Friday, 14 December 2012

Bumetanide for autism?

The paper by Lemonnier and colleagues* (open-access) reporting results from a randomised, placebo-controlled trial of the diuretic drug bumetanide in cases of autism has received quite a bit of publicity over the past few days. As with other big autism research news, the study was accompanied by quite a good write-up in Nature (see here) which very conveniently allows me to skip over the ins and outs of the study and pick out a few notable points in this brief post.

As always with the 'no medical advice given' caveat in full working order:

  • This was a gold-standard trial insofar as similar to other research discussed on this blog it was randomised and also incorporated a placebo into the methodology which meant that participants were randomly assigned to treatment or not and the 'not' consisted of something that I assume, looked, smelled and tasted the same as bumetanide. Indeed the study lists 'lactose' as being the placebo which is fine as long as participants with autism did not have a lactose intolerance as per other autism research findings.
  • Bumetanide as well as being a diuretic (increasing urine excretion) is a loop diuretic acting on a specific part of the kidney. Its uses are varied but mainly focus on reducing swelling and fluid retention following problems with the heart and other organs. It's also apparently quite good for treating hypertension (high blood pressure) too** and potentially useful for certain types of epilepsy*** (although I'd like to see more data on this effect). 
  • Quite a lot of the focus on why the drug seemed to affect autistic behaviours has been on the GABA side of things and how "disruption of GABA is due to increased levels of chloride ions in the brain cells" in case of autism. The theory goes that bumetanide has an effect of decreasing levels of chloride in neuronal cells, which theoretically should positively alter that GABA disruption. In particular is the proposed action of bumetanide on NKCC1 an importer of chloride, where if I understand it correctly, bumetanide blocks NKCC1 from doing its duties. Indeed I might be confusing myself even further but NKCC1 also has something of a relationship with hypertension****.
  • Why am I focusing on the hypertension side of things? Well, with all that we think we know about autism in terms of stress responses and comorbidity potentially focused on things like hypertension***** as part of the whole metabolic syndrome side of things, one might also be minded to look at whether this might have been part and parcel of any effect noted. Of course, I'm just speculating, bearing in mind that no measure of blood pressure for example, was seemingly reported during the trial. 
  • As per this review by Ward & Heel****** (open-access), there are several other physiological changes/effects associated with taking bumetanide, all of which should remain at the back of one's mind when thinking about potential mechanisms of effect.  

I've not got too much more to say about this work aside from it being quite an interesting study and indeed (a) providing further support for how the myriad of pharmaceutical compounds we use might have many more uses than those cited on the patient information leaflet, and (b) how some of the effects of such medicines in cases of autism might be more evidence for the 'whole-body' nature of the condition, or at least some cases of the condition.

'Nuff said.

[Update: February 2014. Well it wasn't exactly 'nuff said as indeed, more was subsequently said on this topic... see this post on bumetanide, GABA, oxytocin and mouse models of autism].

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* Lemonnier E. et al. A randomised controlled trial of bumetanide in the treatment of autism in children. Translational Psychiatry. 2012: e202.

** van der Heijden et al. A randomized, placebo-controlled study of loop diuretics in patients with essential hypertension: the bumetanide and furosemide on lipid profile (BUFUL) clinical study report. J Clin Pharmacol. 1998; 38: 630-635.

*** Eftekhari S. et al. Bumetanide reduces seizure frequency in patients with temporal lobe epilepsy. Epilepsia. October 2012.

**** Ye ZY. et al. NKCC1 upregulation disrupts chloride homeostasis in the hypothalamus and increases neuronal activity-sympathetic drive in hypertension. J Neurosci. 2012; 32: 8560-8568.

***** Tyler CV. et al. Chronic disease risks in young adults with autism spectrum disorder: forewarned is forearmed. Am J Intellect Dev Disabil. 2011; 116: 371-380.

****** Ward A. & Heel RC. Bumetanide: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic use. Drugs. 1984; 28: 426-464.

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ResearchBlogging.org Lemonnier, E., Degrez, C., Phelep, M., Tyzio, R., Josse, F., Grandgeorge, M., Hadjikhani, N., & Ben-Ari, Y. (2012). A randomised controlled trial of bumetanide in the treatment of autism in children Translational Psychiatry, 2 (12) DOI: 10.1038/tp.2012.124

12 comments:

  1. As with most pharmaceutical drugs, this has a long list of potential side effects. GcMAF, on the other hand, is a naturally occuring protein in a healthy immune system. Dr Bradstreet discovered that autistic children have a higher than normal level of nagalase, and this disrupts the body's ability to make GcMAF. By reintroducing this protein, he found that 85% responded positively and some even went on to lose the label of autism as they no longer displayed autistic traits. See his speech on it (the paper to which he refers was peer-reviewed and published this week) http://www.youtube.com/watch?v=FZ5wog0oig0 . I fail to understand why FirstImmune GcMAF does not get more publicity. I've met parents whose children are now verbal after starting the therapy. Seeing the joy on their faces, this new discovery should be shouted from the rooftops. Its making me feel that the 'conspiracy theorists' have a point, that media is owned and managed by big money including big pharma.

