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Tuesday, 20 January 2015

Treatment of Autism with low-dose Phenytoin, yet another AED

I do like coincidences and I do like not struggling to find a picture for my posts. 

Phenytoin (Dilantin) is a drug that appeared in the novel and film, One Flew Over the Cuckoo's Nest, but then it was not used in low-doses.

Today’s post follows from a comment I received about using very low doses of anti-epileptic drugs (AEDs) in autism.

First of all a quick recap.

Clonazepam was discovered by Professor Catterall, over in Seattle, to have the effect of modifying the action of the neurotransmitter GABA to make it inhibitory, at tiny doses that would be considered to be sub-clinical (i.e. ineffective).

Valproate, another AED, was discovered by one of this blog’s readers also to have an “anti-autism” effect in tiny doses of 1 mg/kg.

A psychiatrist from Australia, Dr Bird, specialized in adults with ADHD has just published a paper about the benefit of low-dose phenytoin in adult autism.  The same psychiatrist has also earlier encountered the effect of low dose valproate in ADHD (autism lite).


Significantly, this beneficial effect of sodium valproate appeared to have a narrow therapeutic window, with the optimal range between 50 and 200mg daily. A complete loss of efficacy frequently occurred above a dose of 400mg.

Case presentation

My patient was a 19-year-old man diagnosed in early childhood with ADHD and ASD

a sublingual test dose of approximately 2mg phenytoin was administered

Within 10 minutes of taking the sublingual phenytoin he reported a reduction in the effort required to contribute to conversation and was able to sustain eye contact both when listening and speaking. He was surprised about the effortless nature of his eye gaze and also commented that he had never done this before.

The following day he started taking compounded 2mg phenytoin capsules in the morning in conjunction with his methylphenidate.

After two weeks both he and his mother stated that his communication with the family had improved and there had been no aggressive outbursts.

Over the next four weeks he became inconsistent in taking the phenytoin, and then ceased altogether. His behavior reverted to the previous pattern of poor social interaction; he became oppositional with outbursts of anger and physical violence.

Nine months later he resumed taking the phenytoin, this time as a single 4mg capsule in the morning. After his first dose there was an improvement of his social behavior similar to his previous response, although there was an apparent deterioration in the late afternoon. The dose was increased from 4mg to 5mg and a larger capsule formulated to try and prolong the release of the phenytoin. This appeared to achieve a more consistent improvement in behavior throughout the day, evident both at home and at work. Increases in the dose above 5mg were not associated with any additional benefit. He remained on the 5mg dose of phenytoin for over 18 months and reported that his work performance had consistently improved sufficient to increase his working hours and his level of responsibility. The violence and destruction at home abated. His confidence improved and for the first time he has established and sustained peer-appropriate friendships.

I hypothesize that, in a similar mechanism to the low-dose clonazepam in this animal model of autism, low-dose phenytoin may enhance GABA neurotransmission, thereby correcting the imbalance between the GABAergic and glutaminergic systems.


Phenytoin

Now let us look at Phenytoin and see if we agree with Dr Bird's hypothesis that the mechanism is the same as low dose clonazepam. 

The accepted method of action is that working as a voltage gate sodium channel blocker.  GABA is not mentioned.


Phenytoin, by acting on the intracellular part of the voltage-dependent sodium channels, decreases the sodium influx into neurons and thus decreases excitability.

The antiepileptic activity of phenytoin was found during systematic research in animals: it suppresses the tonic phase but not the clonic phase elicited by an electric discharge and is not very active against the attacks caused by pentylenetetrazol.

Phenytoin was the first non-sedative antiepileptic to be used in therapeutics.
It decreases the intensity of facial neuralgia and has an antiarrhythmic effect.

