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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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