Bromide for Autism? Plus ça change, plus c'est la même chose!

 

Hôtel de Ville (City Hall) Tours, France, Gateway to the Loire Valley and Home to iBrain

Source: https://commons.wikimedia.org/wiki/user:Tango7174

 

We do seem to be going round in circles in this blog.  One doctor reader contacted me recently to tell me about Pentoxifylline for cognitive improvement. I told him that I am not surprised and that in the world of autism Pentoxifylline has been known to be beneficial for half a century. 

The abstract below is from a Japanese paper in 1978

 

On our experience in using pentoxifylline for abnormal behavior and the autistic syndrome

Abstract

Describes the successful use of pentoxifylline (150–600 mg/day) with 3–15 yr old children with abnormal behavior (e.g., self-mutilation, aggressiveness, and hyperkinesis) and with autism. It is noted that while the drug was effective in reducing symptoms of autism, developmental factors in the disorder should not be ignored.

 

You might wonder why it has not been widely adopted, at least for some people with autism. 

When it comes to Potassium Bromide (KBr) I found a case history from 150 years ago of its successful use in a little girl with epilepsy, autism and impaired cognition. She was treated at what is today London’s top children’s hospital, Great Ormond Street.

KBr was the original treatment for epilepsy.  It is still used in countries following German medicine; indeed, it is can be the only effective treatment for those with Dravet Syndrome.

Interestingly, Great Ormond Street Hospital has restarted the use of KBr in childhood epilepsy, specially importing its drugs from Germany.

 

Bromide for epilepsy – Great Ormond Street Hospital

            https://www.gosh.nhs.uk/conditions-and-treatments/medicines-information/bromide-epilepsy/

 

In the US, KBr is only used for canine and equine epilepsy.  It does not work well on cats, incidentally.

Back in 2016, I did propose KBr as an add-on therapy for those with autism who respond to bumetanide.  This was part of my effort to develop a “super bumetanide”, to increase the bumetanide effect.

 

In a quote from today’s feature paper, from iBrain at the University of Tours, France:- 

“beneficial effects (of bromide) were superior to those of chronic bumetanide administration” 

in one mouse model of autism. 

When I was asked to give a presentation in the US on bumetanide for autism, there was one condition, “please don’t mention potassium bromide … we don’t want people trying it.”

Yes, it’s OK to talk about treating autism, but please don’t actually do it.

Move forward a few years and a doctor friend recently highlighted to me a new paper from France proposing Sodium Bromide for autism.

I did rather think here we go again, been there done that.

My conclusion back in 2016 was that yes it does provide a benefit; but it does have some drawbacks.  It has a very long half-life, meaning if you keep taking the same daily amount, it will take 5 weeks to reach its peak level in your bloodstream.

It does increase mucous secretions, in a dose dependent fashion.  This is not a problem in canine epilepsy, but in humans it will lead to spots (bromo-acne).  It could make asthma worse.

In the case of children with Dravet Syndrome, they have a high rate of death from epilepsy, or SUDEP (Sudden unexpected death in epilepsy).  So, I don’t suppose parents are going to worry about a few spots.

 

Potassium bromide in clinical trials for Dravet Syndrome

Potassium bromide has not been tested in randomized clinical trials specifically for Dravet syndrome patients. Some small studies suggest, however, that it might benefit Dravet syndrome patients.

A retrospective study analyzed data from 32 Dravet syndrome patients carrying an SCN1A mutation. Six patients received potassium bromide temporarily as monotherapy, while 26 patients received the medication as add-on therapy. The mean treatment duration was 47 months with a mean maximum daily oral dose of 63.2 mg per kilogram (kg) body weight of potassium bromide.

Three months after treatment began, 31 % of the patients experienced complete seizure control. Seizures were reduced by more than 75% in 6% of the patients, and by more than 50% in 19% of them.

 

My old post from 2016:

 

Potassium Bromide for Intractable Epilepsy and perhaps some Autism

My idea was to see if you can get a meaningful benefit from a low dose and avoid any side effects. Rather than the 63.2 mg/kg for Dravet Syndrome seizures, I thought a reasonable dose was 8 mg/kg to further treat the E/I imbalance in Bumetanide responsive autism.  Why 8mg/kg? Well, that was half a tablet. 

