For the past few years, the National Institutes of Health (NIH) has been calling post-traumatic stress disorder (PTSD) a growing epidemic. The organization estimates that nearly 8 million American adults are plagued with this disorder, characterized by flashbacks, arousal deficits, and avoidance symptoms. And with so many U.S. servicemembers still in harm’s way, it’s likely that number will grow. While neuroscientists are learning much more about this complex neuropsychiatric disorder, there are still few treatment options that effectively treat all its symptoms. But new work presented at the Society for Neuroscience's annual meeting suggests that ketamine, a fast acting anesthetic with anti-depressant properties, may provide a new avenue to help extinguish the fearful memories at the heart of this disorder.
Ketamine and depression
Many may know ketamine as a veterinary tranquilizer or a drug of abuse with the street name “Special K.” But it was first approved as an anesthetic in 1970, and was used during the Vietnam War in military operating rooms. But in a landmark 2000 study published in Biological Psychiatry, Robert Berman and colleagues at the Yale School of Medicine demonstrated that ketamine also had quick-action anti-depressant properties on people with treatment-resistant depression. James Murrough, a psychiatric researcher at the Mount Sinai School of Medicine, says that the finding was a complete surprise: While most traditional anti-depressant medications work on the serotonergic system, ketamine does not.
“Patients with depression were administered ketamine in this study to look at the cognitive effects of ketamine in depression. Lo and behold, it was discovered that it had rapid antidepressant effects,” says Murrough. “That was not precedented. And it was not expected. It was a serendipitous observation and something that we’ve been building on ever since.”
Since then, labs across the country have been trying to understand just how ketamine is working its magic—at the behavioral, cellular, and molecular levels. That bench work has discovered that ketamine influences the neurotransmitter glutamate, a mediator of excitatory signals in the brain and a major contributor to learning and memory. Given that PTSD is has been characterized as being an issue with learning, specifically an inability to extinguish past memories, Neil Fournier and his colleagues at the Yale University School of Medicine wondering if ketamine might also help treat this disorder.
“We’ve known for some time that glutamate is important in burning in memories. And we know that about 30-40 percent of PTSD patients also have depression,” he says. “So we thought that ketamine might be an important treatment possibility.”
Ketamine helps inhibit fearful memories
To test that idea, Fournier and colleagues used a classic fear conditioning paradigm in rats. The group conditioned the animals to associate an electric shock with an auditory tone. After conditioning, whenever they heard the tone, the rats exhibited a fear response: They froze in place. After the fearful memory was firmly in the place, Fournier and colleagues then tested the animals in an extinction paradigm: They sounded the tone but no longer followed it with a shock. Over time, most animals stop associating the tone with the pain, but it can take some time. When animals were treated with ketamine during this extinction process, though, they showed significantly lower freezing behaviors within 24 hours, compared with animals treated with a placebo.
“The ketamine-treated animals showed a significant reduction in fear-related responses,” says Fournier. “This suggests that ketamine, in some way, when given in conjunction with extinction training, seems to help extinguish the traumatic memory.”
The group then went on look at which parts of the animals’ brains were being affected by the drug. They found that ketamine-treated animals showed enhanced activity of the medial frontal cortex. “This is important,” says Fournier. “Because the frontal cortex has an inhibitory connection to the amygdala, shutting off the amygdala and reducing the fear response.”
From bedside to bench and back to bedside
Of course, many drugs that have proven successful in animal testing have not translated to success in people. But Murrough says that Mount Sinai is currently running a clinical trial using ketamine with PTSD patients that it expects to complete within the next year. Still, he cautions that there is still a lot more to learn about this drug and how it works—both in depression and PTSD—before we get too optimistic about it.
“We know very little about how ketamine might actually be used in practice,” he says. “The safety issues are completely unknown. It appears to be very safe in the short-term but we don’t know the kind of risks might be involved with chronic treatment.”
It’s an important point. Usually, novel therapeutic drugs are discovered in the laboratory and only tested on humans after rigorous study at the laboratory bench. Murrough says that ketamine has taken the opposite path: Scientists discovered that it worked well on patients and are now trying to understand the underlying mechanisms. Still, Sheena Josselyn, a neuroscientist from the University of Toronto, and the moderator of the Stress and PTSD press conference at Neuroscience 2012 where Fournier’s research was presented earlier this year, believes that there is a lot of promise in the ketamine approach.
“This is fascinating, cutting-edge research,” says Josselyn. “This is the kind of work that is not only going to help us to better understand disorders like depression and PTSD, but, more importantly, help us discover new ways to really treat them. And that’s exactly what’s needed.”