Diuretic drug improves core autism symptoms
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Double-blind randomized multicenter trial finds bumetanide ameliorates symptoms of autism.
A medical drug normally used to relieve fluid retention has been repurposed as a treatment for the core symptoms of autism. Following on from the promising results of their earlier preliminary trials completed in 2010 and 2013, the same team of French researchers and clinicians have recently tested bumetanide again on a larger group of children.
In the new work, published in March 2017 in Translational Psychiatry, the researchers tracked the effects of bumetanide in children with autism taking three different doses of the drug or a placebo. They found that bumetanide appears to decrease the severity of core autism symptoms in a dose-dependent manner.
“Interestingly, responders were found in all subpopulations, ages and ASD severity… Our results suggest that bumetanide known to specifically act on NKCC1 in central neurons attenuated ASD severity.”
Apart from helping fluid retention and lowering blood pressure, bumetanide is also known to modulate the levels and activity of chemical messenger, gamma-aminobutyric acid (GABA), thought to play an important role in the underlying pathophysiology of autism.
While the GABA messenger calms neuronal responses, early in development it has the opposite, excitatory, effect in the brain. It is thought that rather than make this developmental switch from excitatory to inhibitory, GABA remains excitatory in children with autism. Recent discoveries in experimental studies also show that adverse events such as severe seizures can reverse GABA’s function from inhibitory to excitatory even in matured, fully developed brains. Giving bumetanide after a seizure reversed the switch and decreased the frequency of seizures in affected animals in a recent Finish study. “We show that GABA can be linked to structural changes in the brain. One could imagine maybe something similar might be happening in children with autism,” says Claudio Rivera, lead investigator and research director at the University of Helsinki in Finland.
It is worth noting that up to 40% of individuals with autism develop epilepsy at some point in their lives, and a large majority suffer subclinical seizure activity even in the absence of a clinical seizure disorder.
For their latest study the French group, led by researcher Yehezkel Ben-Ari, recruited 88 children aged from 2 to 18 years. One group received a placebo, and the others received either 0.5, 1 or 2 milligrams of bumetanide twice daily for three months. Of the 66 children in the bumetanide group, 23 showed an improvement of more than 6 points on the Childhood Autism Rating Scale (CARS), while only 1 of the 22 children in the placebo group made such progress. While the children taking the highest dose of bumetanide, 2 milligrams twice a day, showed the most improvement, this group also recorded the highest number of side effects, such as dehydration, hypokalemia and loss of appetite. The scientists concluded that the “drug presents a favorable benefit/risk ratio at 1mg twice daily”.
Ben-Ari and his team plan to begin recruiting participants for a large multisite European Phase III trial, which will test bumetanide on a group of 370 children, at the dosage of 1mg twice a day. If the study confirms their earlier findings, the drug could be on the market for autism in Europe by 2021.
“We highlight that a paradoxical response to GABA-enforcing drugs may offer a rationale for administration of bumetanide in individual cases. … The effects of bumetanide on cognition and EEG seemed to mirror the “nonparadoxical” responses to benzodiazepines in healthy subjects.”
This article is part of Treating Autism Clinical & Research Newsletter: Issue 2
Lemonnier E., Villeneuve N., Sonie S., et al. (2017) Effects of bumetanide on neurobehavioral function in children and adolescents with autism spectrum disorders. Transl Psychiatry. Mar 14;7(3):e1056. doi: 10.1038/tp.2017.10.
Bruining H., Passtoors L., Goriounova N., et al. (2015) Paradoxical Benzodiazepine Response: A Rationale for Bumetanide in Neurodevelopmental Disorders? Pediatrics. Aug;136(2):e539-43. doi: 10.1542/peds.2014-4133.
Kourdougli N., Pellegrino C., Renko J.M., et al. (2017) Depolarizing γ-aminobutyric acid contributes to glutamatergic network rewiring in epilepsy. Ann Neurol. Feb;81(2):251-265. doi: 10.1002/ana.24870.
Marrosu F, Marrosu G, Rachel MG, et al. (1987) Paradoxical reactions elicited by diazepam in children with classic autism. Funct Neurol. 1987 Jul-Sep;2(3):355-61.