 

Sodium Bromide for Autism, proposed by the French researchers

 

Chronic sodium bromide treatment relieves autistic-like behavioral deficits in three mouse models of autism

 

Autism Spectrum Disorders (ASD) are neurodevelopmental disorders whose diagnosis relies on deficient social interaction and communication together with repetitive behavior. To date, no pharmacological treatment has been approved that ameliorates social behavior in patients with ASD. Based on the excitation/inhibition imbalance theory of autism, we hypothesized that bromide ions, long used as an antiepileptic medication, could relieve core symptoms of ASD. We evaluated the effects of chronic sodium bromide (NaBr) administration on autistic-like symptoms in three genetic mouse models of autism: Oprm1−/−, Fmr1−/− and Shank3Δex13-16−/− mice. We showed that chronic NaBr treatment relieved autistic-like behaviors in these three models. In Oprm1−/− mice, these beneficial effects were superior to those of chronic bumetanide administration. At transcriptional level, chronic NaBr in Oprm1 null mice was associated with increased expression of genes coding for chloride ions transporters, GABAA receptor subunits, oxytocin and mGlu4 receptor. Lastly, we uncovered synergistic alleviating effects of chronic NaBr and a positive allosteric modulator (PAM) of mGlu4 receptor on autistic-like behavior in Oprm1−/− mice. We evidenced in heterologous cells that bromide ions behave as PAMs of mGlu4, providing a molecular mechanism for such synergy. Our data reveal the therapeutic potential of bromide ions, alone or in combination with a PAM of mGlu4 receptor, for the treatment of ASDs.

 

Compromised E/I balance in ASD may result from several neuropathological mechanisms. On the excitation side, glutamatergic transmission was found altered both in patients and animal models, although in different directions depending on genetic mutations/ models [9, 18, 19]. On the inhibition side, decreased levels of GABA [20] and expression of GABAA and GABAB receptors (postmortem analyses, [21, 22]), as well as genetic polymorphisms in GABAA receptor subunits [23, 24], have been detected in patients with autism. Accordingly, decreased GABAergic neurotransmission has been reported in several ASD models [25–29]. Alternatively, it was proposed that GABA neurons remain immature in ASD, maintaining high intracellular concentrations of chloride ion (Cl−) whose efflux through activated GABAA receptor induced neuronal depolarization [30]. Intracellular Cl− concentration is under the control of the main Cl− importer NKCC1 (Na+-K+-2Cl− cotransporter) and its main exporter KCC2. Therefore blocking NKCC1 using the loop diuretic and antiepileptic drug [31, 32] bumetanide appeared a promising therapeutic approach in ASD. Accordingly, bumetanide improved autistic-like phenotype in rodent models of ASD [33] and relieved autistic behavior in small cohorts of patients [34, 35].

 

Bromide ion (Br−) was the first effective treatment identified for epilepsy [36] and long used as anxiolytic and hypnotic [37]. With the advent of novel antiepileptic and anxiolytic drugs, its use was progressively dropped down, although it remains a valuable tool to treat refractory seizures [38, 39]. At molecular level, Br− shares similar chemical and physical properties with Cl−, allowing it substituting Cl− in multiple cellular mechanisms. These include anion influx through activated GABAA receptor, with higher permeability to Br− compared to Cl− resulting in neuronal hyperpolarization [40], and transport through the NKCC and KCC cotransporters [41, 42]. In view of the E/I imbalance theory, these properties point to Br− as an interesting candidate for ASD treatment.

