Discovery of the mechanism through which ketamine relieves depressive symptoms within hours may help development of faster-acting antidepressants, according to an article published online July 23 by Biological Psychiatry.

Although ketamine itself probably will not become used as an antidepressant due to side effects, especially the hallucinations seen after it is used as an anesthetic, the current study, funded by the National Institute of Mental Health, does provide a target for new agents.

The new research built on the observation in humans that ketamine is an antagonist of the NMDA receptor. Using a mouse model, the researchers studied effects after initial binding and found that blockade of NMDA receptors increases activity of a second receptor, AMPA, and it is the increase in AMPA activity that is key to antidepressant action.

In the new study, researchers induced depression-like behaviors in mice; for example, the mice gave up after being forced to engage in hopeless tasks, such as prolonged swimming. A dose of ketamine reversed the depression-like behaviors for at least two weeks.

When the researchers gave the mice a substance that blocks the AMPA receptor beforehand, ketamine was not able to reverse the depression-like behaviors. The boost in AMPA thus appears to be a necessary ingredient for ketamine’s antidepressant effects.

In a related experiment, the scientists used two different compounds instead of ketamine to try to block just one part of the NMDA receptor, an even more precise target. These other compounds also reduced depressive behaviors, suggesting that it may be feasible to develop other fast-acting antidepressants without ketamine’s side effects.

“Our research is showing us how to develop medications that get at the biological roots of depression. This new finding is a major step toward learning how to improve treatment for the millions of Americans with this debilitating disorder; toward eliminating the weeks of suffering and uncertainty they have to endure while they wait for their medications to work,” said National Institutes of Health Director Elias Zerhouni, MD.

Both receptors identified in the current work, NMDA and AMPA, are receptors for glutamate. The glutamate system has been implicated in depression recently, leading to efforts to unravel its molecular machinery in search of abnormalities and better targets for antidepressant medications. This focus on the glutamate system is a departure from the thinking that led to currently available antidepressants, which are thought to relieve depression through a lengthy trickle-down process of biochemical reactions that affect the circuitry underlying depression.

The fact that NMDA and AMPA receptors are part of the glutamate system and that targeting them directly led to such rapid, sustained relief of depression-like behaviors in this study - and that a single dose of ketamine did the same in humans in the earlier study - suggests that they are probably the key targets for antidepressant medications.

“In any other illness of depression’s magnitude, patients aren’t expected to just accept that their treatments won’t start helping them for weeks or months. The value of our research on compounds like ketamine is that it tells us where to look for more precise targets for new kinds of medications that can close the gap,” said National Institute of Mental Health Director Thomas R. Insel, MD. “We’re making tremendous progress.”