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Showing posts with label Oxytocin. Show all posts
Showing posts with label Oxytocin. Show all posts

Friday 25 September 2015

OPN-300 Oxytocin and Autism



This post is about nasal spray drugs and Oxytocin.

Monty, aged 12 with ASD, uses a conventional anti-histamine nasal spray and I do sometimes wonder just how much of the drug reaches its target.  

With inhalers for asthma this is a well known problem and often even adults do not use them correctly; they are proven to work much better when they are fitted with a spacer chamber, that way the drug ends up in your lungs and not stuck to the inside of your mouth.






Many adults with asthma and COPD nowadays use spacers.

So my interest was drawn to a company called Optinose that is developing drugs for nasal delivery using a novel dispenser.  I was particularly surprised that in its small drug pipeline is an oxytocin spray for autism.

If you look on the US National Institute of Health website listing clinical trials of oxytocin and autism, you will find that thirty, yes three zero, studies are listed.


According to their website, Optinose intend to be the first to bring a product to the market approved for autism.











On the clinical trials website you may notice that other trials use an existing drug called Syntocinon that is a synthetic form of Oxytocin already approved for other purposes.






I did mention in an earlier post that the US rights to Syntocinon were sold to a company hoping to develop a therapy for Schizophrenia and Autism.


Retrophin Signs U.S. License Agreement for Syntocinon™ Nasal Spray (Oxytocin)


In Europe Syntocinon is available in most countries as a prescription drug.


The Optinose idea is that their dispenser can much more reliably dispense the correct amount of drug and have it reach the membrane deep inside the nose.  None gets in the mouth and less should get stuck at the entrance to the nose.

Previous trials of Oxytocin have yielded very mixed results.  Perhaps part of this is due to the nature of the spray pump being used?  It is certainly plausible.


The Optinose Spray

The Optinose spray is inserted in one nostril and your mouth.  You blow out through mouth, sealing the nasal cavity in the process, and the spray is forced out into your nose.  This should ensure it goes deep inside to the nasal membrane, where the oxytocin can cross directly into the blood stream.





Click on the link below and then click to play the short video.



As the video points out, this kind of drug delivery can “enable new and improved brain treatments”


They are talking about direct nose-to-brain drug delivery, bypassing the blood brain barrier (BBB).  This is not fantasy and is already quite well studied.

Direct nose to brain drug delivery via integrated nerve pathways bypassing the blood-brain barrier: an excellent platform for brain targeting.

Coming back to Oxytocin ...

Not only is Oxytocin a well-known hormone affecting social behavior, but it also plays a role in switching the neurotransmitter GABA between excitatory and inhibitory.


Oxytocin and GABAA

Oxytocin has a role at birth in the GABA “switch”, but it also has an ongoing role via binding to a particular subunit of GABAA receptors.



We report that the oxytocin-mediated neuroprotective γ-aminobutyric acid (GABA) excitatory-inhibitory shift during delivery is abolished in the valproate and fragile X rodent models of autism. During delivery and subsequently, hippocampal neurons in these models have elevated intracellular chloride levels, increased excitatory GABA, enhanced glutamatergic activity, and elevated gamma oscillations. Maternal pretreatment with bumetanide restored in offspring control electrophysiological and behavioral phenotypes. Conversely, blocking oxytocin signaling in naïve mothers produced offspring having electrophysiological and behavioral autistic-like features. Our results suggest a chronic deficient chloride regulation in these rodent models of autism and stress the importance of oxytocin-mediated GABAergic inhibition during the delivery process. Our data validate the amelioration observed with bumetanide and oxytocin and point to common pathways in a drug-induced and a genetic rodent model of autism.

Further evidence as to the precise effect of Oxytocin on GABA receptors was found by chance.  It was found that having dosed rats with Oxytocin, they did not get drunk when fed alcohol.





Specifically, oxytocin (1 µg i.c.v.) given before ethanol (1.5 g/kg i.p.) attenuated the sedation and ataxia induced by ethanol in the open-field locomotor test, wire-hanging test, and righting-reflex test in male rats.

Vasopressin, which is a nonapeptide with substantial structural similarity to oxytocin, did not alter ethanol effects at δ-GABAARs. This pattern of results confirms the specificity of the interaction between oxytocin and ethanol at δ-GABAARs

The profound and direct interaction observed between oxytocin and ethanol at the behavioral and cellular level may have relevance for the development of novel therapeutics for alcohol intoxication and dependence.



Is Oxytocin a useful Autism Therapy?

Given the large number of trials and the number of people already taking Oxytocin, some people clearly believe in the therapeutic potential of Oxytocin.

What is clear is that there a numerous modes of action for Oxytocin, some of which relate to GABAA receptors.

So why is it taking so very long for these trials to come to any usable conclusion? Well just looking at the long list of researchers, it includes some of those who have spent twenty years "researching" autism and producing absolutely nothing tangible, just papers concluding more research is needed or even producing, supposedly therapeutic, cartoons (Cambridge University).

