While post-traumatic stress disorder (PTSD) is often associated with military veterans, the Veterans Administration will be the first to tell you that this disorder is not limited just to current and former service members. It estimates that nearly 8 percent of all Americans will struggle with some form of the disorder during their lives. The symptoms of PTSD—including hypervigilance, nightmares, flashbacks, hyperarousal, and depression— are debilitating. While scientists have been working tirelessly to better understand why some people are so affected mentally and emotionally by trauma but others seem to survive it unscathed, PTSD remains a difficult disorder to treat. New research on ketamine, a drug that has been shown to successfully treat depression as well as to help extinguish fearful memories (see “Ketamine May Help Extinguish Fearful Memories”), suggests that a single dose given one week before a traumatic event might prevent the development of PTSD.

Trying to treat

Many people who have been diagnosed with PTSD have had little success with current therapies. Others do find help through cognitive behavioral therapy, including prolonged exposure therapy (where people are asked to gradually face any trauma-related thoughts and feelings head-on), as well as with medications like selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). But it’s difficult to treat a disorder that one can’t objectively define, says Mohammed Milad, a neuroscientist at Harvard Medical School who studies PTSD.

“PTSD isn’t quite like many other anxiety disorders in that it’s not clear what exactly it is that we’re treating. We rely so much on the subjective reports of symptoms—and each individual is quite different,” he says. “It’s not like there’s a hard objective test or measure that you can look at, like a high white blood count that tells you that there’s an infection. The symptoms can vary quite a bit, so doctors tend to treat based on the symptoms that are reported.”

He says that there are many variables at play; the type of PTSD you have may vary both based on the type of traumatic event and the time of life in which it was experienced.

“Whether we’re talking about sexual abuse or a car accident or some kind of combat-related trauma, when people have difficulty dealing with those traumatic memories, we call it PTSD. But it’s not clear that they are all the same or that they can or should be treated in the same way,” he says. “We just don’t know enough about what these stressors are actually doing to the brain.”

Previous studies suggested that ketamine, long known as a veterinary tranquilizer and anesthetic drug, as well as an illegal party drug, could be a successful treatment for PTSD. Its use was found to help extinguish fearful memories in animals as well as to reduce symptoms in human patients  given an intranasal dose of the drug. So when Christine Denny, a neuroscientist at Columbia University Medical Center, came across a study in Military Medicine that found that service members who had been treated with ketamine for burns were nearly 50 percent less likely to develop PTSD later, she wondered if the drug could be used as a preventive.

“Ketamine, as a treatment, is often paired with the experience or during consolidation of memories or some type of arousal related to the experience,” she says. “But this study in Military Medicine made us think that ketamine might be essentially prophylactic to developing PTSD. And we wondered if there was perhaps a window we could give ketamine and potentially prevent PTSD altogether.”

An ounce of prevention

To test the idea, Denny and colleagues gave mice a small dose of ketamine or a placebo to mice one month, one week, or one hour before being given them a severe stressor—in this case, a series of electric shocks in a special cage. The mice were later returned to that cage, which they associated with the shocks, and were assessed for a freezing behavior, traditionally considered a fear response.

“When we gave the ketamine a week before, the mice were much less likely to freeze up,” she says. “And it’s a really interesting finding. Because the drug is not still in the animal’s system. It’s been washed out. But it still has this protective factor and allows them to experience the stressor differently. This suggests that it may be activating pathways that promote resilience or that it could be used prophylactically to help people avoid later mental illness.”

Dennis Charney, a psychiatrist at the Icahn School of Medicine at Mount Sinai who has tested ketamine as a treatment in clinical trials for depression, suicidality, and PTSD in the past, says the idea of the drug as a prophylactic is intriguing.

“The results have been incredible. In depression, we found the drug could help patients get better in a matter of hours. Nobody believed it could be replicated. But it was. And we’ve seen the same thing with PTSD and suicidal feelings. That work is now being replicated,” he says. “So using it in a preventive way, it sounds like it would be unbelievable. But you never know. The idea is fascinating. And we’d certainly like to test the hypothesis in humans to see whether giving the drug before a stressor could prevent the detrimental effects of that stressor.”

Practical prophylaxis?

Denny says that this work is preliminary and that there are still many questions that need to be answered.

“Is this the only window in which this can work? Do you need multiple doses of the drug? Are there long-term effects for taking multiple doses of the drug? Is the effect long-lasting? We don’t know. We literally don’t know,” she says. “But this finding gives us a framework for studying the drug’s effects—and its possibilities as a prophylactic for PTSD.”

But the question remains whether treating something like PTSD preventively is possible—or even practical. Milad says that while there has long been interest in a “fear vaccine,” it would be difficult to determine how or when it should be administered.

“Some of these fears, while they are maladaptive later in life, can help people when they are in the midst of dealing with the trauma itself. So if we give a drug in advance of the trauma, we may be getting in the way of survivorship,” he says. “But we also know that having too much fear is detrimental to survival. That if we fear too much we can be like a deer in headlights. If we work towards inoculation or prophylaxis, these are things we have to think about.”

Denny says the last thing she is advocating is to give everyone ketamine in hopes of avoiding the effects of later trauma; she agrees that is not practical or ideal. Yet, she argues, understanding how ketamine helps the brain offer this protection in response to trauma may offer critical insights into the biological basis of resilience.

“I would not propose to give ketamine every week to military personnel or other people who know they are going to experience a big stressor,” she says. “But I think this work is a great starting point that can lead us to develop new methods to protect against PTSD and stress-induced depressive behavior. We don’t wait for polio to happen and then give someone a polio vaccine. So if we can start thinking about preventive measures that we can put in place to help people avoid developing these kinds of mental disorders, to use prevention in psychiatry the same way we do in other parts of medicine, we may have the opportunity to really make a difference.”