July 6, 2017 -- Major depression affects more than 16 million American adults each year, nearly a third of whom don't find relief from antidepressants and other traditional treatments. When depression isn't treated, it increases the chance of alcohol and drug dependence, as well as suicide.

The anesthetic ketamine could offer hope for people who don't have other depression treatment options. The most recent research on ketamine, as well as a statement from experts on its use published in April, finds the drug works quickly, makes dramatic improvements in mood, and can work on people who haven’t gotten better with other depression treatments.

The evidence is so enticing that the FDA has granted two ketamine-based drugs breakthrough therapy status and fast-tracked them to market. Yet the studies done so far on ketamine have been small, and its availability is so far limited mainly to ketamine clinics and research studies.

Researchers still have a lot to learn about how well it treats depression and its long-term side effects, yet they say ketamine could be very helpful.

"It is potentially the most exciting development in my lifetime for the treatment of mood disorders, but there is still a way to go before this is ready for prime time," says Gerard Sanacora, MD, PhD, director of the Depression Research Program at Yale University.

What is ketamine?

Ketamine is an anesthetic drug that blocks pain. It was first developed in the 1960s and was used to operate on soldiers during the Vietnam War. It's also been used as an animal tranquilizer.

In addition to dulling pain, ketamine makes users feel like they're detached from their own body. This out-of-body sensation has made it a popular club or party drug, and it goes by nicknames like "Special K."

In 2000, researchers started studying ketamine as a treatment for depression. Over the years, they've discovered it improves mood much faster than traditional antidepressant drugs, and it works when some of these drugs have failed.

What is ketamine used to treat?

Ketamine is FDA-approved as an anesthetic for surgery and diagnostic procedures. It's also used to treat depression, suicidal thoughts, posttraumatic stress disorder (PTSD), other mood disorders, and nerve-related pain.

Where can you get ketamine?

You can get it at a ketamine clinic. There are more than two dozen clinics around the country, but the drug is only available in 12 states, mostly along the coasts. Ketamine is also given experimentally in clinical trials.

How is it given?

Usually, ketamine is given as an IV into a vein, which is the quickest route for the medicine to get to the brain. Most people start with about six doses over a period of 1 to 2 weeks, and then get booster IVs once every 3 to 5 weeks. You may need to continue treatments for a year or more to see long-term results.

How does it work?

Researchers don't know exactly how ketamine works to treat depression, but they have some ideas. Unlike antidepressants, which work by shifting the balance of brain chemicals like serotonin and dopamine, ketamine is thought to change the way brain cells communicate with each other. "If you think of it in terms of a computer, what ketamine does is a hardware fix -- not like antidepressants, which are like a software fix," says Glen Brooks, MD, an anesthesiologist and medical director of NY Ketamine Infusions.

Ketamine blocks a type of receptor in the brain, known as NMDA, thought to play a role in depression. Recent studies find that ketamine can have long-lasting effects on depression, even though the drug only stays in the body a short time.

Ketamine also acts on other brain receptors -- like opioid receptors, which affect pain and depression. "I think it is the ability of ketamine to not just hit one target like NMDA, but also to hit other receptors that create its unique effect," says Ruben Abagyan, PhD, a professor at the UC San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences who has studied the use of ketamine for depression.

How well does it work?

Unlike antidepressants, which can take weeks or longer to take effect, ketamine starts working within a few hours. For people who are suicidal, this rapid effect can be lifesaving. Ketamine can also help people who haven't found relief from other depression treatments.

Brooks says some of the patients he sees have been to several psychiatrists and have tried half a dozen to a dozen medicines. Many have attempted suicide. "What patients report is a lightening of their mood [with ketamine]. The dread begins to lift. If there was anxiety before, all of a sudden there's less anxiety," he says. "It's not uncommon for people to sit in my office and say, 'Dr. Brooks, this is the first time I've gotten out of bed in a week.' "

However, Sanacora emphasizes that ketamine isn't a quick fix. "People are getting the idea that this is a miracle cure -- you get one dose and then your depression is going to go away. We have very little evidence of that," he says. The initial effects of the drug on depression can fade quickly -- within 1 to 3 days. Most people need to get repeat treatments over many months or years to see long-term improvements. Adding cognitive behavioral therapy might help ketamine's antidepressant effects last longer, according to a 2017 study Sanacora co-authored.

What are the side effects?

Right after getting the drug, people often experience "dissociative" side effects, which is kind of like having an out-of-body experience. "Things may look and sound different than they usually do," Sanacora says. Colors might look blurred, or you can have the sensation that you're looking down at your body. The feeling lasts for about an hour after the IV, and then it should wear off, while the drug’s benefits continue.

The drug can also cause a spike in blood pressure and heart rate in the short term. "For most people, that's probably not a problem. It's the equivalent of walking up a flight of stairs carrying a bag of groceries." Sanacora says. But he says the spike could be riskier for people with heart disease.

Doctors don't know much about the long-term effects of ketamine because they haven't studied it over long periods of time. Studies have linked regular ketamine use to memory issues and other problems related to thinking, but this doesn't seem to be the case with the doses used to treat depression. Doctors also worry that the drug might lead to abuse, but this hasn't been proved.

How much does it cost?

The price can vary based on the doctor and location. Generally, each IV costs $400 to $800. Insurance often doesn't cover the cost.

Why isn't ketamine FDA-approved to treat depression?

To approve any new drug, the FDA needs evidence that it works and it doesn't cause major harm. The FDA gets that evidence from clinical trials involving hundreds or thousands of people. Most of the studies that have been done on ketamine so far have been small -- with just 25 to 50 people.

The reason larger studies on ketamine haven't been done is that these studies can cost millions of dollars. Because ketamine is a generic drug, pharmaceutical companies can't patent it and earn their money back, Brooks says.

However, companies are developing other drugs based on ketamine. In August 2016, the FDA put the drug esketamine on a fast track to approval by designating it as a breakthrough therapy. Esketamine, which is given as a nasal spray, is being tested in phase III clinical trials. Another drug that acts on NMDA receptors called rapastinel (GLYX-13) also received breakthrough therapy status in early 2016.

What should people consider before they try ketamine?

There are no guidelines on treating depression with ketamine. But in March, the American Psychiatric Association published a consensus statement, an analysis of the issue by a group of experts that helps further our understanding.for doctors and patients, which Sanacora co-authored.

Some advice from the statement:

  • Make sure your doctor asks about your depression symptoms, treatment history, other medical conditions, and whether you've had any problems with substance abuse before starting you on ketamine. Knowing your health history will help ensure that the benefits of this treatment outweigh the risks.
  • The doctor should check your vital signs -- including blood pressure, heart rate, and oxygen levels -- before and after treatment.
  • While you get the IV, medical staff at the clinic should monitor you for any physical and mental effects from the drug. "The facility should have a clear operating procedure on how to manage things if there is a problem," Sanacora says.

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