Yet more bumetanide and autism findings

Bumetanide, a loop diuretic medicine typically used to treat heart failure, is probably not something that most people would associate with 'attenuating' some of the presented characteristics of autism. This Na-K-Cl cotransporter (NKCC) blocking drug (influencing chloride concentrations in neurons and impacting on the actions of gamma-Aminobutyric acid, GABA) has however made quite a few appearances in the peer-reviewed autism research literature (see here and see here) and beyond (see here). The results of a further "multicenter phase 2B study primarily to assess dose/response and safety effects of bumetanide" in relation to autism [1] (open-access) add to the research in this area.

The names on this recent paper are familiar ones to the bumetanide-autism story as 'dose' and 'adverse effects' were the primary factors in this most recent gold-standard "double-blind, randomized, placebo-controlled, multisite dose-ranging study." Looking at some 88 participants diagnosed with an autism spectrum disorder (ASD) and "spanning across the entire pediatric population (2–18 years old)" various doses of [liquid] bumetanide or a placebo were given over 3 months. Assessments were carried out using various schedules including the Childhood Autism Rating Scale (CARS). As per the 'phase 2B' status of this research, the name of the game was optimising effective dosage of bumetanide against safety (side-effects) including gathering data on pharmacokinetics.

Results: "our results showed that bumetanide is safe but is associated with adverse events related to diuresis and dehydration." It's perhaps not surprising that a medicine classed as a loop diuretic does what it says on the tin. Authors describe various adverse effects - treatment emergent adverse events (TEAEs) - associated with bumetanide use: "The most frequent adverse events were hypokalemia, increased urine elimination, loss of appetite, dehydration and asthenia." Several participants withdrew from the study as a result of them.

Further: "The results of this dose-ranging study demonstrated the highest efficacy of bumetanide 2 mg twice a day on both primary and secondary end points." Various improvements were noted in the CARS and other scores as a consequence of the use of bumetanide (at various dosages): "23 bumetanide-treated and only one placebo showed more than six-point reduction in CARS from screening to day 90."  Marrying the safety (TEAEs) and effectiveness data (CARS et al) together, the authors concluded that: "bumetanide improves the core symptoms of ASD and presents a favorable benefit/risk ratio particularly at 1.0 mg twice daily."

I know for some any adverse effects from a 'treatment' option with autism in mind is going to be too much. I respect this view particularly in light of the medical tenet: first do no harm. But I don't think these latest results from Lemonnier and colleagues can just be ignored in terms of the potential hows-and-whys of response to bumetanide in relation to the presentation of autistic behaviours. Many (all) medications 'indicated' for the management of core or peripheral features associated with a diagnosis of autism have a risk profile attached to them (see here for example) but are still often quite widely used. This is not an excuse, just a statement of fact until someone, somewhere develops side-effect free versions of medicines in use. There is also another angle to this 'risk' profile to consider: "There was no simple relation between TEAEs and efficacy." What this tells us is that those 'best' responders to bumetanide were not necessarily the same participants who experienced adverse effects from the [active] medication; for example: "none of the moderate hypokalemic patients (<3 mm l−1) were high responder patients with at least 6 points in CARS change from screening to day 90." Sweeping generalisations are not required.

Where next for bumetanide?  Well, I don't doubt we will be hearing more from this group as they report: "this trial must be viewed as a source of data on the safety and dose-ranging usage of bumetanide and it provides further support to justify a large multisite European Phase III trial." Large, multi-centre trials are both expensive and take a considerable amount of planning so I'm not expecting to see anything too soon. But I don't think we've heard the last of bumetanide and autism...

----------

[1] Lemonnier E. et al. Effects of bumetanide on neurobehavioral function in children and adolescents with autism spectrum disorders. Translational Psychiatry. 2017; 7: e1056.

----------

Lemonnier, E., Villeneuve, N., Sonie, S., Serret, S., Rosier, A., Roue, M., Brosset, P., Viellard, M., Bernoux, D., Rondeau, S., Thummler, S., Ravel, D., & Ben-Ari, Y. (2017). Effects of bumetanide on neurobehavioral function in children and adolescents with autism spectrum disorders Translational Psychiatry, 7 (3) DOI: 10.1038/tp.2017.10

Bumetanide for schizophrenia? A case report

Bumetanide - a medicine known as a diuretic - has appeared before on this blog (see here for example) in relation to some preliminary suggestions that at least some types of autism might be sensitive to intervention using this particular compound [1]. The names Lemonnier (Eric) & Ben-Ari (Yehezkel) are a big part of the research group interested in bumetanide and its use outside of more traditional indications; particularly, the focus on its action on NKCC1 onwards to an effect on GABA.

Whilst there is still interest in the use of bumetanide for 'some' autism [2], today I'd like to briefly bring your attention to an interesting report on the use of this pharmaceutic in an adolescent diagnosed with schizophrenia [3]. The case report by Lemonnier et al details how following the use of bumetanide, there was a corresponding effect on some of the positive symptoms of schizophrenia; in particular: "Long-term treatment reduced hallucinations significantly." The authors conclude that "Further clinical trials and experimental studies are warranted."

Although still early days, I find this to be interesting research if not the first time that NKCC1 has been mentioned with schizophrenia in mind. When one looks at the range of 'effects' potentially linked to the NKCC1 inhibitors such as bumetanide [4] one gets a flavour for what might be potentially linked. As Jaggi et al suggest: "The inhibitors of NKCC1 are shown to produce anxiolytic effects; attenuate cerebral ischemia-induced neuronal injury; produce antiepileptic effects and attenuate neuropathic pain." I'm particularly drawn to the 'antiepileptic effects' bit in particular, as a function of the quite long-standing association between schizophrenia and epilepsy (see here). I'm not putting my eggs in one scientific basket by saying that, but given what is known about NKCC1 and some 'refractory' epilepsy [5] for example, it sounds as good a place to continue investigations as any...

