Ketamine is a drug that was first synthesized in the 1960s to be used as a powerful anaesthetic in hospitals. In the 1980s, it gained prominence as an illegal recreational drug for its ability to cause dissociations. Earlier this year, the FDA approved a novel ketamine-based antidepressant, but it wasn’t until this month that scientists began to figure out how ketamine is able to accomplish all of these things.
It has been well-known that ketamine is capable of alleviating symptoms of depression, particularly suicidal thoughts, for years now. Clinics began popping up around the country specializing in ketamine infusions, in which ketamine is administered intravenously and relief comes in a matter of hours. Each infusion costs approximately $500 and its effects wear off a week or two later.
Because the infusions began working instantly and wore off in a short period of time, they were typically reserved for people who hadn’t responded well to a handful of other marketed antidepressant medications. Most antidepressant medications take approximately four to six weeks for patients to begin feeling the effects, and a few rounds of ketamine infusions made it easier for patients to get through that time period.
“The ketamine may be a way to improve their mood and stop their suicidal thinking until the other antidepressants — the more standard antidepressants — have the six-week time window to work,” said Dr. Kevin Kane, a practicing anesthesiologist and director of a ketamine clinic in Milwaukee. “Ketamine may be just the thing that gets someone through that window until other medications get the chance to kick in.”
Despite this history, scientists still didn’t know how ketamine was capable of improving mood in a matter of mere hours. That is, until April 11 when a team of scientists from the United States and Japan reported that the drug was improving the functioning of certain brain circuits and restoring faulty connections between cells in these circuits.
The scientists, led by neuroscientist and psychiatrist Dr. Conor Liston, determined this by studying mice. After giving the mice a stress hormone that caused them to act depressed, they used a special laser microscope to determine that there was a loss of functioning synapses in the mice’s brains. It is thought that both stress and depression are associated with a loss of synapses.
Then the scientists gave the mice a dose of ketamine and used technology that makes living brain cells glow under a microscope in order to study when cells become active or inactive.
“You can kind of imagine Van Gogh’s Starry Night,” said Liston. “The brain cells light up when they become active and become dimmer when they become inactive.”
By looking for different groups of brain cells to light up together, the scientists were able to see that ketamine was repairing damaged brain circuits in less than six hours. The mice also stopped acting depressed during this time period, and regained interest in favorite activities such as eating sugar and exploring a maze.
“Ketamine was actually restoring many of the exact same synapses in their exact same configuration that existed before the animal was exposed to chronic stress,” said Liston.
After 12 hours, ketamine was able to restore most of the synapses and successfully form new connections between neurons.
Because the mice demonstrated a significant change in behavior prior to all, or even most, of the synapses being repaired, the scientists believe the drug works in a two-step process. First, it helps faulty brain circuits function better temporarily. Then it provides a more long-term fix by completely restoring the synaptic connections that were between cells originally.
This would also explain why ketamine’s effects wear off within a week or two.
“What we can imagine is that ketamine always has this short-term antidepressant effect, but then if the synaptic changes are not maintained, you will have relapse,” said Anna Beyeler, a neuroscientist who wrote a commentary accompanying the study. Beyeler says that scientists’ next goal is to figure out how to maintain these restored circuits to prevent relapse.
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