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Mon January 30, 2012
Shots - Health Blog

'I Wanted To Live': New Depression Drugs Offer Hope For Toughest Cases

Originally published on Thu March 27, 2014 7:52 am

A club drug called "Special K" is generating a lot of buzz among researchers who study depression.

That's because "Special K," which is actually an FDA-approved anesthetic named ketamine, can relieve even suicidal depression in a matter of hours. And it works on many patients who haven't responded to current antidepressants like Prozac.

Those traditional drugs, which act on the brain's serotonin system, can take more than a month to kick in, and don't work for up to 40 percent of people with major depression.

"We can take care of a migraine in hours," says Carlos Zarate, a brain researcher at the National Institute of Mental Health who is studying ketamine. "So why do we have to wait weeks or months with depression?"

Ketamine itself isn't likely to become the next big drug for depression because it has troubling side effects, including hallucinations, Zarate says. But understanding how ketamine works could lead to safer drugs that are just as effective, he says.

Drugs For Depression, Without Success

Ketamine was developed in the 1960s as an anesthetic and pain reliever. In the 1970s, recreational drug users figured out that if you take enough ketamine, you can have a mind-bending experience.

But the drug's ability to relieve depression wasn't clear until just a few years ago. And since then, most of the people who have received ketamine for depression have been participants in scientific studies of the drug.

One of those people is Christopher Stephens, 28, who lives in the San Francisco Bay Area and was diagnosed with depression when he was just 15.

"My first prescription was for Paxil," he says. "Then I started on Prozac, and then, you know, at 19, that's when I decided that I had to go and try new medications."

It's hard to remember all of those medications, Stephens says. Then he reels off a list that includes Klonopin, Ativan, Valium, Xanax, Remeron, Gabapentin, Buspar and Depakote.

Some of these drugs didn't work, Stephens says. Others caused nausea, headaches and insomnia, as well as sexual side effects.

And despite all the drugs, Stephens' depression kept getting worse.

Ultimately, he just couldn't function. He lost his job as a special education assistant. Even his greatest joy, teaching martial arts, wasn't enough to keep him going, he says.

"I went on the Internet and I started researching ways to end your life," he says. "A lot of people think, 'Oh, I can down a bottle of Tylenol and that'll do it.' What that'll actually do is kill your liver and you slowly die, which is not a good way to go. I wanted to research the most efficient and painless way to do it."

But Stephens wanted to do something good before he died, something that might help other people avoid the hopelessness he was feeling.

So he called up the University of California, San Francisco, and offered himself up as a sort of human lab animal. He thought maybe scientists could learn something about depression by studying his brain.

Depression: A Leaky Faucet In The Brain

The call to UCSF got Stephens referred to Zarate, a researcher who thinks current depression drugs are on the wrong track.

Zarate sees depression as a bit like a leaky faucet in the brain. There are different ways to stop the leak, he says. "You can go straight to the faucet and you can fix it," he says. "Or you can go to the water plant and shut down the water plant. The end result will be the same."

The current antidepressants act in a way that is like shutting down the water plant, Zarate says. It takes a long time for the water to stop flowing through the miles of pipes that eventually lead to the leaky faucet.

He thinks the reason is that these drugs act primarily on the brain chemicals serotonin, norepinephrine and dopamine. Ketamine acts on a chemical called glutamate, which is much closer to the problem, Zarate says.

So Zarate was intrigued in the early 2000s when he began to hear anecdotal reports that ketamine could relieve depression almost instantly. But as a scientist, he says, he was concerned that these dramatic reports might be too good to be true. So he and other researchers decided to conduct a scientific study.

It involved 17 patients with depression — people who, like Christopher Stephens, had tried lots of medications without success. After a single dose of ketamine, though, 12 of the 17 got much better within hours. And the effect lasted for more than a week.

The result, published in 2006, got international attention. And since then, Zarate has given ketamine to many more patients, including Stephens.

'I Wanted To Live Life'

Stephens himself has vivid memories of the day he got ketamine.

It was a Monday morning and he woke up feeling really bad, he says. His mood was still dark when doctors put in an IV and delivered the drug.

"Monday afternoon I felt like a completely different person," he says. "I woke up Tuesday morning and I said, 'Wow, there's stuff I want to do today.' And I woke up Wednesday morning and Thursday morning and I actually wanted to do things. I wanted to live life."

About 18 months ago, researchers at Yale found a possible explanation for ketamine's effectiveness. It seems to affect the glutamate system in a way that causes brain cells to form new connections.

Researchers have long suspected that stress and depression weaken some connections among brain cells. Ketamine appears to reverse the process.

But the drug has some serious drawbacks, Zarate says.

For example, it's given intravenously, and patients often report alarming side effects during the infusion, he says. These include out-of-body experiences, hallucinations and memory problems.

Also, people can get hooked on ketamine, and habitual use has been linked to serious mental and physical health problems.

