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.”