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Tuesday, 2 February 2016

Central histamine (dys)function, antidepressants, appetite, autism and behavior

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:-

HR occupancy (HRO) of mirtazapine reached 80-90 % in the cerebral neocortex


Histamine H 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 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 HR occupancy in the brain.



For those still hungry (too much histamine) for more:-



Histamine H3 receptor antagonists/inverse agonists on cognitive and motor processes: relevance to Alzheimer's disease, ADHD, schizophrenia, and drug abuse


The role of hypothalamic H1receptor antagonism in antipsychotic-induced weight gain.

  

Therapeutic potential of histamine H3 receptor agonist for thetreatment of obesity and diabetes mellitus






5 comments:

  1. Don't forget histamine also binds to the histamine site on NMDA receptors:

    http://www.ncbi.nlm.nih.gov/pubmed/20008958

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    Replies
    1. Thanks Tyler, just to show how complex things are, the study below shows that Histamine also modulates GABAa receptots as well:-


      Histamine Action on Vertebrate GABAA Receptors
      DIRECT CHANNEL GATING AND POTENTIATION OF GABA RESPONSES

      http://www.jbc.org/content/283/16/10470.abstract?ijkey=285851598b460924df37a478528730d0fc8fb716&keytype2=tf_ipsecsha

      "Despite the vast number of synthetic modulators of GABAA receptors widely used in medicine, which act on several distinct sites, only a few endogenous modulators have yet been identified. We show here for the first time that histamine modulates heteromultimeric GABAA receptors and may thus represent an endogenous ligand for an allosteric site."

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    2. Another interesting thing with respect to much of the research concerning the various autisms is that many of the dysregulated systems seem to originate in the hypothalamus, including the histaminergic neurons.

      The opioid system which has been an old area of research with respect to autism, also originates in the hypothalamus as well and I have had success with anxiety and SIBing issues, not to mention improving general mental function lately with a therapy that addresses the opioid system of the hypothalamus.

      Another thing that is very interesting about the hypothalamus is that it is not completely protected by the blood brain barrier so dysregulated systems in the body can have a deleterious effect on hypothalamic function which can cascade to other problems in other regions of the brain if improper signaling is coming from the various nuclei of the hypothalamus.

      Not saying the hypothalamus is the source of autism by any stretch of the means, but it does offer an alternative hypothesis to the source of activation for many symptoms of autism, rather than the conventional "the blood brain barrier is leaky in autism and therefore everything bad gets in". Blood brain barrier permeability seems to have a much wider scope recently than it was thought in the past, so assuming a compromised blood brain barrier is the cause of many autistic symptoms might be masking other problems as the blood brain barrier in healthy individuals may be more permeable than once thought. Nitric oxide increases blood brain barrier permeability, but also increases circulation to the brain. In a very recent Alzheimers study:

      http://www.jneurosci.org/content/35/15/5969.full

      they offer a compelling hypothesis that L-arginine deprivation in the brain causes a lack of nitric oxide production that essentially starves the brain of oxygen and other nutrients. Obviously, too much nitric oxide is not good, but not enough in the brain can cause serious problems as well and so this avenue of inquiry should probably be pursued in autism research as well. Cocoa flavonols improve blood flow to the brain and likely also enhance blood brain barrier permeability as well, albeit indirectly. In addition, histamine of course promotes vasodilation, but what if the histamine H3 autoreceptors are desensitized or damanged somehow, leading to excessive histamanergic activity in the brain that are independent of any mast cell disorder. Eventually over time as the histamine system is overloaded you might have histamine receptor sensitivity issues that could cause too much vasoconstriction in the brain, leading to circulation problems (which are a hallmark of Alzheimer's and have been found in some autism studies as well).

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  2. The links and interactions of (anti)histamines with adrenalin and its receptors is also pertinent and likely fits this picture, as is the potential benefit of propranolol for (some) autism.

    If nothing else good response to one of those meds might indicate that the child or adult would be a responder to these other, related treatments.

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  3. Also to add that it bears keeping in mind that propranolol has potentiating effects on antidepressants (and 5-htp itself) and vice-versa, so if one takes both of these meds the doses should be reduced accordingly to avoid potentially dangerous rise in serotonin levels.

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