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Controversial study touts blood pressure drug for autism

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Virginia Hughes
18 February 2013

Quiet time: Bumetanide decreases the level of chloride ions inside cells, which in turn affects the cell’s ability to fire. 

Bumetanide, a drug that’s long been used to treat high blood pressure, modestly improves social behaviors in children with mild forms of autism, according to the results of a small trial published in December in Translational Psychiatry1.

After three months of bumetanide treatment, 27 children, aged 3 to 11 years, improved more on the Childhood Autism Rating Scale (CARS) than did 27 children taking placebo. Children with severe symptoms of autism did not seem to benefit from the drug, however.

“Of course it doesn’t work for every kid, but the results were satisfactory enough to have virtually all of the parents want to continue when the trial was finished,” says lead investigator Yehezkel Ben-Ari, director of the Mediterranean Institute of Neurobiology at INSERM in Paris, France. He is also the founder and chief executive of Neurochlore, a company based in Marseille, France, that is developing bumetanide and related treatments for autism and other disorders.

Ben-Ari says many parents used the same phrase — “more present” — to describe their children’s behavior after taking bumetanide. The drug is a diuretic — meaning that it increases urine production — but it has no serious side effects, he says. “Some of the kids have been using the diuretic for two years now.”

Families and doctors are eager for new treatments for autism. Just two drugs, risperidone and aripiprazole, are approved to treat the disorder, and they improve irritability and aggression rather than social and communication difficulties.

Still, several experts are puzzled because the study used diagnostic measures of autism in unusual ways. They also say that the sample size is too small to know whether the effects are real.

“Until a big study with a better design is done, we can’t think of this as a real treatment,” says Elizabeth Berry-Kravis, professor of pediatrics, neurological sciences and biochemistry at Rush University Medical Center in Chicago. Berry-Kravis has led several clinical trials of treatments for fragile X syndrome and was not involved in the new work. “We have to think of this as an exploratory first step.”

Small samples:

In 2010, Ben-Ari’s group published results from a pilot study of bumetanide in five children with autism2. Although that trial found positive effects, it did not compare the effects with those of a placebo.

The new trial includes a placebo arm and is double-blind, meaning that neither the parents nor the researchers knew which children received bumetanide and which placebo.

The children took the drug or placebo in pill form once a day for three months. Some researchers say they worry that the drug’s side effects may have effectively unblinded some of the participants. Of the 27 children treated with bumetanide, 6 developed a potassium deficiency that had to be treated with a potassium syrup.

However, the psychologists who assessed the children did not know which children had received the potassium treatment, Ben-Ari says.

Children on bumetanide shifted from ‘severe’ scores on the CARS test to ‘mild’ or ‘medium’ severity scores. The change is statistically significant, but some experts question whether it means much.

“The changes in the CARS are puny and have no clinical significance,” says Catherine Lord, director of the Center for Autism and the Developing Brain at Cornell University in New York.

Lord and Berry-Kravis both note that the researchers implemented CARS in a strange way. The test is typically done by having a parent or a clinician who knows the child fill out a questionnaire. In the new study, the researchers instead made assessments of the children based on videos of their behavior, a method that has not been validated.

The findings were even less clear based on scores on the Autism Diagnostic Observation Schedule (ADOS), which Lord developed.

Bumetanide treatment was associated with statistically significant improvements on total ADOS scores only when the researchers removed the nine most severely affected children from the group. Seven of the nine were in the placebo group, suggesting that the placebo group was skewed toward the more severe end of the spectrum.

“I think this study, at least in terms of the outcome measures, is very problematic,” Lord says.

Ben-Ari admits that the study is small and that the differences based on severity may not persist in a larger study. “It’s very difficult to say which of the kids will be ameliorated. We need a much, much larger sample.”

In unpublished experiments, he says, his team used functional magnetic resonance imaging to show that the children taking bumetanide were more accurate in labeling facial expressions and showed more activity in brain regions related to social and emotional perception.

