After completing a pioneering study on vegetative patients’ response to the drug zolpidem (known as Ambien, but now available generically) researchers at Moss Rehabilitation Research Institute (MRRI) are embarking on a three-year, nationwide examination of how and why the drug has such a dramatic effect on some patients but not others.

Case reports of the rousing effect of zolpidem on vegetative and minimally conscious patients have appeared sporadically in the literature. The reports tell of patients who, after being vegetative for several years, suddenly regain consciousness for a period of hours shortly after receiving the drug. Their reactions have ranged from eye and body movement in response to external stimuli, to actual speech.

John Whyte, MD, PhD, director of MRRI, was intrigued by these findings but mindful of the publication bias inherent in case reports. In response, he designed a study that would determine the likelihood of a vegetative patient responding to zolpidem. In 2007, he and his colleague Robin Myers administered zolpidem to 15 vegetative and minimally conscious patients. Of these, one patient showed a dramatic temporary improvement consistent with the published case reports.

“He followed a number of commands very clearly to move his arm, move his leg, and wave goodbye. And he followed people with his eyes as they walked around the room, none of which he did off the drug,” Dr. Whyte said.

Zolpidem did not cause this patient to regain speech, but it did produce the greatest improvement in his condition since he had become vegetative four years earlier. The researchers’ next step was to establish why he responded to the drug while the others did not.

“Was it the case that this drug worked for some patients and didn’t work for other patients? Or maybe it worked for everyone, but the response was dependent on the amount of brain that was not irrevocably damaged,” Dr. Whyte said.

What Makes a Responder?

To answer this question, the researchers analyzed the behavior of the 14 “non-responding patients” while they were on zolpidem versus placebo. They showed no trend toward better performance on the zolpidem day — the drug was simply not affecting these patients.

 “It’s looking like it’s a yes or no reaction. You’re either a responder or you’re not a responder,” Dr. Whyte said, “as opposed to being big responder, medium responder or small responder.”

Zolpidem’s exact mechanism of action in the brains of vegetative patients is still unknown, but Dr. Whyte sees a potential explanation in the drug’s similarities to benzodiazepines.

“This class of drug inhibits certain populations of neurons. What we have to assume is that this drug is inhibiting some neurons that in turn are inhibiting the function of some viable parts of the brain. But we don’t know where or exactly how that’s happening,” he said.

Dr. Whyte presented his findings earlier this year at the Seventh World Congress on Brain Injury of the International Brain Injury Association in Lisbon, Portugal. His study is also under review for publication in the American Journal of Physical Medicine & Rehabilitation.

Dr. Whyte now wants to pull together a group of responders and clinically similar non-responders to further identify the causes behind the zolpidem reaction.

“If there’s a part of the brain that’s critical for allowing this drug to work, that implies that part of the brain has the ability to allow a person who appears vegetative to regain consciousness and start functioning again,” he said. “Then there’s a lot of research we might want to do about that part of the brain, and about many other treatments that might improve the functioning of that part of the brain.”

MRRI has received a three-year grant from the National Institute on Disability and Rehabilitation Research to expand its zolpidem research. Physiatrists and caregivers across the country will soon be able to enroll their vegetative patients in a new MRRI study. Family members of the enrolled patients will receive two pills in coded form —one zolpidem, and one placebo—to be administered on separate days. Patients who react differently on the zolpidem day will be classified as probable responders. Probable responders will then go through the same process in a rehabilitation center. If the same reaction is observed, they will be classified as a definite responder. Once a list of definite responders has been developed, the grant will cover the cost of flying these patients and a group of clinically similar non-responders to Philadelphia for further intensive study using structural and functional neuroimaging and event related potential methods.

Physiatrists who wish to enroll their patients should contact:

Patient Registry Recruitment Office
Moss Rehabilitation Research Institute
215-663-6456
participants@einstein.edu