A new version of old drugs could help treat autism

One night in 2006, Kathy Roberts rushed her autistic daughter, Jenny, to the hospital. Nothing had been able to stop the young woman, then in her mid-20s, from vomiting. Jenny had recently suffered several major seizures and her entire gastrointestinal system was going haywire.


To try to calm Jenny's GI tract, doctors at Massachusetts General Hospital prescribed baclofen, an antispasmodic drug that is also being studied as a potential treatment for alcoholism and other addictions. The drug relieved Jenny's vomiting, but it did something else too — a completely unexpected and welcome side effect.

"Within 24 hours, I saw a change," says Roberts. "Right away, I saw that it was globally calming. I've always described a state that she would get into where it seemed like she wasn't comfortable in her own skin, and was trying to crawl out. I saw that calmed down."
Roberts, founder of the Giant Step school for children with autism in Southport, Conn., called Mark Bear, professor of neuroscience at MIT and advisory board member of Giant Step. In 2005, Bear had co-founded a drug company called Seaside Therapeutics to develop treatments for autism and other developmental disorders. Roberts told Bear about baclofen's effect on her daughter, and a new line of research was born.

In September, Seaside announced positive results from a phase II clinical trial of STX209, an experimental drug that is chemically related to baclofen. In the trial, which was not blinded or placebo controlled, STX209 led to a reduction in agitation and related emotional outbursts in autistic people. Such behavior is common in people with autism — often, a result of anxiety caused by extreme sensory oversensitivity or frustration over being unable to communicate their needs. To cope, autistic people often develop behavioral mechanisms, include tantrums, social withdrawal or repetitive behaviors like rocking or hand flapping.
STX209, while not a cure, appeared to ease anxiety. "We're seeing reductions in a lot of types of outbursts and irritable behavior, along with increased communication and social behavior," says Dr. Randall Carpenter, co-founder, president and CEO of Seaside.

Carpenter says his team has conducted two clinical studies of STX209. One trial included 32 people with autism spectrum disorders. The other involved 63 people with Fragile X syndrome, a family of inherited developmental disorders linked with autism that are caused by changes in a single gene, the FMR1 gene. Fragile X is the most common known single-gene cause of autism, associated with 2% to 6% of all autism cases. About 25% of people with Fragile X have full-blown autism, but "pretty much 100% are on the spectrum," according to Carpenter.

"A common characteristic in Fragile X is that people would like to be social, but [their condition] makes them very anxious," Carpenter says. Children with the disorder often shy away from new people — or approach them and then withdraw into repetitive motions.
But when these children take STX209, Carpenter says, "What we end up seeing is that they are more sociable. They communicate more, they make friends, they interact more and are less withdrawn."

What Is Baclofen — and STX209?
Like many drugs, baclofen contains two types of its main molecule, which are mirror images of each other. Often, one is an active ingredient, while the other is not. STX209, also known as arbaclofen, contains only the "right-handed" molecule of baclofen, the drug's active component.

According to Carpenter, STX209 is about 10 times more potent than baclofen. In mice with a genetic mutation similar to the one that produces Fragile X in humans, Seaside's research found that the baclofen's left-handed molecule did not have the same effect as STX209 and, in fact, actually increased anxiety-related behavior.
Baclofen itself is a very old drug. It has been used since the 1920s as a treatment for muscle spasticity in conditions like cerebral palsy. Because of the way it affects a neurotransmitter called GABA, it has also been studied in animals since the 1980s as a potential treatment for addiction.  Recently, it got a boost from a French doctor who himself suffers from alcoholism, who published a book on his recovery via baclofen called The End of My Addiction in 2009.

Increasing GABA action calms the brain: drugs like Valium (benzodiazepines) and alcohol increase the neurotransmitter's activity. But unlike these drugs, which can produce an addictive high, baclofen eases anxiety without the euphoria. For all the time its been on the market, it has never become a drug of abuse. (Baclofen can cause withdrawal symptoms, however, if stopped abruptly.)
And interestingly, treating anxiety could be one key to treating addiction. Alcoholics and addicts often describe themselves without their drug of choice as being "not being comfortable in my own skin"— exactly the expression Roberts used to describe her daughter's state of discomfort before taking baclofen.