Ben-Ari’s team is planning to do another double-blind trial later this year, testing 80 children with autism with different doses of bumetanide, to see whether larger quantities lead to better outcomes. (The Simons Foundation, SFARI.org’s parent organization, is funding part of this trial.) If that goes well, he plans to launch a phase III trial of 120 children, recruited from several European sites, at the end of 2014.

Some children with autism have trouble taking pills. Neurochlore is developing bumetanide as a syrup that can be mixed with juice. The company plans to fund later clinical trials of bumetanide and is also developing alternatives to the drug.

Paradoxical effect:

Nobody knows exactly how the drug works in the brains of children with autism.

“Some of the changes, in some children, seem spectacular,” says Enrico Cherubini, professor of physiology at the International School for Advanced Studies in Trieste, Italy, who was not involved in the trial. “But the mechanism is completely obscure.”

Ben-Ari says his theory is that the drug works by altering levels of chloride ions inside brain cells.

Bumetanide blocks a chloride channel in the cell wall of a neuron, decreasing the level of chloride inside. This chloride level can determine whether gamma-aminobutyric acid (GABA), a chemical messenger that binds to a different chloride channel, has an inhibitory or excitatory effect on neurons.

In the adult brain, chloride levels inside the cell are lower than they are outside, so when GABA binds, chloride ions rush into the cell and make it more difficult for the cell to fire. But in the developing brain, GABA seems to have the opposite effect, according to Ben-Ari.

In 1989, he and Cherubini found that brain cells in newborn rats have excessive levels of intracellular chloride. When GABA opens chloride channels in these immature neurons, the ions rush out of the cell, rather than into it, triggering the cell to fire3.

Ben-Ari hypothesizes that GABA has a similar excitatory effect in certain brain disorders. Some infants with severe epilepsy don’t respond to anti-seizure medications, such as Valium, that turn up GABA activity4. And one small study of children with autism reported that Valium paradoxically causes them to be anxious and aggressive5.

Taken together, these studies led Ben-Ari to propose that autism stems from immature neurons holding too much intracellular chloride. “After insults, the brain returns to an immature state,” he says. “It recapitulates immature features, among them elevated chloride.”

Because bumetanide decreases chloride levels inside cells, it’s being tested in clinical trials in the U.S. and in Europe for treating epilepsy in newborn infants.

Ben-Ari says he assumes that’s why the drug works in autism, though it’s impossible to know for sure. “The proof that chloride is elevated in autism, I don’t have [that],” he says.

Other neuroscientists have called Ben-Ari’s hypothesis into question, claiming that the original result of GABA’s excitatory effects in the developing brain is the result of an experimental artifact6.

Ben-Ari’s team is trying to confirm his theory by looking at intracellular chloride levels in two animal models of autism: mice lacking FMR1, the gene that causes fragile X syndrome, and rats whose mothers were exposed to the common epilepsy drug valproate during pregnancy. Prenatal valproate exposure is a well-known environmental risk factor for autism.

However, the mechanism may be difficult to discern even with animal models because the disorder is so heterogeneous, notes Cherubini. In unpublished work, his group has found that in at least one mouse model of autism, GABA excites neurons in early brain development and then inhibits them later on, just as happens in controls.

News and Opinion articles on SFARI.org are editorially independent of the Simons Foundation.

References:

1. Lemonnier E. et al. Transl. Psychiatry 2, e202 (2012) PubMed

2. Lemonnier E. and Y. Ben-Ari Acta Paediatr. 99, 1885-1888 (2010) PubMed

3. Ben-Ari Y. et al. J. Physiol. 416, 303–325 (1989) PubMed

4. Painter M.J. et al. N. Engl. J. Med. 341, 485-489 (1999) PubMed

5. Marrosu F. et al. Funct. Neurol. 2, 355-361 (1987) PubMed

6. Bregestovski P. and C. Bernard Front. Pharmacol. 3, 65 (2012) PubMed

Comments

Name: Ruth Cooper
19 February 2013 - 6:34AM

Thanks for a very fair and comprehensive account of this study. Any parent would love to find an effective and safe treatment for even one aspect of autism (unlikely as a single drug is to achieve this), which makes it all the more important to have good critical evaluation of every possibility.

