A promising clinical trial to reduce the severity of autistic disorders
INSERM press release | 11 december 2012
Yehezkel Ben-Ari, Founder and Honorary Director of INMED (Institut de Neurobiologie de la Méditerranée), INSERM, and Eric Lemonnier, a clinician specialising in autism at the CHRU of Brest, recently published the results of a double-blind clinical trial to evaluate the usefulness of a diuretic in the treatment of autism. Sixty children between 3 and 11 years old with autism or Asperger’s syndrome were treated for 3 months either with a diuretic to reduce their intracellular chloride levels or with a placebo. Although this therapy is not curative, it nevertheless reduced the autistic disorders’ severity in three-quarters of the children. The researchers have filed a request for authorisation to perform a multi-centre European clinical trial in order to determine more precisely the population concerned by this therapy.
Details of this work have been published in the Translational Psychiatry review dated 11 December 2012.
Contribution made by the fundamental research on neuronal chloride
Previous work carried out by the team of researchers led by Yehezkel Ben-Ari in INSERM unit 901, the Institut de Neurobiologie de la Méditerranée (INMED) in Marseille, on intracellular chloride concentrations have demonstrated that they are abnormally high in immature neurons or neurons previously affected by epileptic seizures or other cerebral lesions. Many anxiolytics, analgesics and antiepileptics act by increasing the effects of GABA – the brain’s main chemical mediator – which normally inhibits the neurons. When the cells contain a very high chloride concentration, however, GABA’s effects are reversed. GABA no longer inhibits the neurons; the anxiolytic molecules accentuate these effects instead. These molecules have an excitatory effect, aggravating the disorder rather than alleviating it[1]. This is what has been observed in the case of epilepsy: diazepam, an anxiolytic, actually aggravated the seizures in certain situations. The research team then showed the benefits of a diuretic in mitigating this effect.
From fundamental research to clinical research
Indirect experimental data suggest that the inhibitory transmitter GABA’s action is modified in autism. Eric Lemonnier, a clinician at the CHRU of Brest, pointed out to Yehezkel Ben-Ari that valium is not prescribed to children suffering from autism because their parents say they become more agitated as a result, suggesting that, as in epilepsy and other brain pathologies, their intracellular chloride concentration is increased. This encounter led to the idea of testing a diuretic – in the same way as for epilepsy – to determine whether this could alleviate autistic disorders. A pilot study in 5 children was rapidly set up in 2010 because bumetanide, the diuretic tested, is in common use, particularly in treating high blood pressure. The taking of these molecules can, however, lower the potassium level, meaning that a potassium supplement is required. The researchers then began a randomised double-blind clinical trial in 60 children between 3 and 11 years old with autism or Asperger’s syndrome.
Reduction in the severity of autistic disorders
The children were monitored for 4 months. One group was treated with the diuretic (1 mg of bumetanide) while a placebo was administered to the second group for 3 months. No treatment was administered in the final month. The severity of the children’s autistic disorders was rated at the beginning of the test, the end of the treatment, i.e. after 90 days and one month after the test ended.
After 90 days of treatment, the mean CARS (Childhood Autism Rating Scale) test score of the children treated with bumetanide had significantly improved. The severity of the treated group’s autistic disorders shifted from high (> 36.5) to medium (< 36.5). No significant difference was observed in the score of the group treated with the placebo, however. In total, the clinical diagnosis of 77% of the children who received the treatment improved in the Clinical Global Impressions (CGI) test. When the treatment was terminated, some disorders reappeared. The treatment with bumetanide is therefore reversible.
Dr. Lemonnier explained the case of a 6-year-old boy:
“Prior to the treatment, the child presented with low language abilities and little social interaction, was hyperactive and exhibited constantly-combative behaviour. After three months of treatment, his parents, teachers, the hospital nursing staff and his friends at school all said that he was participated more, particularly in the games proposed by the psychologist. His attention and eye contact also improved.”
“Even though it is not curative, the diuretic reduced the severity of most of the children’s autistic disorders. According to the children’s parents, they are more “present””, added Yehezkel Ben-Ari.
