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Case Studies: Using Arbaclofen to Treat Autism and Fragile-X Syndrome

Arbaclofen for autism treatment

As far as treatment options go when it comes to Autism, we are lacking a variety of them that work. One medication has shown some promising responses when combating the “core symptoms” of Autism. That medication is called Arbaclofen, or Bacofen. Originally it is used to treat muscle spasms. Many Scientist believe that in comparison to the study done of Oxytocin Nasal Spray and Autism that this medication shows more incalculable improvements. Back in 2012 there were several studies into this medication. Two with promising results, one with mixed reviews leading to further researching. So, let’s look at this medication and its treatment of Autism.


A problem that most parents notice, and all doctors know is that there are no medications proven to help reduce the real symptoms seen in our children; let alone any approved that work for all symptoms needed working on. Typically, the medications that doctors use on our children are not approved for the purposes in which we are using them and are more aimed at symptoms such as anger and speech apraxia. We need medications that treat the more “core symptoms.”

Studies in Mice

The first study on this medication was done on mice, as it is with most medications. Researchers took mice and essentially turned off their FMR1 gene. Now, what is the FMR1 gene? Common people do not need to know about genetics and tend to not know what each specific gene does or does not do. It is suggested that the Autistic brain has a habit of overproducing a particular protein called glutamate. When the FMR1 gene is muted the brain loses the mRNA translational repressor protein resulting in the development of Fragile X mental retardation proteins in the mouse, or FMRP. Once the gene is mutated the mice are said to begin showing the core symptoms of Fragile-X. From this point it is like a domino effect.

Slowly their brains lose their ability to respond to the Neurotransmitter Gluamate. Once this happens the cells begin to overproduce some proteins and the end result is deformities in the dendritic spine (the connectors between the brain cells that receive information.) All these changes cause Fragile-X Type Autism in children and in mice. Fragile-X Syndrome can cause several deficits in children. These deficits range anywhere from learning disabilities to behavior issues; even sensory issues. It’s not an easy disorder to raise or live with, but it is an easy disorder to love.

Some Common Symptoms of Fragile-X Syndrome:

-Learning issues ranging from extreme to mild
-Speech and Language impairments; stuttering, etc. (more likely in boys)
-Some Fragile-X Syndrome children never become verbal
-Physical differences noticed toward puberty such as: Narrow faces, Large ears, Flat feet, Large Heads, and a Prominent Forehead
-Hyperactivity and Aggressive behaviors
-inability to maintain eye contact
-sensory issues

The mice exhibited some of the same symptoms once the FMR1 gene was muted. Their seizures seemingly stopped, and their repetitive behaviors lessened when the medication Arbaclofen was introduced. Not only that but the proteins in their brains seemed to start to regulate themselves and became more able to communicate between brain cells.

Studies in Children

Because of this trial one in children was started. The aim of said study was, of course, to see if Arbaclofen had any effects on children with Fragile-X and how it may relate to Autism. The findings were rather thought-provoking, especially if you look at the amount of shared “core symptoms” there are between classic Autism and Fragile-X Syndrome.

In the first double-blind study researchers took 63 individuals with a complete FMR1 gene mutation between the ages of 6-39 and tested them with the medication against a placebo. I think it is important to mention that 55 of the 63 were males. During this placebo-controlled study the individuals were given Arbaclofen then closely watched and tested to determine whether there were changes to their “core behaviors.”

By the end of said study it was determined that there were not significant improvements noted for individuals using this medication; however, when they took a side group of individuals that would fit the severe end of the disorders and tried it with them; the results were very different than with the first study. After being given the medication individuals on the severe end of the spectrum saw improvement on all global measures. These results were the same in the entire group of 27 on the severe end that were used. The individuals were tested using the Vineland II-Socialization Raw Score and with the ABC-Social Avoidance Scale, both showing improvements.