Name: Anne Dumont
19 February 2013 - 3:35PM

I would like to bring to your attention the following article by Wang and Kriegstein, http://www.ncbi.nlm.nih.gov/pubmed/20624842 which basically cautions the use of bumetanide on developing (neonatal) brains, as “disruption of GABA signaling during this window resulted in permanent decreases in excitatory synaptic transmission and sensorimotor gating deficits, a common feature in schizophrenia. Our study identifies an essential role for GABA-mediated depolarization in regulating the balance between cortical excitation and inhibition during a critical period and suggests a cautionary approach for using bumetanide in treating neonatal seizures.” Although Ben-Ari’s work seems to open a very promising line of research, I think it is important to remind parents, who are understandably desperate to try anything that might help their children, to be cautious before trying experimental treatments.

Name: yehezkel ben-ari
20 February 2013 - 2:42PM

the paper of Wanng and kriegstein corresponds primarily to preterm babies in humans and concerns "normal rodents". This situation of course is not relevant to humans as nobody would give a diuretic to normal healthy pregnant women... unless there is a reason to do that -hypertension or oedema- and then this is justified as the levels of intracellular chloride are important and the diuretic will reduce them to the better...therefore, one whould not compare the effects of a drug to naive persons and diseased ones.
I have replied in detail to this paper eg

Ben-Ari Y, Tyzio R. Is it safe to use a diuretic to treat seizures early in development ? Epilepsy Curr. 2011 Nov;11(6):192-5.