Given the population’s heterogeneity, the researchers assume that the treatment could act differently depending on the severity of the autistic disorders. By forming groups based on severity, the results suggest that the treatment would be more effective in the least seriously-affected children.
As a result, the researchers have filed an authorisation request for a multi-centre European clinical trial in order to determine more precisely the population concerned by this treatment and ultimately obtain a marketing authorisation for this therapy. This test is supervised by a company created by Prof. Ben-Ari and Dr. Lemonnier (Neurochlore). Analyses are also essential in order to assess the long-term effects of taking these molecules and the required dose. Lastly, the researchers stress the need to continue the work on experimental models to determine how chloride is regulated and how it is deregulated in the neural networks of autistic patients.
A patent application has been filed for this work, and a licence has been granted to the Neurochlore start-up. Neurochlore has received funding from the French National Research Agency (ANR) (in the Biomedical Innovation in public-private Research Partnership (BIRP) “Cure Autism” project).
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Various criteria for assessing the severity of disorders: CARS, CGI and ADOS G
The widely-applied Childhood Autism Rating Scale (CARS) behavioural scale was used to rate the severity of the disorders, based on videos of the children’s behaviour during an activity led by a caregiver. The films were analysed with the assistance of their parents. A rating is obtained from the analysis as follows: if the rating is between 30 and 36, the child suffers from a moderate or average disorder; if the rating is higher than 36, the child is severely autistic.
Two other indicators were used to assess the severity of the disorders: the Clinical Global Impressions (CGI) clinical diagnosis, and the Autism Diagnostic Observation Schedule – Generic (ADOS–G) indicator combining assessment criteria such as social interaction and communication.
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Nature | News | 11 December 2012
Link to the original Nature article
Diuretic drug improves symptoms of autism
Small-scale trial provides hope for treatment of autistic behaviour in children.
by Mo Costandi
A drug normally used to increase the rate at which people urinate improves some of the symptoms of autism in children, according to a small clinical trial published today in Translational Psychiatry (1).
Autism is a neurodevelopmental disorder characterized by impaired communication and social interactions, and also by repetitive behaviours in those affected. Research has shown that signalling by a molecule called GABA, a neurotransmitter which normally dampens down neuronal activity, is altered in autism. And that this disruption of GABA is due to increased levels of chloride ions in the brain cells.
Reducing these chloride ion levels might help to treat the condition, hypothesized Yehezkel Ben-Ari, a neuroscientist at the Mediterranean Institute of Neurobiology (part of INSERM, France’s national biomedical research agency) in Marseilles, and his colleagues .
In 2010, Ben-Ari and his co-author reported that a three-month course of bumetanide — a diuretic that lowers the concentration of chloride ions by blocking the entry of ions into the cell — decreased autistic behaviour in five infants without causing side effects (2).
Now, the researchers have conducted a randomized, controlled clinical trial to confirm their earlier findings and to evaluate the safety of the drug.
They recruited 60 children for the study, aged between 3 and 11 years, who had been diagnosed with either autism or Asperger’s syndrome, and randomly assigned them to receive either 1 milligram of bumetanide daily for three months, or a placebo daily for the same period. The researchers used a standard scale to assess the children’s behaviour at the start and end of the three-month dosing period, and then assessed them again a month later.
Take notice
Video footage of the children was also taken at the start and end of the study, so that their behaviour could be examined by independent evaluators. And their parents were asked to report any change in the severity of symptoms that they saw in their children.
In children taking bumetanide who were less severely affected by autism, the researchers saw small but significant improvements in behaviour. The drug also seemed to be safe and well tolerated with few side effects, they say.
“This study is based on a randomized, controlled design and that makes me take notice,” says cognitive neuroscientist Uta Frith, who studies autism at University College London, UK.
She adds, however, that the effects of the drug were small, and that one-third of the placebo group also showed some amelioration of symptoms.
“The effects were only noticeable on some gross behavioural measures, [but the findings are] consistent with my view that there is a lot of spontaneous fluctuation in symptoms and a general tendency to improve over time,” she adds.
Neurons and networks
The authors suggest that bumetanide could be a new type of treatment for autism, and that their findings warrant larger trials. Earlier this year, Ben-Ari co-founded a company called Neurochlore, based in Marseilles, which is now aiming to develop and commercialize bumetanide as a treatment.
