One day last
week Monty, aged 12 with ASD, was watching an old Tom and Jerry DVD. These DVDs, along with the other action-packed
ones, once got hidden away because they drove Monty wild; now they do not.
This is what I was doing while Tom was chasing Jerry.
I received
another interesting comment from a reader who found a small dose of an
antidepressant had a very positive effect on his 9 year old daughter:-
“My
daughter (9, ASD) recently started on a very small dose of Remeron, in an
effort to increase weight and as a bonus, hopefully improve sleep. It has done
both. It also had an immediate unexpected but delightful side effect of
improved social skills, more fluent speech and increased amount of
conversation. The first day she tried it she made friends with random children
in the park, and they had a discussion about how they would design their dream
playground. (DD said she would invent and upside down slide, where you start at
the bottom and slide up.) It has been amazing for her (so far.)
”
In most
families it is the parents who take the antidepressants.
I recalled
that one class of antidepressant was actually developed from an old
antihistamine drug, tricyclic antidepressants.
Remeron,
otherwise known as Mirtazapine, is indeed a tricyclic antidepressant.
Not only is
Remeron, in effect, a first generation antihistamine, i.e. one that was not
designed to stay outside the blood brain barrier, but it is a rather potent
one.
Within the
brain Remeron/Mirtazapine:-
H₁R occupancy (H₁RO) of mirtazapine reached 80-90 % in
the cerebral neocortex
Histamine H₁ receptor occupancy by the new-generation antidepressants fluvoxamine and mirtazapine: a positron emission tomography study in healthy volunteers.
This means
that 80-90% of the type 1 histamine receptors in that part of the brain are
blocked from action.
Histamine Receptors and the Blood
Brain Barrier
There were
several earlier posts in this blog regarding histamine.
There are
four known types of histamine receptors H1, H2, H3 and H4.
In one way
or the other, all four are likely relevant to autism. Drugs are not yet available for H4. H3 therapies are likely to improve cognitive
function in some. H4 appears to play a role in the overexpression of mast cells
in allergic tissues. So those with
severe mast cell issues should watch the H4 drug pipeline.
Histamine H4 Receptor Mediates Chemotaxis and Calcium Mobilization of Mast Cells
An important
point to remember is that while histamine does
not cross the Blood Brain Barrier (BBB), H1 antihistamines do cross, including the ones
designed not to cross.
All antihistamines cross blood-brain barrier
Within the
brain, histamine functions as a neurotransmitter, but it is not the same
histamine as that released by mast cells in your nose, when you have hay
fever. Histamine is also produced inside the
brain.
H3 receptors
in the brain modulate the release of histamine.
Histamine
release in the brain triggers secondary release of excitatory neurotransmitters
such as glutamate and acetylcholine via stimulation of H1 receptors in the cerebral
cortex. Consequently, unlike the H1 antagonist antihistamines which are sedating, H3 antagonists have stimulant and nootropic effects, and are being researched as potential drugs for
the treatment of neurodegenerative conditions such as Alzheimer's
disease and also for ADHD.
H1 agonists
should increase appetite and H3 agonists should reduce appetite. So one day do not be surprised to read about
wonder H3 slimming pills.
Outside the
brain (CNS) all four types of receptor are found and have specific functions.
H1 receptors
modulate circadian
rhythm (sleep) as well as all those allergy and asthma symptoms.
H2 receptors modulate sinus rhythm (in your
heart), stimulate gastric acid secretion, inhibit antibody synthesis, T-cell proliferation and cytokine production.
So histamine dysfunction would
contribute to many conditions that are known to be comorbid with autism:-
·
Obesity
and also low appetite (both extremes)
·
Poor
sleep
·
GERD/GORD/reflux
·
Cognitive
impairment
·
Allergy
·
Mood
disorders
As usual
things are complicated, because the histamine receptors are slightly different
in each part of the brain so your histamine antagonist/blocker “sticks” better
on some than on others. So one H1
antihistamine will be more sedating, or more appetite-increasing than another
one.
H1 antihistamines in Autism
Most
attention in this blog has been directed to the effect of H1 antihistamines
outside the brain/CNS. To a greater or
lesser extent, all H1 antihistamines are also mast cell stabilizers. They reduce the release of histamine itself, as well as blocking H1 receptors (and so relieving allergy symptoms).
Blocking the
release of histamine outside the BBB stops the release of inflammatory
cytokines like IL-6, which can, directly or indirectly, cross the blood brain
barrier.
However many
people report that common H1 antihistamines seem to improve autistic behavior, irrespective of any allergy being present. My assumption is that this may be the case with nine year old girl, certainly worth investigating.
Either there
is a mild allergy that has gone unnoticed, or this must be the effect of
blocking H1 receptors within the brain/CNS.
H3 antihistamines in Autism
I think it quite
likely that some people with autism and schizophrenia would experience
cognitive improvement from H3 antagonists.
It is
perhaps odd that nobody has investigated the cognitive effects of Betahistine.
Betahistine has a very strong affinity as
an antagonist for histamine H3 receptors and a weak affinity as an agonist for histamine H1 receptors.
The
disadvantage is that betahistine increases histamine levels outside the BBB, so
not good for someone with asthma.
There is data on the effect of Betahistine on weight gain in schizophrenia:-
Reducing antipsychotic-induced weight gain in schizophrenia: a double-blind placebo-controlled study of reboxetine-betahistine combination.
It was safe, well tolerated and did reduce weight gain. I would have liked to know the effect on cognitive function.
Conclusion
There may be
too much histamine being released, or its degradation might be impaired (DAO,
SAMe, & HMT are all implicated in autism/schizophrenia), or there may be
over/under expression of histamine receptors in certain places.
For example
in schizophrenia, metabolites of histamine are increased in the cerebrospinal
fluid of people, while the efficiency of H1 receptor binding sites is decreased.
The role of the central histaminergic system on schizophrenia.
It would not
be surprising if people with autism and histamine/mast cell related issues
outside the brain, also have central (in the brain) histamine dysfunctions.
There are
only 24,000 genes found in humans (there are 700+ autism genes). As a result these genes have to be reused
many times all over the body. Any
dysfunction may be reappear in surprising parts of the body. Add to this the way the body is controlled by
feedback loops and you can see a how very many things are inter-related.
This also explains why very clever ideas can work in vitro (in the lab) but completely fail when applied to humans. "Stumbled upon", which must really annoy some clever scientists, is a very valid discovery method and can still earn you top marks.
This also explains why very clever ideas can work in vitro (in the lab) but completely fail when applied to humans. "Stumbled upon", which must really annoy some clever scientists, is a very valid discovery method and can still earn you top marks.
This also
means that many potential therapies can have unintended side effects. Like the
H3 antagonist Betahistine, which can cause gastric acid problems and
itching. Betahistine acting in the brain
might be good for cognition, but might not be without drawbacks elsewhere in
the body.
Coming back to Tom and Jerry and
where this post started
As usual Jerry got the better of Tom.
Since
continued used of Remeron might lead to obesity, it would be interesting to see
if the autism benefits were maintained by using a more conventional H1
antihistamine. The older ones should
better cross the BBB, but will be more sedative.
The people currently
using conventional H1 antihistamines to treat their n=1 case of autism, might
want to compare the effect of the very small dose of Remeron.
The people
using second generation conventional H1 antihistamines (Zyrtec, Claritin etc) to
treat their n=1 case of autism might want to compare the effect of the old
fashioned versions that, like Remeron, have high much higher H₁R occupancy in the brain.
For those
still hungry (too much histamine) for more:-