Name: yehezkel ben-ari
22 February 2013 - 8:48AM

A diuretic to treat autism: neither puny nor more controversial than other studies
Y Ben-Ari and E Lemonnier
In her review, the scientific journalist V Hughes stresses limitations of our clinical study1 and the experimental observations underlying them. Scientific debated are always useful and we agree with many of the critical statements made by well-known experts. Yet to fully comprehend the concept, experimental observations and clinical trials on which they are based, the following points must be stressed:
The GABA Excitatory/inhibitory developmental sequence: is one of the most classically and widely accepted developmental sequences. In fact all voltage and transmitter gated ionic currents differ in the developing and adult brains consequently to different subunit compositions and other major differences. Therefore, the progressive reduction of intracellular chloride during development that underlies the GABA polarity shift is not an exception; it is a rule 2,3,4. Excitatory GABA serves a crucial trophic role in brain development including neuronal growth, synapse formation, and network construction (idem). This sequence has been observed by labs all around the world in a wide range of brain structures and animal species from worms to mammals and has been respected throughout evolution (idem). V Hughes refers to the single paper that has challenged these observations 5. Unfortunately, she should have noted that their observation on the need of ketone metabolites to provide adequate metabolic supply to young slices has been infirmed by 7 different labs and not confirmed by a single one 6. In addition, the arguments developed in this review are erroneous, based on biased readout of the literature and the references quoted in support reach opposite conclusions as stressed recently in a review written by 13 different experts 7. In fact, one of the principal arguments of this review has been infirmed recently by a leading author of the original paper 8. Therefore, discovered more than 2 decades ago 2, the GABA developmental sequence is a fundamental feature of brain development.
The underlying concept: Relying on studies on developmental sequences that we and many other groups have conducted, N Spitzer and Ben-Ari 9 have suggested that during brain development, neuronal activity serves as a check-point of brain development confirming or infirming the correct implementation of the developmental program. Again, this is in full agreement with the fact that neurons and networks generate immature patterns from very early developmental stages 2-4 including an oxytocin mediated unique shift of polarity during delivery that is probably the most significant illustration of the biological significance of the sequence 10. We also proposed that genetic or environmental insults during brain maturation deviate these developmental sequences leading to the expression in an adult brain of immature electrical properties. This “neuroarcheology” concept 11 suggests the presence of pre-symptomatic electrical and architectural signatures in many disorders. In essence, this concept states that neurons that do not fulfil their assigned program remain “frozen” in an immature state, generating currents that perturb the operation of brain networks. This concept has already been confirmed in several migration and developmental disorders raising the possibility of therapeutic interventions based on blocking these immature currents in an adult brain 12,13.
Elevated intracellular chloride and excitatory GABA following adverse conditions: many studies have shown that following seizures, spinal chord lesions and other insults, GABA excites neurons because of altered activity of chloride co-transporters and elevated intracellular chloride 14,15. This is thought to underlie the paradoxical actions of benzodiazepines in epilepsies and other insults (idem). These observations suggest that reducing intracellular chloride –notably with a diuretic- could constitute a useful therapeutic approach to reinstate low chloride and inhibitory GABA. Indeed, this is currently tested in epilepsies relying on the converging experimental observations the NKCC1 chloride importer is up-regulated and the KCC2 chloride exporter down regulated (idem). In addition, the NKCC1 specific antagonist bumetanide has been shown to reduce intracellular chloride levels thereby reinstating low levels and inhibitory GABA. Therefore, and even without taking into account the high incidence of epilepsies in autism, testing its effects in autism is not astonishing. However, this suggestion remains to be confirmed in neurons of animal models of autism and may as stressed by E Cherubini be valid only in some models.
Heterogeneity of mutations and expected alterations: There is little doubt that with hundreds of mutations awaiting serious experimental research, nobody expects a simple straightforward unique common mechanism. This is and will remain a major limitation of unravelling novel mutations without necessarily finding unifying pathways and a conceptual basis of how to unify the results. This limitation applies to our works as it does to all other studies. To state that “the excitatory /inhibitory balance “ is shifted as done in so many reports is quite general and can be produced by a plethora of mechanisms. Intracellular chloride accumulation is one of them endowed with substantial experimental observations in other pathologies in support. We anticipate that at least in some animal models GABA may exert such aberrant actions. Therefore, the heterogeneity has not and should not discard us form our efforts to investigate common substrates as is the case for other experimental scientists
The clinical trials: there is little doubt that the sample of 60 children with autism is small and we have repeatedly insisted that larger trials are needed and we are planning to do large multi-centric European trials this year and next one. In particular, as we have used large inclusion criteria and our cohort is very heterogeneous. Stated differently, our approach will only be validated by definition when larger trials are made, confirm our results and a drug placed in the market. But is that not the case for all other clinical trials including those advocated by our detractors?
Indeed, the claims that our observations “are puny and have no clinical significance” and that this study “at least in terms of the outcome measures is very problematic” is to say the least debatable and unsubstantiated. First, the arguments that CARS was used in a “strange way” is inadequate perhaps because we did not state things properly. The CARS evaluation was made both relying on films made by a psychologist unaware of the treatment and by the clinician (also unaware of the treatment) following discussion with the parents and the children at D0, 90 and 120. The films are useful as they can be analysed separately by another person and they provide useful information confirming or infirming the parent indications. In addition, the ADOS – that seems to be more relevant as a diagnostic method rather than for therapeutic tests- was significant when the most severe children (more than 2 SD of the mean estimated by CARS) were removed. This is not unusual and has been used repeatedly including in tests made by the experts criticising our results.
Perhaps more importantly, the only reasonable approach is to compare the results obtained with bumetanide to other trials conducted and /or considered by these experts as being convincing enough to justify large trials. The widely used apiriprazole or risperidone in autism have no experimental support from animal models! They are widely used, have important side effects and are considered to treat irritability not the core of the symptoms of autism 16-19. Other drugs advocated notably by Berry-Kravis and colleagues and promised to large developments such as mGlur5 antagonists in Fragile X are also in a quite preliminary state at this stage. Indeed, in the most recent study made by Berry-Kravis and colleagues, there was no significant effect of the treatment on the primary outcome measure and a significant effect was restricted to a few patients who had a complete loss of the FMR1 protein 19. Therefore, if successful, this treatment will ameliorate a small population of Fragile X children but not children with autism. Similar remarks can be made concerning other treatments notably the GABA B analogues advocated to treat fragile X and autism, although they rely on experimental observations 20, they are in preliminary observations that await confirmation.
Therefore, our results are preliminary and should be considered as such but no they are neither puny nor of no clinical significance. The concepts behind them are certainly as solid as other suggested mechanisms and will be strongly reinforced soon. Over 100 children are still under treatment and our phase 2/3 trial will we hope show that this is a serious attempt to treat the core syndromes of at least some forms of autism rather than other components of the syndrome. At the end of the day, the proof is in the pudding and as hundreds of parents are awaiting to trys this drug, some responses will be available soon from other centres to confirm or infirm our observations.

