A study in mice has identified a new player in triggering the antidepressant response produced by ketamine.

By deactivating a little-known enzyme, the drug takes the brakes off rapid synthesis of a key growth factor thought to lift depression, say researchers supported by the National Institutes of Health. "Other agents that work through this pathway and block the enzyme may also similarly induce anti-depressant-like effects and hold promise for development of new treatments," says Lisa Monteggia, PhD, of the University of Texas Southwestern Medical Center.

Ketamine can lift one’s mood within hours, yet adverse side effects of this animal anesthetic and sometime “club drug” preclude it from becoming a practical treatment. Researchers have been studying its mechanism of action, in hopes of developing safer alternatives that work the same way.

Earlier studies have shown the growth factor, called brain-derived neurotrophic factor (BDNF), produces antidepressant-like effects. To find out if BDNF is involved in ketamine's action, the researchers gave the drug to mice genetically engineered to lack BDNF. Unlike in control mice, ketamine failed to produce a fast-acting antidepressant-like response in such BDNF knockout mice exposed to experimental situations that trigger depression-like behaviors. This and other tests confirmed that ketamine's rapid antidepressant effects depend on rapid synthesis of BDNF in the brain's memory center, or hippocampus.

The researchers determined that this happens so quickly (within 30 minutes) because time-consuming intermediate steps have already been completed. It only requires the translation of BDNF mRNA, (an intermediate form), into the final protein. Conventional antidepressants are thought to work through a lengthy and indirect process that requires the birth of new neurons and their integration into circuits.

Ketamine achieves the boost in BDNF levels by first blocking the NMDA receptor, a protein on neurons. The team discovered that this blockade deactivates a eukaryotic elongation factor 2 enzyme (eEF2) kinase, which restrains BDNF synthesis. Ketamine effectively takes the brakes off of this antidepressant mechanism.

"Selectively inhibiting the eEF2 kinase was sufficient to trigger a rapidly acting antidepressant response in control mice but not in mice lacking BDNF," explains Monteggia. The researchers discovered the boost in BDNF occurs while neurons are in their default mode – not doing anything in particular. But the cells continue communicating via a low level of background chatter, spontaneously releasing chemical messengers that bind to receptors. So when ketamine blocks NMDA receptors, it prevents their naturally occurring messenger chemical, glutamate, from binding to them. "Interference with such spontaneous neurotransmission to trigger production of a protein represents a novel mode of drug action," Monteggia notes. "It may also hold clues to what goes awry in the brain in disorders like depression."

Although BDNF levels fall off sharply following the transient increase triggered by ketamine, she says evidence may also support a role for BDNF in the drug's longer-term antidepressant effects. "This discovery of a novel pathway involved in mediating fast-acting antidepressant action holds hope for development of new rapid-acting medications," adds Monteggia.

The research was published online in the journal Nature.

Release Date: June 22, 2011
Source: National Institute of Mental Health