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Ketamine, a drug once popular in clubs, is now a psychiatrist’s secret weapon in the fight against depression. Perhaps you’ve heard of it, either from the personal stories of celebrities – such as former NBA players Lamar Odom or Sharon Osbourne – or through the many studies currently underway to evaluate its effectiveness.

You may not know how this drug relieves depression and why it seems to help patients for whom all other treatments have failed. In that case, you wouldn’t be alone. Dr. Steven Levine, a board-certified psychiatrist who developed a clinical use protocol for ketamine in 2011, says scientists are still determining that. The U.S. Food and Drug Administration also approved a ketamine nasal spray called esketamine in 2019. Here’s what you need to know as the scientific community continues to explore how a drug once used as an anesthetic on the battlefield has revolutionized the world of mental health.

Ketamine offers “a more optimistic model of depression”

The basic way to explain it, Levine says, is that the drug more or less wakes up the brain and allows it to form new connections. “We think it affects the glutamate system. Glutamate is a neurotransmitter, [which] is a chemical messenger that carries information signals in the brain,” he says. “It allows the brain to heal and change, to learn and become more resilient.”

He sees this as a “more optimistic model of depression” than drugs like Prozac, which is part of a class of drugs called selective serotonin reuptake inhibitors (SSRIs). The theory behind SSRIs is that depression is caused by a deficiency of serotonin, a feel-good chemical, in one part of the brain. Ketamine is based on the idea that depression affects many areas of the brain, inhibiting its “neuroplasticity” – or, “the brain’s ability to reorganize itself by forming new neural connections throughout life “.

Rebecca Price, an associate professor of psychiatry and psychology at the University of Pittsburgh who studies ketamine, says ketamine’s ability to affect neuroplasticity may be why patients who benefit from the drug often feel immediate relief. “In terms of the brain receptors it acts on, ketamine has a very different mechanism than an SSRI,” Price says. “The main hypothesis for why ketamine works so quickly, even in treatment-resistant patients, is that it will rapidly restore neuroplasticity in key brain circuits involved in regulating mood, cognition and emotion within about a day.”

The mechanism behind ketamine has some similarities to the main chemical in cough medicine

Levine, a pioneer in ketamine and depression research, said his interest began a decade ago when he was asked to provide a second opinion to a patient suffering from severe depression. The woman, who had been struggling to find relief from other treatments, revealed that she had been using something unusual to treat her depression: cold medicine.

“It was a random, funny thing. She admitted to me very guiltily that despite the fact that she was getting excellent care and a wonderful psychiatrist, the one thing on earth that seemed to help was when she coughed and would take over-the-counter cold medicine,” Levin explained. “So she found herself – at her worst – taking half a bottle to help her feel better.”

Determined to find out the mechanism behind this, Levine quickly narrowed it down to dextromethorphan, the active ingredient in cold medicine. “I was curious about what the mechanism of action of …… dextromethorphan was, and then [found] that other medications had that mechanism, too,” Levin said. “It reminded me of some of the papers that were starting to be generated at the time that looked at repurposing this really old anesthetic called ketamine for this new purpose.”

Soon after trying the hallucinogenic agent on one patient, he saw results almost immediately – treating more than 6,000 patients over more than a decade, time and time again. “I’m really grateful that I’ve had the opportunity to sit with so many people who have shared with me how much their lives have changed and improved as a result of [ketamine] treatment,” Levin says. “It’s just, it’s hard to put into words.”

The treatment can be “dramatically life-changing,” but it only works for 50 percent of patients

Levin emphasized that while the drug can work miracles, it is by no means a panacea. Many people feel a huge boost from the drug, but just as many – for reasons that are not clear – do not. “Only about 50 percent will respond to ketamine treatment, and maybe 60 to 70 percent will get that lower standard of clinical significance,” Levin said. “So a lot of people won’t get that much benefit from ketamine. But I’ve seen people who are really in distress and they’ve tried everything under the sun …… people who really believe there’s nothing on earth that can help them. I’ve seen some pretty amazing dramatic reactions. I’ve been lucky enough to get a lot of hugs. “

This drug is helping move the world of psychiatry forward

Pryce, who has pioneered new research combining ketamine treatment with neurocognitive training, confirms that ketamine represents a major breakthrough in the field of mental health treatment. “It’s very important to us that depression can indeed be reversed so quickly and profoundly, even in patients who don’t respond well to existing treatment options,” Price said. “I think the field is much more open to the idea that we can and should expect to get better from our treatments for depression and related disorders. A rapid and profound shift is possible, and we should leave no stone unturned until we can find safe, effective, efficient methods and lasting approaches to help everyone who struggles.”

Nonetheless, Price said the psychiatric community has a long way to go in embracing new ideas. “The promise and potential of this initial discovery has not yet been fully realized in the clinic due to a number of barriers to widespread adoption by providers and patients,” she said. “One of the key issues is the lack of proven, safe, feasible and effective methods to make these rapid effects more sustainable in the long term. Rapid remission may be important in some clinical situations – for example, perhaps to address a suicidal crisis – but what people ultimately want, need and deserve is a way to stay healthy for the rest of their lives.”

Ketamine “takes you to the parking lot”

Those who remain confused about the way ketamine works may think of it in terms of analogies. While some liken it to a “flash mob” in the brain, Levin likes to explain it differently.

“One of the analogies I use when comparing traditional antidepressants to ketamine is that it’s like deciding to go to the supermarket. With a traditional antidepressant, you start at home and there are a lot of steps. You have to find your keys, get your car, open the door, turn on the ignition, drive down the street, make a lot of turns, get into the parking lot, get out of the car, and then walk in and find the frozen food section,” he said. “There are a lot of things that can go wrong and get in your way. With ketamine, it doesn’t put you directly into the frozen food section, but at least takes you into the parking lot. So it’s a shorter route, and that’s probably why more people can benefit in a shorter amount of time.”


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