 

Here we assessed the effects of chronic sodium bromide administration on core autistic-like symptoms: social deficit and stereotypies, and a frequent comorbid symptom: anxiety, in three genetic mouse models of autism with different etiologies: Oprm1−/−, Fmr1−/− (preclinical model of Fragile X syndrome) and Shank3Δex13-16−/− mice, lacking the gene coding the mu opioid receptor or the FMRP protein for the formers, or the exons 13−16 of the Shank3 gene, coding for the PDZ domain of the SHANK3 protein, for the later. Altered E/I balance and/or modified expression of involved genes have been reported for these three models [28, 43–47]; the Oprm1 knockout model presents the advantage of limited impact on learning performance [44]. We evidenced that Br− treatment alleviates behavioral deficits in these three models and increases expression of various genes within the social brain circuit of Oprm1 null mice. We unraveled that Br− not only increases mGlu4 receptor gene expression but also potentiates the effects of the positive allosteric modulator (PAM) of mGlu4 VU0155041, in Oprm1−/− mice and in hetero[1]logous cells. Our data reveal the therapeutic potential of Br− administration and its combination with a PAM of mGlu4 receptor for the treatment of ASD. 

 

RESULTS

Chronic sodium bromide relieved autistic-like symptoms in Oprm1−/− mice more efficiently than bumetanide

Chronic sodium bromide relieved social behavior deficits, stereotypies and excessive anxiety in Fmr1−/− and Shank3Δex13-16−/− mice

Chronic sodium bromide modulates transcription in the reward circuit of Oprm1−/− mice

Synergistic effects of chronic bromide and mGlu4 receptor facilitation in Oprm1 null mice

Bromide ions behave as positive allosteric modulators of the mGlu4 glutamate receptor

 

In conclusion, the present study reports the therapeutic potential of chronic bromide treatment, alone or in combination with a PAM of mGlu4 receptor, to relieve core symptoms of ASD. Beneficial effects of bromide were observed in three mouse models of ASD with different genetic causes, supporting high translational value. Moreover, bromide has a long history of medical use, meaning that its pharmacodynamics and toxicity are well known, which, combined with long-lasting effects as well as excellent oral bioavailability and brain penetrance, are strong advantages for repurposing.

 

 

Conclusion

The doctor treating Ida at Great Ormond Street 150 years ago noted that after treatment with KBr she developed age-appropriate play skills.  That is very much the same effect as bumetanide in a young child with severe autism and IQ<70.

My trials of 400mg of KBr produced a “bumetanide+” effect and feedback from other bumetanide super-responders was in line with this. Higher doses than mine were used.

The effects of KBr overlap with those of Bumetanide, but it is possible that there may be more KBr responders than Bumetanide responders.  KBr has interesting effects beyond those of Bumetanide. It is definitely worth considering KBr, even if the person is not a bumetanide responder.

The French researchers in today’s paper propose that Bromide be repurposed for autism – they definitely have the right idea.  They did note the 8-14 day half-life in humans.

In the advisory from Great Ormond Street it is noted:

“Your child will need to have regular blood tests to monitor the amount of bromide in their blood – this usually happens around four weeks or so after starting to take the medication, or four weeks after the dose is increased.” 

I think the aim should be maximize the benefits of KBr, without incurring the side effects that will occur at high doses.  KBr might be best as an add-on therapy in autism.

The 60mg/kg dose from Dravet Syndrome is 8 times the bumetanide add-on dosage I suggested.

One of the models used in the French trial was that for Fragile X syndrome, the others were the Mu Opioid Receptor Null model and the Shank3B−/−, lacking the PDZ domain.

Fragile X is one of the most common types of human autism and is apparent from facial features. Bromide for human Fragile X ?

In case you are wondering, whether to choose sodium bromide (NaBr) or potassium bromide (KBr), it is the bromide ions (Br-) that are critical to its effect on the E/I imbalance.  Personally, I prefer KBr, because most people have too much sodium and too little potassium in their diet.  People taking bumetanide should be taking extra potassium anyway.

Interestingly, from the UK guidance: -

“Salt and salty foods can reduce how well bromide works. Try to limit the amount of salty foods your child eats and do not add salt to cooked foods if possible.”

One other medical formulation of bromide is called triple bromide and contains three different variations of bromide:  ammonium bromide, potassium bromide and sodium bromide.

Hopefully it will not take 50 years to establish the usefulness (or not) of bromide as an autism therapy.

It was mentioned first in this blog, back in 2016.

In 2017 some French people filed a patent, claiming to be the inventors of bromide as a treatment for autism.

WO2018096184- BROMIDE SOURCE FOR USE IN TREATING AUTISM SPECTRAL DISORDER