Faster than Prozac

SAN DIEGO—Scurrying to find a more effective and faster way to alleviate the debilitating symptoms of depression, researchers at the University of California, San Diego (UCSD) School of Medicine have discovered that inhibiting an enzyme called glyoxalase 1 (GLO1) relieves signs of depression in mice—and kicks in quicker than the antidepressant Prozac.

The UCSD study, published in the March 21 issue of Molecular Psychiatry, sets the stage for the researchers’ discovery of a completely new class of potentially faster-acting antidepressant medications.

“Depression affects at least one in six of us at some point in our lifetime, and better treatments are urgently needed,” says senior author Abraham Palmer, professor of psychiatry and vice chair for basic research at UCSD. “A better understanding of the molecular and cellular underpinnings of depression will help us find new ways to inhibit or counteract its onset and severity.”

Palmer notes that current treatments not only take weeks to reduce the symptoms, but at best are often only modestly effective and produce undesirable side effects.

“Developments of novel antidepressants have stalled, and many of the largest pharmaceutical companies have de-emphasized this area because they believe that the problem is too difficult to solve,” Palmer says. “A new class of antidepressants would be game-changing, especially if they were fast-acting and addressed some of the other shortcomings of currently available treatments.”

“We are currently working with medicinal chemists to develop better GLO1 inhibitors that would have a longer half-life and be orally available,” he adds. “Those drugs would have to be evaluated for safety in animal models and then in humans before we could evaluate their efficacy to treat depression.”

UCSD researchers have patented both the approach and also the specific structures that are mentioned in the paper in Molecular Psychiatry.

Ironically, Palmer and his team began the search for a possible depression treatment by unraveling a previously underappreciated molecular process that ultimately influenced mouse models of depression. Here’s how the process works: Cells generate energy. In doing so, the cells produce a byproduct which then inhibits neurons and thus, influences various behaviors.

Typically, the enzyme GLO1 removes this byproduct, but inhibiting GLO1 can also increase the activity of certain neurons in a beneficial way. Palmer and others have shown that more GLO1 activity makes mice more anxious, but less was known about the system’s effect on depression. Palmer wondered if they could reduce signs of depression by inhibiting the GLO1 enzyme.

To test this theory, the UCSD researchers used several different antidepressant tests then compared responses in three groups of mice: untreated ones, mice treated by inhibiting GLO1 (either genetically or with an experimental compound) and mice treated with Prozac.

The first tests they used were the tail suspension test and the forced swim tests, which are often used to determine whether or not a compound is an antidepressant. In each of these tests, inhibiting the GLO1 enzyme reduced depression-like symptoms in five days, whereas it takes 14 days for Prozac to have the same effect.

Stephanie Dulawa, associate professor of psychiatry at the UCSD School of Medicine, also published a separate article that critiques the use of specific behavioral and molecular approaches, with the goal of helping other researchers identify new antidepressant targets.

“A major limitation of classical antidepressants is that two- to- four weeks of continuous treatment is required to elicit therapeutic effects, prolonging the period of depression, disability and suicide risk,” she states. “Therefore, the development of fast-onset antidepressants is crucial. Preclinical identification of fast-onset antidepressants requires animal models that can accurately predict the delay to therapeutic onset.”

The UCSG enzyme protocol has only been tested in mice. Researchers believe it will take several years before GLO1can be tested in humans. In the meantime, the enzyme provides a target for future therapies.