April 12, 2008
Old Antibiotic Gets New Life in Modern Medicine
For a half-century, D-cycloserine has led a quiet, workmanlike existence as an antibiotic, primarily for tuberculosis in developing countries. Its patent has long since expired, and its popularity has waned as newer antibiotics have appeared.
But D-cycloserine might now get a second act: A growing number of researchers say the drug could transform the way doctors treat a range of psychiatric ailments, including anxiety, phobia and obsessive-compulsive disorder. It could also help alleviate addiction, post-traumatic stress disorder, depression and chronic pain.
The drug has become a hot topic in anxiety research, with about 30 studies now under way. And a biotech company is seeking approval from the Food and Drug Administration to use D-cycloserine for anxiety disorders.
"It's a very exciting treatment, and it holds great promise," says Michael Otto, director of the Center for Anxiety and Related Disorders at Boston University. "It gives us a whole new direction to go in."
Otto, who has studied the drug's effect on panic and obsessive-compulsive disorders (it worked on both), says the field needs new approaches. More than 40 million Americans suffer from anxiety disorders, according to the National Institutes of Mental Health. Only a third get treatment, and only half of those are satisfied with the results.
The drug could offer significant improvements over current anti-anxiety medicines, which must be taken for months or years. D-cycloserine, by contrast, requires just a few doses.
The drug was introduced in 1955. Now made by Eli Lilly, it's used mostly in the developing world -- in part because it's less expensive than newer antibiotics.
In the mid-1990s, Emory University neuroscientist Michael Davis became fascinated with D-cycloserine. He had been studying how certain compounds in the brain produce intense, long-lasting anxiety. In particular, he focused on a chemical receiving station called the N-methyl-D-aspartic acid (NMDA) receptor, which seems to play a key role in the process of acquiring -- and losing -- fears.
For years, researchers had known that D-cycloserine can do more than kill bacteria: It increases the activity of NMDA. Davis began experiments on rats and found that animals given a combination of training and D-cycloserine lost their fears more often, and more quickly, than those that received training alone.
Four years ago, he moved on to humans. In a study of 30 subjects who were terrified of heights, he found the drug significantly better than standard treatment.
"It worked spectacularly," says Davis. "There was a fourfold increase in effectiveness." Since then, other studies have shown that D-cycloserine can also help with social anxiety and obsessive-compulsive disorder.
Two months ago, largely for his work on D-cycloserine, Davis won the Scolnick Prize in Neuroscience from MIT, awarded every year to a researcher who has done outstanding work.
"There's an increasing amount of data to support the idea that this could be really important," says NIH neuroscientist Dr. Daniel Pine, an anxiety expert. Along with colleagues at Johns Hopkins Hospital, Pine has started a study to find out whether D-cycloserine can help intensely shy children learn to be more outgoing.
In anxiety disorders, D-cycloserine is not used alone but combined with a treatment called exposure therapy. The treatment puts patients through the experience they fear, teaching them that their dread is exaggerated.
Such therapy is not new. It can work, but it is often terrifying and lengthy, and many patients drop out before their fears diminish. Davis and others say D-cycloserine can speed up the process.
Scientists aren't sure how the drug works. The main theory: By juicing NMDA, the drug helps the brain cement newly acquired learning from exposure therapy.
The D-cycloserine research adds evidence for an emerging view of how people overcome anxiety. Until recently, scientists thought the key was to somehow "erase" fear. But most researchers now think people succeed by acquiring new knowledge -- for example, that riding an elevator will not kill you.
"The new idea is that anxiety disorders are in part a learning disorder. Think of D-cycloserine as a learning aid," says Johns Hopkins University child psychiatrist Mark Riddle, who is working with Pine on the anxiety study.
A key piece of evidence for this theory: Patients need only a few doses of D-cycloserine, which must be taken around the time of exposure therapy.
"On its own, it does nothing," says Otto.
In this respect, D-cycloserine differs from other drugs used to treat fear-related conditions. These medicines -- anti-anxiety drugs such as Xanax or antidepressants such as Prozac -- work without therapy.
But they have disadvantages: Anti-anxiety drugs wear off quickly and are addictive. Antidepressants can take months to kick in and can have unpleasant side effects. Both must be taken for months or years, and neither addresses the underlying fear.
So far, few practitioners have used D-cycloserine on patients who were not in a study. One who has is Philadelphia psychologist Melissa Hunt, who tried the drug on a woman with a long-standing terror of driving.
The patient had tried therapy and other drugs, without success. So last year, Hunt put the woman on D-cycloserine and exposure therapy. Within a month, she was driving. "It was pretty astounding," says Hunt.
An Atlanta biotech company, Tikvah Therapeutics, is seeking FDA approval to sell D-cycloserine as an anti-anxiety medicine. Several D-cycloserine researchers, including Davis, are working with the company. This summer, Tikvah will begin a $15 million trial of the drug for social anxiety. Harold Shlevin, the company's CEO, says he hopes to get FDA approval within two to three years.
The drug is already available as a prescription antibiotic. But the FDA can grant a "new use" indication, which allows a company to sell an old drug under a different, patent-protected, name. Tikvah has an easier road than most FDA supplicants: D-cycloserine has been used for decades, so it has been proved safe -- the company must show only that the drug works for anxiety.
If Tikvah does persuade the FDA, doctors wouldn't be obligated to prescribe the "new" version for psychiatric conditions. In fact, they can already prescribe D-cycloserine, or any other drug, for so-called "off-label" purposes.
But Shlevin says Tikvah's version would make the process easier because the new pills would be offered in the lower doses used for anxiety. He said he doesn't know how much his version might cost compared with generic D-cycloserine.
D-cycloserine might have other uses, too. Scientists at Northwestern have found that in rats, it reduces pain.
"If you give [D-cycloserine] for a few weeks, it starts acting as an analgesic," says Northwestern researcher A. Vania Apkarian, who led the study. Intriguingly, D-cycloserine's effect lasted for weeks after the animals stopped getting it -- other pain relievers stop working within hours or days. When the rats started up again, the drug became more effective.
"The longer you use it, the better subjects get," says Apkarian. He thinks the drug modifies cortical structure. "We think we are reorganizing the connectivity of the brain," he says.
In recent studies, Apkarian has shown that the brains of people in chronic pain continue to transmit heightened pain signals even after the actual stimulus stops. Their pain-sensing apparatus gets stuck in the "on" position. In these people, brain areas that block pain actually shrink.
Apkarian suspects that D-cycloserine helps these regions regenerate, allowing them to properly dampen pain again. He will soon begin a study to test the theory on patients with chronic back pain.
"We certainly expect that this drug will make chronic pain patients feel better. That possibility does not really exist now," he says. "If D-cycloserine does the same thing in humans as it does in rats, it will have huge effects."