Ketamine’s antidepressant effect explained

Potential fast-acting treatment boosts BDNF

The anesthetic ketamine works against depression by quickly boosting levels of a brain compound that has been linked to the condition, a new study in mice shows. The research may lead to highly effective and fast-acting antidepressants that provide relief within hours instead of weeks, scientists report online June 15 in Nature.

Traditional antidepressants can be effective but often take weeks or months to improve symptoms. “You can control malignant hypertension within minutes; a bad increase in blood sugar, bad migraines, asthma attacks, within minutes,” says psychiatrist Carlos Zarate of the National Institute of Mental Health in Bethesda, Md. “Yet why in psychiatry should we be satisfied with, ‘Just hang on for a few weeks or a few months, and you’re going to get better?’ That’s not acceptable in my mind.”

The new study may point to faster alternatives, Zarate says: “Here is increasing evidence that you can go more directly at the target, and that’s maybe why you get more of a rapid antidepressant effect.”

Mice receiving a single injection of ketamine showed fewer signs of depression just half an hour after the shot, and they continued to show multiple signs of reduced depression for a week, researchers at the University of Texas Southwestern Medical Center at Dallas found. For example, after one dose of ketamine, mice struggled longer to stay afloat in a beaker of water instead of giving up and sinking.

At high doses, ketamine renders a person unconscious. At lower doses, the drug can induce euphoria, hallucinations and out-of-body experiences, properties that make “Special K” a popular drug of abuse. In the study, Ege Kavalali and his colleagues used low doses that wouldn’t induce psychotic effects.

They found that ketamine kicks off a series of biochemical changes in the brain that culminate in the production of a protein called BDNF. Low BDNF levels have been linked to depression. The researchers also found that mice genetically engineered to be unable to produce BDNF didn’t respond to ketamine.

So far, ketamine has been used in several small trials to treat people with severe depression. The drug seems to work quickly and effectively, but scientists haven’t clearly understood how.

“Originally, it was a rather serendipitous finding that this thing works,” Kavalali says. Understanding how ketamine triggers antidepressant effects opens up a whole new way to think about treating depression, he says, perhaps by developing drugs that have the same net effect as ketamine.

“This article gets to the idea that there are probably agents that have similar potential and might not have the drawbacks of ketamine to give people relief a lot faster,” says clinical psychologist Rebecca Price of the University of Pittsburgh.

Researchers caution that more studies are needed to fully understand how ketamine works in people. Severely depressed people, who have made up the bulk of study groups so far, may respond differently than people with less severe depression.

Laura Sanders is the neuroscience writer. She holds a Ph.D. in molecular biology from the University of Southern California.

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