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KETAMINE makes waves in the field of mental health, there’s a mystery around the drug that continues to elude scientists: how, exactly, it works in the brains of people with depression.


KETAMINE makes waves in the field of mental health, there’s a mystery around the drug that continues to elude scientists: how, exactly, it works in the brains of people with depression.

Now, scientists have uncovered a process that might contribute to ketamine’s antidepressant effect. In in mice published Thursday in Science, researchers report that ketamine appears to spark the growth of neural connections that had been diminished by chronic stress. They also discovered that the survival of those new connections — known as synapses — seems to be critical to maintaining some of ketamine’s effects.

“To the extent that what we’re modeling in the brains of mice captures something that’s happening in the brains of depressed people, this could be a promising future avenue for research,” said Dr. Conor Liston, neuroscientist and psychiatrist in the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine and an author of the new study.

But experts caution that there are still significant unknowns about how ketamine works in the brain — and at this point, it’s not possible to confirm whether the new observations in mice are also happening in humans.

“It’s interesting, it’s fascinating, but it cannot explain the whole story. It’s one additional piece of a very complex puzzle,” said Dr. Cristina Cusin, who leads a ketamine treatment program at Massachusetts General Hospital and

Ketamine — a longtime anesthetic — is known to work on certain receptors in the brain known as NMDA receptors, which are involved in learning and memory. Research over the last two decades has suggested it can ease symptoms of depression, but scientists don’t understand the biology behind that effect, why the response to ketamine varies so much from one patient to the next, or why the drug’s effects wear off over time. Witha ketamine-derived nasal spray last month for treatment-resistant depression, patients have to take eight doses over their first month of treatment before being moved to a maintenance dose.KETAMINE

In the new research, neuroscientists at Weill Cornell looked specifically at circuitry in the medial prefrontal cortex, an area of the brain thought to be involved in depression. Research has suggested that chronic stress can affect the number of synapses, or the connection between two neurons in the brain. Liston and his colleagues wanted to see if ketamine might have reversed those effects. So they looked at what are known as dendritic spines, tiny projections that shoot off branches of neurons known as dendrites. Most dendritic spines contain functional synapses, so scientists consider them a sign of a connection between two neurons.KETAMINE

New research in mice suggests that ketamine can promote the growth of new synapses in a particular part of the brain, often in places where synapses have been depleted after chronic stress.NIRJA DESAI/SCIENCE

As mice experienced chronic stress, which is commonly used as a stand-in for depression in humans, the researchers saw an uptick in the number of dendritic spines that died off and a decrease in the number of new dendritic spines being formed.KETAMINE

Then, they gave the mice an antidepressant dose of ketamine — and kept watching.

“The effects on behavior were rapid — detectable just three hours after treatment,” Liston said. The mice were more likely to try to escape an unpleasant situation, prefer sugary water over plain water, and explore a maze. All three are considered markers of the chronic stress response: the lack of struggle to escape is interpreted as a lack of motivation, the disinterest in sugar water is seen as a sign that a mouse doesn’t take pleasure in a happy activity, and the tendency to stay in the closed areas of a maze suggests anxiety and a desire to stay in a safe area.


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