So scientists have been checking out other drugs that also tweak the glutamate system.

Depression Drugs, Without The Side Effects

One is a pill called riluzole, which seems to be less potent than ketamine. Christopher Stephens has been taking it ever since his ketamine treatment at NIH. It's been more than a year now, and his depression hasn't returned, he says.

Another possibility is a drug called scopolamine, which is used to prevent seasickness.

Maura Furey, another researcher at the National Institute of Mental Health, began studying scopolamine about the same time Zarate began looking into ketamine.

And when the public heard about her work, Furey says, she started getting phone calls, including one from a depressed woman who had tried scopolamine by accident.

"She had gone out on a boat with her sister and used a scopolamine patch and noticed that her symptoms had lifted," Furey says.

Furey's research showed that scopolamine often does work, though not as quickly as ketamine.

One of the people who has been helped by the seasickness drug is Helene Najar, who lives in Bethesda, Md., with her family, a dog, a cat and a parrot named Wilbur.

Current drugs helped control her depression, but always came with side effects, Najar says. So about five years ago she signed up for an NIH trial run by Furey. The study would give her scopolamine once a week for three weeks.

The first dose didn't seem to make a difference, Najar says. But after the second one, she began to feel a change.

"By the third, I was like a new person," she says.

Scientists are still trying to figure out precisely how scopolamine works against depression. But there's evidence that the glutamate system is involved.

And Najar says the effect is unlike any other drug she has taken.

"There's no doubt in my mind [that] however it works or whatever receptors in the brain it works on, absolutely it has nailed exactly where my imbalance is," she says.

The goal of the NIH experiments with ketamine, riluzole and scopolamine is to identify compounds that pharmaceutical companies can use as molecular models to develop an entirely new class of antidepressants, Furey says.

"For people who actually design drugs, it would tell them chemically what they need to focus on," she says.

Drug companies have taken notice. Several are now working on glutamate drugs for depression.

Copyright 2014 NPR. To see more, visit http://www.npr.org/.

Transcript

RENEE MONTAGNE, HOST:

This is MORNING EDITION, from NPR News. I'm Renee Montagne.

STEVE INSKEEP, HOST:

And I'm Steve Inskeep. Good morning.

For half a century now, most drugs for depression have targeted the same short list of chemicals in the brain, especially serotonin. But antidepressants like Prozac can take more than a month to kick in, and they don't work at all for up to 40 percent of people with major depression.

So researchers are looking for antidepressants that work in totally new ways. We reported yesterday on one possible drug, and we have more this morning. NPR's Jon Hamilton reports on this drug best known by its street name: Special K.

JON HAMILTON, BYLINE: The buzz about Special K has been building for several years now. Of course, researchers use the drug's proper name: ketamine. It's an FDA-approved anesthetic that's been around for decades.

Back in the 1970s, recreational drug users realized that if you take enough ketamine, you can have a mind-bending experience. But the drug's ability to relieve depression wasn't clear until just a few years ago.

I wanted to talk to someone who'd actually taken ketamine for depression. So I contacted researchers at the National Institute of Mental Health, who put me in touch with a man named Christopher Stephens. He's 28, and lives near San Francisco. Stephens told me he was diagnosed with depression when he was just 15.

CHRISTOPHER STEPHENS: My first prescription was for Paxil. Then I started on Prozac. And then, you know, at 19 when - that's when I decided that I had to go and try new medications.

HAMILTON: And what did you try?

STEPHENS: Klonopin, Ativan, Valium, Xanax, Remeron, Gabapentin, Buspar. Depakote, they had me on for a while.

HAMILTON: Stevens says some of these drugs just didn't work. Others caused nausea, headaches, insomnia - not to mention some really unpleasant sexual side effects. And despite all the drugs, Stephens' depression kept getting worse. What had been a dull ache was now a stabbing pain. Ultimately, he just couldn't function. He lost his job as a special-education assistant. Even his greatest joy, teaching martial arts, wasn't enough to keep him going.

STEPHENS: I went on the Internet, and I started researching ways to end your life. You know, a lot of people think oh, I can down a bottle of Tylenol, and that'll do it. What that'll actually do is kill your liver, and you slowly die - which is not a good way to go. I wanted to research the most efficient and painless way to do it.

HAMILTON: But Stephens wanted to do something good before he died, something that might help other people avoid the hopelessness that he was feeling. So he called up the University of California-San Francisco, and offered himself up as a sort of human lab animal. He thought maybe scientists could learn something about depression by studying his brain.

That call got Stephens referred to Carlos Zarate, a brain scientist at the National Institute of Mental Health in Bethesda, Maryland. Zarate thinks current depression drugs are misguided. I ask him why, and he offers an analogy. He says depression is a bit like a leaky faucet in the brain. And there are different ways to stop the leak.

