—though it didn’t prove effective in treating those conditions.
Researchers caution that it will take several more years to get the compound into phase II clinical trials to test its potential as an effective and safe antidepressant for people.
A US Public Health Service Grant supported the work.
Source: Johns Hopkins University