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.