But Frith remains sceptical. “I have seen a number of treatments for autism come and go, and this leaves many questions open, such as what is the [drug’s] mechanism, and will the effect be replicated?”
Ben-Ari says: “We do not claim that we are curing autism … but want to determine how neurons and networks operate in animal models and humans.” He adds that understanding this is more important than identifying genetic mutations in autism, as mutations do not “really tell us what is happening”.
Nature
doi:10.1038/nature.2012.12000
References
1. Lemonnier, E. et al. Transl. Psychiatry 2, e202 (2012).
2. Lemonnier, E. & Ben-Ari, Y. Acta Paediatr. 99, 1885–1888 (2010).
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SCIENCE | NOW | 11 December 2012
Link to the original Science article
Diuretic Drug Offers Latest Hope for Autism Treatment
by Greg Miller
Social studies. Recent research suggests that enhancing inhibition in the brain may help improve social interactions in people with autism.
A drug used for decades to treat high blood pressure and other conditions has shown promise in a small clinical trial for autism. The drug, bumetanide, reduced the overall severity of behavioral symptoms after 3 months of daily treatment. The researchers say that many parents of children who received the drug reported that their children were more “present” and engaged in social interactions after taking it. The new findings are among several recent signs that treatments to address the social deficits at the core of autism may be on the horizon.
Several lines of evidence suggest that autism interferes with the neurotransmitter GABA, which typically puts a damper on neural activity. Bumetanide may enhance the inhibitory effects of GABA, and the drug has been used safely as a diuretic to treat a wide range of heart, lung, and kidney conditions. In the new study, researchers led by Yehezkel Ben-Ari at the Mediterranean Institute of Neurobiology in Marseille, France, recruited 60 autistic children between the ages of 3 and 11 and randomly assigned them to receive either a daily pill of bumetanide or a placebo. (Neither the children’s parents nor the researchers who assessed the children knew who received the actual drug.)
As a group, those who got bumetanide improved by 5.6 points on a 60-point scale that’s often used to assess behaviors related to autism, the researchers report today in Translational Psychiatry. That was enough to nudge the group average just under the cutoff for severe autism and into the mild to medium category. The study did not look directly at whether the drug improved all symptoms equally or some more than others. “We have some indications that the symptoms particularly ameliorated with bumetanide are the genuine core symptoms of autism, namely communication and social interactions,” Ben-Ari says. More work will be needed to verify that impression. Ben-Ari says his team is now preparing for a larger, multicenter trial in Europe.
The current study already looks interesting to some. “It’s enough to make me think about trying it in a few of my autism patients who haven’t responded to other interventions,” says Randi Hagerman, a pediatrician who studies neurodevelopmental disorders at the University of California, Davis. Social interactions tend to be reinforcing, Hagerman adds, so getting an autistic child to start interacting more can have a positive effect on subsequent brain development.
Other drugs have recently shown promise for autism. In September, Hagerman and colleagues reported that arbaclofen, a drug that stimulates a type of GABA receptor, reduced social avoidance in people with fragile X syndrome, a genetic disorder that shares many features with autism. Many researchers are also hopeful about clinical trials under way with drugs that block certain receptors for glutamate, the main neurotransmitter in the brain that excites neural activity. Results from those trials should come out next year.
All of this work, including the new study, suggests that drugs that reduce neural excitation by blocking glutamate or enhance inhibition by boosting GABA may be helpful for treating autism, says Elizabeth Berry-Kravis, a pediatric neurologist at Rush University in Chicago, Illinois, and a collaborator on the recent arbaclofen study. “There seems to be this imbalance between excitation and inhibition in people with autism.”
That’s a potentially game-changing insight. Now doctors can only prescribe drugs that treat individual symptoms of autism rather than the underlying cause of the disorder, Berry-Kravis says. Doctors often prescribe antipsychotic drugs to reduce irritability, for example, but those drugs don’t address the social and communication problems at the heart of the disorder. “It’s exciting that now we’re thinking about the underlying mechanisms and treating those.”
Link to the video