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Mechanism of Fast-Acting Antidepressant Revealed

Neurons in the brain.Kim Hager, University of California

A new study in mice has identified the molecular players involved in the rapid antidepressant effects of ketamine, a common anesthetic. The findings could lead to better, faster-acting antidepressant medications in the future.

Major depressive disorder affects about 7% of adults in the United States each year, with about 30% of these cases considered severe. Symptoms can include insomnia, an inability to concentrate, lack of energy and suicidal thoughts. While effective antidepressants exist, they often take weeks or months to start working. This delay can be dangerous for certain patients, especially those at risk for suicide.

Clinical studies have shown that ketamine, an anesthetic that blocks certain receptors in the brain called NMDA receptors, eases depression symptoms within 2 hours. Moreover, just 1 dose can produce antidepressant effects that last for 2 weeks. Figuring out how ketamine works could lead to the development of better antidepressant medications.

Drs. Lisa Monteggia and Ege Kavalali of the University of Texas Southwestern Medical Center led a team seeking to understand ketamine’s effects on the brain. NIH’s �����鶹��Ƶ Institute of Mental Health (NIMH) funded the study, and the results were published online on June 15, 2011, in Nature.

The team used a test called a “forced swim test” to judge the success of the ketamine treatment. In this test, a mouse is placed in a beaker of water for 6 minutes. Mice showing successful antidepressant effects, as they do with ketamine treatment, swim more than control mice. This effect persists when animals are re-tested without ketamine a week later.

The team discovered that a protein called brain-derived neurotrophic factor (BDNF) is critical for ketamine’s antidepressant effects. Studies have shown that BDNF is involved in the activity of other antidepressants, and when the team looked at its presence in the hippocampus region, they found that ketamine rapidly increased BDNF protein levels. When they genetically engineered mice to lack BDNF, ketamine could not produce its antidepressant-like effects in the animals.

The team turned their attention to NMDA receptors to explore the chain of events that lead to altered BDNF protein levels. Through a series of experiments, they found that ketamine’s blockade of NMDA receptors leads to the activation of a protein called elongation factor 2 (eEF2), which helps to create more BDNF protein. When the researchers used specific enzyme inhibitors to manipulate this pathway and boost BDNF protein levels, they saw antidepressant-like effects in the swim test similar to those seen with ketamine.

These experiments reveal how ketamine exerts its fast antidepressant effects. They also show that targeting other molecules in the pathway might be just as effective at lifting depression symptoms as using ketamine and other NMDA receptor blockers.

“Other agents that work through this pathway and block the enzyme may also similarly induce antidepressant-like effects and hold promise for development of new treatments,” Monteggia says.

— by Allison Bierly, Ph.D.