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  2. Many thanks for dropping by Lesley.

    I've covered Gc-MAF quite recently on this blog and the paper from Dr Bradstreet....

    http://questioning-answers.blogspot.co.uk/2012/12/gcmaf-nagalase-and-autism.html

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  3. I have to wonder if this result with be replicated quickly because it looks so promising or whether it will be ignored and left as a historical curiosity. It would be very nice if there were evidence based treatment options available that actually treated the core symptoms of autism.

    BTW, your link to Ward & Heel doesn't seem to be working, is this the paper you are referring to?

    http://link.springer.com/article/10.2165/00003495-198428050-00003

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  4. Thanks for the comment MJ (and the correct Ward/Heel reference!)

    I'd hazard a guess that this might be one intervention which might be followed up quite quickly simply because there is already talk of 'commercializing bumetanide as a treatment'. Much like Dr Fallon's CM-AT work and that of the whole glutamate-targeting interventions and indeed the N-acetylcysteine (NAC) work, commercial operations seem to be a driver for getting pharmaceutical interventions potentially pertinent to autism on a fast research track.

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  5. I was very impressed by Lemmonier’s research and looked into his previous trials and also the safety of Bumetanide. The study was quite a big story in France with TV coverage. I contacted Lemmonier about joining his follow on trial, but in the end decided to do my own trial, under supervision of course. The result was rather shocking; reduced bad behaviours and lots of nice new behaviours, just as in the French research. Having previously believed Autism to be irreversible pharmacologically, life has changed somewhat. Now I am spending a fair few hours on Google Scholar and a fair few $$ on academic research, to see what else is out there.

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  6. Thanks for the comment Peter.

    You raise an important point there about how we view autism (the autisms!) and the stability of its characteristics among different people with autism.

    The recent paper by Deborah Fein and colleagues (here: http://questioning-answers.blogspot.co.uk/2013/01/some-children-lose-their-autism-diagnosis.html) opened the door (or Pandora's box...) to the fact that at least some cases of autism might be more sensitive to change and intervention than others.

    The bumetanide story (and all the other pharmacotherapies being put forward) represent an additional dimension to that viewpoint.

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    Replies
    1. Paul, I have been trying to find a neuro biologist with an interest in autism. I have been doing a great deal of desk research and came up with some observations that no researcher seems to be pursuing. I am applying Lemmonier's common sense approach to research. His bumetanide trial was prompted by a desire to know why Valium works "backwards" in kids with ASD (it excites rather than calsm them). He then took some observations from epilepsy research, made his hypothesis and then tested it on his own patients (he runs a big ASD clinic). In the US there are many universities actively involved in trials/research. I did read that Kings College in London are supposed to be doing some research, but it all tends to be genetic. My old college, Imperial College, also has a Brain Science department, but there seems to be little applied research. Most scientists are very focused on one pet theory and seem to ignore or even rubbish other ideas. Your blog is great in this respect, particularly. Do you have any ideas ? I can fully document by "work" with citations, but I lack somebody to discuss it with.

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    2. Many thanks again Peter.

      There are a few people who might be able to offer some feedback to you.

      1. Martha Herbert - very well known in autism research circles. Her site: http://www.marthaherbert.org/

      2. Manuel Casanova - another big name in autism research
      His site: http://corticalchauvinism.wordpress.com/

      3. Emily Williams - a rising star (more molecular biologist than neuro..)
      He site: http://insolemexumbra.wordpress.com/

      Ever thought of starting your own blog and putting your ideas out to the masses?

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    3. Paul, I think a blog is a bit advanced for me. My mother, a retired GP, thinks I should write a book. In all seriousness, I have found it very difficult to help other parents with kids with ASD. I do not live in the UK, maybe parents are more open there. I brought US-trained behavioral specialists to help set up a home based ABA/VB programme. I found great computer based learning software to help with learning first to talk, then to read and now with numeracy. I shared all this with other parents, who then proceeded to do nothing. Post my bumetanide experiment in December I am moving to biology. The less interest I get from the professionals the further I will go myself. I concluded that the only people you get anywhere with are those with a scientific background and a child with autism. I am very happy to share my ideas with you and your followers. Your blog is great. I am not sure where/how to post a large document.

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    4. Thanks Peter. I would perhaps encourage you start a blog on something like Google Blogger. Take it from me, it is easy to set up, free and is a great way to air opinions and views.

      Maybe this document can help:

      http://www.wikihow.com/Start-a-Blog-on-Blogger

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    5. Thanks Paul. Now I no longer need to write a book !

      http://www.epiphanyasd.blogspot.com/

      The science part will follow shortly.

      My elder son will be impressed that his Dad now knows how to blog !

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    6. Very good luck to you Peter.

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