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Ketamine powerfully affects the anatomy of the brain. It’s possible to see the change just by studying rodent brain cells with a microscope, says Carlos Zarate from the Mood and Anxiety Disorders Program at NIMH.

A healthy neuron looks like a tree in spring, he says, with lots of branches and leaves extending toward synaptic connections with other neurons. “What happens in depression is there’s a shriveling of these branches and these leaves and It looks like a tree in winter. And a drug like ketamine does make the tree look like one back in spring.”

Anatomy of brain - Tree like structure

Ketamine And Neural Connections

There’s also indirect evidence that ketamine is restoring synaptic (neural) connections in people, Zarate says.

His team studied 30 depressed patients who got ketamine. And they found changes in brainwave activity that indicated the drug had strengthened connections between neurons in areas of the brain involved in depression.

Why Ketamine Works Rapidly

The anti-depressant qualities of ketamine, initially developed as an anesthetic before drifting into recreational circles due to its hallucinogenic properties, have been a booming topic of research over the past few years. Anecdotal evidence of the drug’s effects have been so strong that “ketamine clinics” have popped up all over the US, delivering experimental treatments to patients for hundreds of dollars a dose. 

Ketamine's Affect On The Brain

Beautiful young lady

Research from Columbia University Medical Center has recently clinically verified the drug’s ability to rapidly reduce major depressive symptoms in a matter of hours, but the actual mechanism underlying these effects has been unclear. It’s been known for some time that ketamine blocks a protein receptor in the brain called N-methyl-D-aspartate (NMDA), and it is this process that some have suspected is the cause of the drug’s fast-acting anti-depressant qualities. But until now it hasn’t been clear where in the brain this process is occurring.

The new research focused on a very small area deep in the center of the brain called the lateral habenula. This area is commonly referred to by researchers as the “anti-reward center,” as it’s known for suppressing nearby reward areas of the brain that release dopamine and serotonin. Following growing evidence suggesting that overactivity in the lateral habenula is related to depression, the researchers examined how ketamine directly affects activity in that region of the brain.

“What happens in depression is there’s a shriveling of these branches and these leaves and It looks like a tree in winter. And a drug like ketamine does make the tree look like one back in spring.”

-Carlos Zarate

Using rodent models, they found that certain patterns of rapid bursts of neuronal activity in the lateral habenula resulted in major depressive behavior in the animals. This correlation was verified by genetically engineering rats to enhance this particular type of brain activity, confirming that it did indeed promote symptoms of depression. The next part of the research revealed that this particular bursting neuronal activity in the lateral habenula was dependent on NMDA receptors, and knowing that ketamine was an NMDA receptor blocker led the researchers to examine if this could be the elusive mechanism behind the drug’s rapid anti-depressant effects.

Administering ketamine directly into the lateral habenula of rats resulted in a very quick reversal of depression-like behaviors in the animals. A second experiment using a more specific NMDA receptor antagonist achieved the same reduction in burst activity and associated anti-depressant effects, suggesting that this is the probable mechanism behind ketamine’s rapid positive effects.

The researchers do note that while this study addresses the rapid effects of ketamine, it doesn’t account for the long-term anti-depressant qualities of the drug. However, suppressing burst activity in the lateral habenula does look like a promising area for new antidepressant research. A second accompanying research paper from the same team examined what could be causing this overactivity in the lateral habenula and suggests a potential protein target that could be manipulated to block it.

Ketamine Molecule

Ketamine Research For Alternative Drugs

Zarate’s research into Ketamine’s affect on the brain s intended to produce drugs that will work like ketamine, but without the hallucinations. The goal is to reduce the risk of abuse. And several of these alternative drugs are already being tried in people.

Preliminary results suggest that “some of these compounds do have rapid antidepressant effects without the side effects that occur with ketamine,” Zarate says.

One of these drugs, called GLYX-13, has already been tested in two large groups of people — a key step toward FDA approval. The company that makes the drug, Naurex, says it will tell scientists how well GLYX-13 works at a meeting in December.

While there is a growing amount of research into the use of ketamine for depression, the drug’s strong psychoactive effect and potential for abuse will certainly limit its widespread application. This research into how ketamine works on the brain will hopefully direct scientists toward the development of new ketamine-inspired drugs that target these same brain areas without the other negative psychoactive effects.

The study was published in the journal Nature.

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