In previous studies, the chemical ketamine blocked a brain cell receptor called NMDA which plays a role in depression. In the latest study, researchers found that this is only the first step. Blocking NMDA increases the activity of a second receptor, AMPA. This boost is the key to ketamine's rapid action as an antidepressant.

Both NMDA and AMPA are receptors for the neurotransmitter glutamate, a chemical messenger between brain cells that has recently been identified as a possible player in depression. Researchers are examining the molecular processes involving glutamate with the hope of better understanding the causes of and treatments for depression.

In order to test ketamine, the researchers induced depressive symptoms in mice. When they gave the depressed mice ketamine, the symptoms were relieved for at least two weeks. However, the effects of ketamine were blocked when they gave the mice medicine that prevented ketamine from reaching the AMPA receptor, proving the importance of the second step in the chain reaction.

Writing in the July 23 online edition of Biological Psychiatry, the researchers cautioned that ketamine itself is not appropriate as an antidepressant because of its side effects, which include hallucinations. However, understanding how ketamine operates will help with the development of faster-acting antidepressants, they reported.

Current antidepressants may take weeks or months to have an effect, leaving people suffering with depressive disorders frustrated and at risk for worsening symptoms, including suicide.

"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 NIMH Director Dr. Thomas R. Insel. "We're making tremendous progress."

By aiming pharmaceutical development at more specific molecular targets such as NMDA and AMPA, scientists may be able to reduce the wait for antidepressants to take effect. The researchers tested the effectiveness of compounds similar to ketamine on the NMDA receptor and found a similarly speedy relief of depression.

Ketamine is currently approved for use as an anesthetic, but its use is limited due to hallucinations during recovery. The doses used in this study were much smaller than the amount approved for anesthetic use.

More information

To learn more about depression, visit the National Institute of Mental Health.