 But as I dug a little deeper, I found from 1995:-



 Abstract
We report here that carbamazepine and phenytoin, two widely used antiepileptic drugs, potentiate gamma-aminobutyric acid (GABA)-induced Cl- currents in human embryonic kidney cells transiently expressing the alpha 1 beta 2 gamma 2 subtype of the GABAA receptor and in cultured rat cortical neurons. In cortical neuron recordings, the current induced by 1 microM GABA was enhanced by carbamazepine and phenytoin with EC50 values of 24.5 nM and 19.6 nM and maximal potentiations of 45.6% and 90%, respectively. The potentiation by these compounds was dependent upon the concentration of GABA, suggesting an allosteric modulation of the receptor, but was not antagonized by the benzodiazepine (omega) modulatory site antagonist flumazenil. Carbamazepine and phenytoin did not modify GABA-induced currents in human embryonic kidney cells transiently expressing binary alpha 1 beta 2 recombinant GABAA receptors. The alpha 1 beta 2 recombinant is known to possess functional barbiturate, steroid, and picrotoxin sites, indicating that these sites are not involved in the modulatory effects of carbamazepine and phenytoin. When tested in cells containing recombinant alpha 1 beta 2 gamma 2, alpha 3 beta 2 gamma 2, or alpha 5 beta 2 gamma 2 GABAA receptors, carbamazepine and phenytoin potentiated the GABA-induced current only in those cells expressing the alpha 1 beta 2 gamma 2 receptor subtype. This indicates that the nature of the alpha subunit isoform plays a critical role in determining the carbamazepine/phenytoin pharmacophore. Our results therefore illustrate the existence of one or more new allosteric regulatory sites for carbamazepine and phenytoin on the GABAA receptor. These sites could be implicated in the known anticonvulsant properties of these drugs and thus may offer new targets in the search for novel antiepileptic drugs.



So not only is it possible that phenytoin can modulate the behaviour of the GABAA receptor like Dr Catterall did with Clonazepam, but carbamazepine is yet another known AED with this effect.

So I expect someone will also go and patent low-dose carbamazepine for autism.


We potentially now have a wide range of low dose AEDs for autism.


·        Valproate (1000 to 2000 mg for adults as AED) at a dose of 1-2 mg/kg

·        Clonazepam (up to 20 mg for adults as an AED)   at a dose of 1.7mcg/kg

·        Phenytoin (up to 600 mg for adults as an AED) at a dose of 0.05 mg/kg

·        Carbamazepine (up to 1,200 mg for adults as an AED) no data for the low dose!

We also have two other drugs that are used as AEDs in high doses and have been used in autism with much lower doses.  I do not have any evidence to show that they affect GABAA receptors.  I think their method of action is unrelated to GABA, or sodium channels.
  
·        Piracetam (up to 24 g as an AED) at a dose of 400 to 800 mg

·        Vinpocetine (up to 45mg for adults as an AED)  at a dose of 1 to 5 mg


Both Piracetam and Vinpocetine are classed as drugs in Europe and supplements in the US.  Both are also used as cognitive enhancers. Both have numerous possible modes of action.  They may not help with behavioral problems, but may well improve cognition.

Interestingly, a clinical trial is underway to look at the cognitive effect of moderate doses of Vinpocetine in epilepsy.







4 comments:

  1. http://www.sunshinecoastdaily.com.au/news/crackdowntoo-late-for-twins-slow-action-way-too-la/1960148/

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    Replies
    1. This news report is perhaps not a surprise.

      What Dr Bird has found regarding low doses of drugs affecting GABAa receptors is real. I was surprised that such off-label prescribing existed in Australia, it is usual only in the US. In the US the best known case is Jay A. Goldstein, who in the end had to surrender his license. He published many papers and books regarding treating brain dysfunctions, some of what he says is true, but often people do not know where to draw the line.

      There is of course a big safety difference between experimental tiny doses and experimental huge doses.

      The net effect though will reinforce the doctor's view that for hard to treat disorders like autism, the best treatment is no treatment.

      Delete
  2. Thanks for your reply.

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  3. I am very interested in this case study on the effect of phenytoin. It is one of the very few drugs or supplements I have read about that might improve social engagement (the only other one being oxytocin). Indeed, the drugs in your polypill appear to target other autistic behaviors such as stereotypy or SIB rather than social interaction. If there are any others you have uncovered in your research, I would really appreciate a direction in finding a treatment for my child, whose social difficulties outside our family are eroding her quality of life. Thank you!

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