Anectodally, baclofen has shown notable success at keeping alcoholics from drinking. But while some clinical trials have found positive results for addiction ranging from nicotine to cocaine, some found no effect. The most recent study, a double-blind placebo-controlled trial involving 80 alcoholics, saw neither a reduction in heavy drinking nor an increase in abstinence. However, that study used a 30-mg dose of baclofen, much lower than the 80-mg dose typically used by individuals and physicians who have reported success with the drug.
"Our research didn't find a separation of baclofen from placebo on drinking outcomes," says James Garbutt, a psychiatry professor at the University of North Carolina-Chapel Hill and author of the study, which was published in Alcoholism: Clinical and Experimental Research in November. "But it did reduce anxiety. We're actually interested in trying to do another trial with a higher dose."
Garbutt adds, "I really don't know a lot about autism but there does seem to be an anti-anxiety effect of baclofen...[and] if the fear circuitry is thought to be involved in autism, potentially, it could be of value."

What GABA and Fear Have to Do with Autism
Animal models of autism and Fragile X suggest that part of the problem in these disorders is overactivity in a brain region called the amygdala, which is associated with fear and anxiety, and is normally calmed by GABA. Another problem may be a general reduction in activity in the whole brain's inhibitory circuitry, which relies on GABA as its main neurotransmitter.
A study published in the Journal of Neuroscience in July found that mice missing the same gene that fails in Fragile X not only had fewer inhibitory brain connections in general, but also had reductions in GABA availability in a key part of the amygdala. In these mice, a drug that increased GABA action (via a different route than that used by STX209) reduced the over activity in the amygdala that resulted from the GABA deficit.
In another animal model of autism which found amygdala effects, researchers exposed pregnant rats to a drug called valproic acid (VPA). One in 10 human babies whose mothers have taken valproic acid during pregnancy develop autism. Rat pups born to exposed mothers were found to have increased activity in the amygdala and a resulting intensification of fear, compared with rats with mothers that didn't get the drug. VPA rats were quicker than unexposed rats to learn to fear a situation; they were also more likely to generalize that fear to other similar experiences, and slower to learn when the scary situation was rendered safe.  They also showed other, autistic-like behavior
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Kamila Markram, director of the Autism Project at the Brain Mind Institute of the École Polytechnique Fédérale de Lausanne in Switzerland, has studied the VPA rat. She also has a stepson with an autistic condition. "We tried quite a lot of medications and therapies, from sports to different diets and all kinds of things," she says. "We did see that reducing anxiety in him was one of things that worked." Markram has not tried baclofen or STX209 for her stepson, but calls the idea of developing such a drug for autism "absolutely interesting."
What Is the Future of STX209?
Carpenter hopes to complete clinical trials of STX209 for autism and Fragile X in 2011. He says that the soonest a drug could possibly hit the market, if all goes well, would be 2013. Meanwhile, some parents are already using baclofen to treat autistic children "off label," a legal practice since the drug is approved for other uses.
Carpenter says that participants in both of Seaside's STX209 trials were offered the option to switch to baclofen once the trial was complete, if they thought their children had been helped. "After about eight or 10 people tried it, the parents and clinicians were up in arms because they didn't think [baclofen] was working as well as what they'd seen in trial," he says. "The FDA allowed us to continue [treating people with STX209] under its provisions for compassionate use. Some are coming up on a year now and they continue to see improvement and stay on. Very few have dropped out."
Whether the drug will prove safe and effective in the long term, of course, is yet to be seen. But with no drugs approved for Fragile X and only two to treat autism — both aimed at relieving symptoms rather than treating the underlying problem — the development of STX209 will undoubtedly be closely watched, both by parents and the pharmaceutical industry.