Music: Me First & The Gimme Gimmes with a classic... Top of the World.

----------

[1] Lemonnier E. et al. A randomised controlled trial of bumetanide in the treatment of autism in children. Transl Psychiatry. 2012 Dec 11;2:e202.

[2] Grandgeorge M. et al. The effect of bumetanide treatment on the sensory behaviours of a young girl with Asperger syndrome. BMJ Case Rep. 2014 Jan 31;2014. pii: bcr2013202092.

[3] Lemonnier E. et al. Treating Schizophrenia With the Diuretic Bumetanide: A Case Report. Clin Neuropharmacol. 2016 Mar-Apr;39(2):115-117.

[4] Jaggi AS. et al. Expanding Spectrum of Sodium Potassium Chloride Co-transporters in the Pathophysiology of Diseases. Curr Neuropharmacol. 2015;13(3):369-88.

[5] Sen A. et al. Increased NKCC1 expression in refractory human epilepsy. Epilepsy Research. 2007; 74: 220-227.

----------

Lemonnier E, Lazartigues A, & Ben-Ari Y (2016). Treating Schizophrenia With the Diuretic Bumetanide: A Case Report. Clinical neuropharmacology, 39 (2), 115-117 PMID: 26966887

More bumetanide and autism discussion

For those with their ear to the autism research ground, the paper by Roman Tyzio and colleagues [1] must have sounded like a freight train coming given the volume of headlines that have been generated from this research (see here for example). Circling around the neurotransmitter, GABA (as in GABA dabba doo!), their findings based on two mouse models of autism, or rather autism and Fragile X syndrome - including the very interesting prenatal valproate (VPA) exposure model - suggested "hippocampal neurons in these models have elevated intracellular chloride levels, increased excitatory GABA, enhanced glutamatergic activity, and elevated gamma oscillations".

If that all that sounds like a different language to you, it basically boiled down to GABA doing the opposite of what it is normally supposed to do i.e. primarily act as an inhibitory neurotransmitter, potentially as a result of issues with chloride levels. The fact that the 'cuddle me' hormone, oxytocin is also a suggested trigger to facilitate that excitatory-to-inhibitory transition for GABA [2] in the early days adds to the intrigue. On it's own, this finding would probably have not generated as many media headlines as it did. But when combined with the suggestion that supplementation to mother rats with the diuretic drug bumetanide just before giving birth might help make that transition for GABA to fulfil it's inhibitory destiny ("it is your destiny") in offspring the research starts to take on a slightly different perspective. The Nature news write-up of the paper provides some additional reading on this issue (see here).

I've talked about bumetanide before on this blog (see here) as a consequence of the previous Lemonnier trial [3] which itself generated a fair few headlines at the time of publication. Since then, I've noted the odd mention on the drug in connection to the autism spectrum as per the case report from Grandgeorge and colleagues [4] and another paper from Lemonnier and colleagues [5] with a case of Fragile X syndrome in mind. The Grandgeorge results in particular, are worthy of inspection not least because of the focus on sensory issues and the link I make back to the very intense, intense world theory of autism [6] which has its roots in the VPA rodent model similar to the one used to test bumetanide in the Tyzio paper. I know we should be cautious of sweeping generalised models when it comes to autism (as per some chatter about the model) but lets not throw baby and bathwater out just yet. The scientific puritans out there might also be shaking their heads at the thought of case reports being mentioned here, but just remember the old adage about meeting one person with autism and all that.

There is obviously a degree of step-back caution to take from the Tyzio results insofar as rats being rats not humans. I believe the accompanying editorial from Zimmerman & Connors also raises a few potential issues which need to be resolved; not least how one ascertains who [humans] might be at risk for this process occurring and therefore when bumetanide might be indicated. Bear in mind too, that there are growing moves to look at reducing things like prenatal valproate exposure on the back of some regulatory statements recently being made (see here).

But I have to conclude that I do find the recent Tyzio report and the previous Lemonnier trial very interesting and look forward to seeing more research on this topic including safety studies, long-term follow-up and perhaps more data on who might be more likely to benefit from this research.

----------

[1] Tyzio R. et al. Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring. Science. 2014 Feb 7;343(6171):675-9.

[2] Tyzio R. et al. Maternal oxytocin triggers a transient inhibitory switch in GABA signaling in the fetal brain during delivery. Science. 2006 Dec 15;314(5806):1788-92.

[3] Lemonnier E. et al. A randomised controlled trial of bumetanide in the treatment of autism in children. Transl Psychiatry. 2012 Dec 11;2:e202. doi: 10.1038/tp.2012.124.

[4] Grandgeorge M. et al. The effect of bumetanide treatment on the sensory behaviours of a young girl with Asperger syndrome. BMJ Case Rep. 2014 Jan 31;2014.

[5] Lemonnier E. et al. Treating Fragile X syndrome with the diuretic bumetanide: a case report. Acta Paediatr. 2013 Jun;102(6):e288-90. doi: 10.1111/apa.12235.

[6] Markram H. et al. The intense world syndrome--an alternative hypothesis for autism. Front Neurosci. 2007 Oct 15;1(1):77-96.

-----------

Tyzio R, Nardou R, Ferrari DC, Tsintsadze T, Shahrokhi A, Eftekhari S, Khalilov I, Tsintsadze V, Brouchoud C, Chazal G, Lemonnier E, Lozovaya N, Burnashev N, & Ben-Ari Y (2014). Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring. Science (New York, N.Y.), 343 (6171), 675-9 PMID: 24503856

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].

----------

* 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.

----------

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