By 2013 they were trying the study again. This time Boston Children's Hospital took it on. They took 150 patients, ages 5 to 21 with autism spectrum disorder (ASD) and administered the medication. In the end it was called a failed study because “no difference in change from baseline in lethargy and social withdrawal scores from the Autism Behavior Checklist (ABC) -- the study's primary outcome measure -- was seen in those assigned to arbaclofen versus placebo.” They attributed the missed endpoint to an unexpectedly strong placebo response while presenting at the Child Neurology Society's annual meeting in 2013.

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“Arbaclofen is believed to be responsible for most of racemic baclofen's clinical effects, with a relative potency of 10- to 100-fold,” researchers said. “The main effect is to stimulate GABA (gamma-aminobutyric acid) neurotransmission. This mechanism has only recently emerged as a potentially beneficial approach to autism spectrum disorders, owing to findings from electroencephalographic studies in ASD patients suggesting that GABA modulation could help normalize electrical activity in the brain.”

However, Arbaclofen did show some significant advantages over placebo on some secondary measures. These included severity scores on the Clinical Global Impressions (CGI) scale and, among certain subgroups like the Vineland II socialization scores, once again. The “primary endpoint was missed in a phase II trial of arbaclofen in Autistic children and adolescents, but positive signs in secondary analyses still give hope for the drug,” say researchers.

Arbaclofen's developer, Seaside Therapeutics of Cambridge, Mass., is conducting another trial to confirm the results of these secondary analyses. Still, the secondary outcomes "are enticing, and should lead to some study redesign, using different primary outcome measures that are more likely to capture the improvements suggested by the findings of this study," said Treadwell-Deering, who is leading a trial of arbaclofen for social deficits in fragile X syndrome patients. "Finding a robust outcome measure that adequately captures the improvements found in this study will be the challenge for the next trials," she said.
"While recommended, these therapies are seldom as successful as we would like; also, they are costly and time-consuming," she said. "The importance of the discovery of a medication that successfully targeted social deficits in ASD could not be overemphasized," she added.

In the most current trial, researchers enrolled 130 patients whom meet DSM-IV criteria for ASD, 17 with Asperger's syndrome, and three diagnosed with pervasive developmental disorder "not elsewhere classified" (PDD-NOS) in the DSM-IV system. “Half the patients were 5 to 11 years old and nearly 80% were male.” Per reports, “they were randomized 1:1 to arbaclofen or placebo for 12 weeks. Drug doses ranged from 5 to 15 mg two or three times daily, with doses titrated to maximize CGI improvement. Most patients in the 5 to 11 age range ended up at 10 mg three times daily or, in the placebo group, the equivalent number of pills; most older patients received 15 mg three times daily or the placebo equivalent.”

Researchers said that, in a post-hoc analysis, the research group decided to examine whether outcomes were different in participants with relatively higher versus lower IQ, with 70 as the cutoff. There was still no advantage or disadvantage for arbaclofen in the primary outcome of ABC lethargy and social withdrawal score. But Vineland II socialization and communication scores emerged as again suggesting greater mean improvement from baseline with arbaclofen in the lower-IQ group, as follows:

-Communication: +4.0 (SD 11.23) with arbaclofen; +0.8 (SD 6.82) with placebo
-Socialization: +5.9 (SD 14.19) with arbaclofen; +2.6 (SD 9.19) with placebo.

At the end of the study it was reported that 51% of this arbaclofen subgroup had increases of at least 5 points, compared with 28% of the corresponding placebo subgroup.

There are side effects to this medication though, as with most medications.

The documented side effects were:

-Respiratory Infections (13 percent)
-Headaches (8 percent)
-And deep sleep (8 percent)

Other events prompting withdrawal from the study included:

-emotional upset
-sleep problems
-skin rash
-oculogyric crisis

Overall, the findings of the studies prove promising, definitely a step in the right direction. As with most new medications, more research is needed into this medication before any commitment is made by parents or by science.