CARLOS ZARATE: You can go straight to the faucet and you can fix it, or you can go to the water plant and shut down the water plant. The end result will be the same. Now, the current antidepressants are probably more like going to that water plant. You shut down the water, and then there's all the pipes that go through the city; eventually, it gets to your town and eventually, to your house and to the faucet.

HAMILTON: Antidepressants like Prozac act primarily on serotonin, a brain chemical once thought to be the key to depression. Other drugs affect the chemicals norepinephrine and dopamine.

But Zarate thinks all of these are a long way from the leaky faucet in the brain. He's thinks there's another chemical that gets much closer to the problem. It's called glutamate. And that's where ketamine comes in. The anesthetic-turned club drug seems to act directly on the glutamate system.

Zarate tells me he was intrigued when he began hearing anecdotal reports that ketamine could relieve depression almost instantly. But as a scientist, he says, he was thinking the reports sounded too good to be true.

ZARATE: In the field, there was really a question whether people really did believe these initial observations because it was so dramatic. And so we decided to test this in a controlled study.

HAMILTON: The study involved 17 patients with depression. They were people like Christopher Stephens, who had tried lots medications without success. After a single dose of ketamine, 12 of the 17 got better within hours. And they stayed better for a week or more.

The result got international attention. And since then, Zarate has given ketamine to many more patients, including Stephens. Stephens himself has vivid memories of the day he got ketamine. It was a Monday morning, and he woke up feeling really bad. His mood was still dark when doctors put in an IV and delivered the drug.

STEPHENS: Monday afternoon, I felt like a completely different person. It was, you know, same day – same-day effects and, you know, I woke up Tuesday morning and I said wow, there's stuff I want to do today. And I woke up Wednesday morning and Thursday morning. And for the first time in - I don't even remember, I actually wanted to do things. I wanted to live life.

HAMILTON: About 18 months ago, researchers at Yale found a possible explanation for ketamine's effectiveness. It seems to affect the glutamate system in a way that causes brain cells to form new connections. Researchers have long suspected that stress and depression weaken some connections among brain cells. Ketamine appears to reverse the process.

But Zarate says the drug has some serious drawbacks. For one thing, patients often report alarming side effects during the infusion.

ZARATE: Feel an out-of-body experience, seeing trails of light. Their memory might be a bit foggy.

HAMILTON: Also, people can get hooked on ketamine, and habitual use has been linked to serious health problems. So scientists have been checking out other drugs that also tweak the glutamate system. One is a pill called riluzole, which is less potent than ketamine. Christopher Stephens has been taking it ever since his ketamine treatment. It has been more than a year now, and he says his depression hasn't returned.

Another possibility is a drug called scopolamine, which is used to prevent seasickness. Maura Furey, at NIH, began studying scopolamine seven or eight years ago, about the same time Zarate began looking into ketamine. [POST-BROADCAST CLARIFICATION: The National Institute of Mental Health is part of the National Institutes of Health (NIH).] Furey says when the public heard about her work, she started getting phone calls, including one from a depressed woman who had tried scopolamine by accident.

MAURA FUREY: She had gone out on a boat with her sister and used a scopolamine patch, and noticed that her symptoms had lifted. She felt better and had been treating herself with the scopolamine patch for quite some time, and was just contacting me to say: It worked for me.

HAMILTON: Furey's research found that scopolamine often does work, though not as quickly as ketamine.

Helene Najar is one of the people who has been helped by the seasickness drug. She's in her late 40s and lives in Bethesda with her family, a dog, a cat...

(SOUNDBITE OF PARROT CHIRPING)

HAMILTON: ...and a parrot named Wilbur. Najar says mainstream drugs helped her control her depression, but always came with side effects. So about five years ago, she signed up for an NIH trial. The study would give her scopolamine once a week for three weeks. Najar says the first dose didn't seem to make a difference. But after the second one, she began to feel a change.

HELENE NAJAR: By the third, I was like a new person. And then I had that - oh, my gosh, how am I going to get the scopolamine; how am I going to continue this treatment? This is like, the best thing that's ever happened to me. I haven't felt this normal in years.

HAMILTON: Najar ended up getting a prescription for the drug, which she continues to use when she feels her symptoms getting worse. Scientists are still trying to figure out precisely how scopolamine works against depression. But there's evidence that glutamate is involved. And Najar says the effect is unlike any other drug she's taken.

NAJAR: There's no doubt in my mind: However it works, or whatever receptors in the brain it works on, absolutely, it has nailed exactly where my imbalance is.

HAMILTON: Maura Furey, from NIH, says the experiments with ketamine and riluzole and scopolamine aren't intended to turn some existing drug into the next big thing for depression. She says the goal is to identify compounds that pharmaceutical companies can use as molecular models for an entirely new class of antidepressants.

FUREY: For people who actually design drugs, it would tell them chemically, what they need to focus on and develop.

HAMILTON: Drug companies have taken notice. Several are now working on glutamate drugs for depression.

Jon Hamilton, NPR News. Transcript provided by NPR, Copyright NPR.