While ketamine itself maybe won't come into use as an antidepressant because of its side effects, the new finding takes scientists significantly closer to understanding how to build up faster-acting antidepressant medications, reports the study by the National Institute of Mental Health (NIMH), part of the National Institutes of Health.
An earlier NIMH study in humans had shown that Ketamine blocks a receptor called NMDA on brain cells, but the new study in mice shows that this is a midway step. It turns out that blocking NMDA increases the activity of another receptor, AMPA, and that this boost in AMPA is crucial for ketamine's rapid antidepressant actions.
"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 NIH Director Elias Zerhouni, M.D.
By aiming new medications at more direct molecular targets, such as NMDA or AMPA, scientists may be able to evade some of the steps through which current antidepressants indirectly apply their effects.
While ketamine appears to realize this, it is still a doubtful alternative to become a new treatment for depression, because of the side effects it can cause in humans, including hallucinations. It is approved as an anesthetic by the Food and Drug Administration at much higher doses than those given in the study, but its use is limited because it may cause hallucinations during recovery from anesthesia.
Both NMDA and AMPA are receptors for the neurotransmitter glutamate, one of the chemical messengers that allow brain cells to communicate with each other. The glutamate system has been implicated in depression recently, leading to efforts to disentangle its molecular machinery in search of abnormalities and of better 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. We're making tremendous progress," said NIMH Director Thomas R. Insel, MD.
To conduct the new study, researchers induced depression-like behaviours in mice; for example, the mice gave up after being forced to take on hopeless tasks, such as prolonged swimming. A dose of ketamine reversed the depression-like behaviours 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 behaviours. 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 accurate target. These other compounds also reduced depressive behaviours, suggesting that it may be reasonable to develop other fast-acting antidepressants without ketamine's side effects.
"Today's antidepressant medications eventually end up doing the same thing, but they go about it the long way around, with a lot of biochemical steps that take time. Now we've shown what the key targets are and that we can get at them rapidly. Ketamine probably can't become the medication of choice, but this research is leading to some very real possibilities for a whole new generation of antidepressant medications," said Zarate.