Animal research reported on March 21 in the journal Molecular Psychiatry has uncovered a drug development strategy that could lead to a new type of antidepressant medication. The study suggests that inhibiting an enzyme called GLO1 could have fast-acting antidepressant effects, relieving patients’ symptoms in a matter of days. Existing antidepressant medications can take weeks or months to become fully effective, and don’t help a considerable fraction of patients. Finding other, faster-acting alternatives is a high priority.

The study was led by Abraham A. Palmer, Ph.D., a NARSAD 2003 and 2006 Young Investigator at the University of California San Diego (UCSD). Dr. Palmer and his colleagues had previously discovered that inhibiting GLO1 can reduce anxiety-like behaviors in mice, and several studies have hinted that overactivity of GLO1 might also contribute to depression. So the team was curious whether inhibiting the enzyme might be an effective way to treat major depression.

The researchers, including Marcia J. Ramaker, Ph.D., a 2016 Young Investigator, and Stephanie Dulawa, Ph.D., a 2016 Independent Investigator and 2007 and 2012 Young Investigator at UCSD, reduced the activity of GLO1 in mice, by genetic manipulation or by administering two different GLO1-inhibiting chemicals.

Then they evaluated the animals’ behavior. They used several established tests to measure depression-like behavior in the animals, such as observing how hard they tried to escape difficult situations and how they coped with chronic mild stress. They performed the same tests with untreated mice and also with mice given the popular antidepressant medication fluoxetine (Prozac).

Depression-like behaviors declined within five days of treatment for the animals in which GLO1 had been inhibited. Depression-like behaviors also declined in animals that were given Prozac, but for this group, it took two weeks for the antidepressant to take effect.

The scientists say inhibiting GLO1 likely increases the level of a brain chemical called methylglyoxal, which influences neural signaling. They are now working with medicinal chemists to try to develop better GLO1-inhibiting compounds. These could give rise to a new, faster-acting treatment for depression, the team says. With further research, this may become a new strategy for treating depression.