References:
1. Lemonnier E. et al. Transl. Psychiatry 2, e202 (2012) PubMed
2. Ben-Ari Y. et al. J. Physiol. 416, 303–325 (1989) PubMed
3. Ben-Ari, Y. (2002). Nature reviews Neuroscience, 3(9), 728-739.

4. Ben-Ari et al Physiological reviews 2007
5. Bregestovski P. and C. Bernard Front. Pharmacol. 3, 65 (2012) PubMed
6. Tyzio R et al J Neurosci. 2011 Jan 5;31(1):34-45

7. Ben-Ari Y et al Front Cell Neurosci. 2012; 6: 3

8. Valeeva G, 2013, Frontiers in Cellular neuroscience (in press)

9. Ben-Ari Y and spitzer N Trends Neurosci. 2010 November; 33(11): 485–492.

10. Tyzio et al Science. 2006 Dec 15;314(5806):1788-92.

11. Ben-Ari Y (2008). Trends in neurosciences, 31(12), 626-636.`

12. Carabalona A et al Hum Mol Genet. 2012 Mar 1;21(5):1004-17

13. Ackmann J et al J Neurosci. 2009 Jan 14;29(2):313-27.

14. Dzhala et al Nat Med. 2005 Nov;11(11):1205-13.

15. Nardou et al Brain. 2011 Apr;134(Pt 4):987-1002
16. Berry-Kravis et al J Neurodevelop Disord (2011) 3:193–210
17. Gross et al, Neuropsychopharmacology reviews (2012) 37, 178–195
18. Erickson C A, et al Neurotherapeutics . 2010 July ; 7(3): 258–263
19. Jacquemont S et al 202 Sci Transl Med 3: 64ra61.

20. henderson et al SCi. Transl.Med. 2012 Sep 19;4(152):152ra128.

Name: Peter Lloyd-Thomas
16 May 2013 - 1:29PM

I can speak from some first hand experience. I read Y Ben-Ari's and E Lemonnier's research paper, checked that indeed Bumetanide is a safe drug and then made my own trial on my 9 year old autistic son. Almost five months later, everyone is shocked with the remarkable positive changes.

I was so impressed I created a blog about my experience, which then lead me to further innovations. http://epiphanyasd.blogspot.com/

I have moved on to NAC and now statins. I owe all this to Y Ben-Ari and E Lemonnier.

I now have a son without obsessions, who speaks spontaneously and in 6 months has gone from playing the piano with one finger to playing with all fingers of both hands and without the music in front of him. I guess that would not show up on CARS !!!!

Name: Anonymous
3 September 2013 - 8:05AM

I would love to try this, myself. I'm an adult with AS, and I'm sick of feeling like there's no hope for life. Everyday I wake up, wishing there was a cure for this, and everyday I'm disappointed. Why has there been nothing more on this trial, since 2005?

Name: C.j
17 October 2013 - 11:10AM

Can't they just test it or trial it out to see whether or not it works? What's the big deal? It's already an approved drug that's safe to take. I don't understand.

Name: jason
25 April 2014 - 1:23AM

I am wondering what a study would show for adults with ASD? Seems like the message I am seeing is that this works best with infants

Name: Nick
1 August 2014 - 12:12PM

A review on bumetanide in childrens' brain disorders I found interesting. It appears there is a big problem getting this drug inside the brain in live animal models.

http://onlinelibrary.wiley.com/doi/10.1111/epi.12620/pdf

Given this, the effects of this drug on ASD are truly astonishing.

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