We have the usual problem that numerous different dysfunctions lie at the root of “autism” and so only a moderate proportion, at best, would be expected to benefit from any therapy.

In the case of nasal sprays we have the question of how much actually gets delivered to the right place deep inside the nose where there is a very thin membrane that allows the Oxytocin to cross over into the blood.


OPN-300 Clinical Trials

The Phase 1 trial for OPN-300 was actually on healthy adults, and looked at things like dosing.  Low doses were more effective than high doses.  Next follows the trial on people with autism.  




Despite the promise of intranasal oxytocin (OT) for modulating social behavior, recent work has provided mixed results. This may relate to suboptimal drug deposition achieved with conventional nasal sprays, inter-individual differences in nasal physiology and a poor understanding of how intranasal OT is delivered to the brain in humans. Delivering OT using a novel ‘Breath Powered’ nasal device previously shown to enhance deposition in intranasal sites targeted for nose-to-brain transport, we evaluated dose-dependent effects on social cognition, compared response with intravenous (IV) administration of OT, and assessed nasal cavity dimensions using acoustic rhinometry. We adopted a randomized, double-blind, double-dummy, crossover design, with 16 healthy male adults completing four single-dose treatments (intranasal 8IU (international units) or 24IU OT, 1IU OT IV and placebo). The primary outcome was social cognition measured by emotional ratings of facial images. Secondary outcomes included the pharmacokinetics of OT, vasopressin and cortisol in blood and the association between nasal cavity dimensions and emotional ratings. Despite the fact that all the treatments produced similar plasma OT increases compared with placebo, there was a main effect of treatment on anger ratings of emotionally ambiguous faces. Pairwise comparisons revealed decreased ratings after 8IU OT in comparison to both placebo and 24IU OT. In addition, there was an inverse relationship between nasal valve dimensions and anger ratings of ambiguous faces after 8-IU OT treatment. These findings provide support for a direct nose-to-brain effect, independent of blood absorption, of low-dose OT delivered from a Breath Powered device.


Importantly, the current findings are the first to suggest that a low dose of OT is more effective than a higher dose in modulating social cognition

Converging biological and behavioral evidence suggests that lower OT doses may be more efficacious than higher doses. For instance, compared with higher doses, lower doses increased peripheral levels of OT in saliva,65 attenuated cortisol stress responses66 and increased eye gaze in patients with Fragile X syndrome.67 In animals, a low dose of OT administered shortly after birth increased partner preference later in life, whereas higher doses did not.68 Similarly, lower doses have been associated with stronger increases in social recognition compared with higher doses.69, 70 The dose–response data reported here provide useful preliminary evidence concerning the optimal dose for social cognition modulation; however, extrapolation from healthy individuals to patients must be with caution. Patients with social-cognitive deficits may respond differently than healthy volunteers, so future studies should explore effects in patient populations to determine the generalizability of these findings to target illnesses. Future work should also further investigate the role of different delivery devices, administration routes, dosages and social cognition tasks on the efficacy of intranasal OT, ideally using larger sample sizes given the limitation of a relatively small sample size in the present study.
In addition, this study provides preliminary evidence that a lower dose (8IU) may offer greater efficacy than a higher dose (24IU) when administered with the Breath Powered device.

There are a number of interpretations regarding why no effect was observed at the 24IU OPN-OT dose, in contrast to the 8IU dose. For example, a higher OT dose is more likely to influence the balance of AVP/OT, as evidenced by the decrease in AVP concentration after 24IU OPN-OT (but not 8IU OPN-OT) observed in the present study, which can modulate social behavior.



OptiNose reports positive results from Phase 1 trial of intranasal oxytocin for autism

Jul 15 2015

OptiNose has announced that a study comparing OPN-300 intranasal oxytocin to intravenous oxytocin for the treatment of autism showed the achievement of similar blood levels but significantly greater social-cognitive effects after intranasal administration. The results were published online July 14, 2015 in Translational Psychiatry.
The randomized, placebo-controlled, double-blind, double-dummy, 4-arm cross-over study involved 16 healthy volunteers who received either intravenous oxytocin or two doses of OPN-300 delivered using OptiNose’s bi-directional breath powered intranasal delivery device. Social-cognitive effects were measured by emotional rating of facial images.
Researcher Ole A. Andreassen of the University of Oslo said, “The OptiNose technology significantly changes the way drug is delivered high up in the nose, and may be the drug delivery solution we’ve been looking for. If we can improve social cognition in healthy people with OPN-300 low-dose oxytocin, then we may be able to address a core symptom suffered by millions of patients worldwide with autism.”
OptiNose Chief Scientific Officer Per Djupesland commented, “Although animal data has been encouraging, many would argue that medication transport from the nasal cavity directly to the brain has not been previously proven in humans. Today’s results are quite promising and bolster our belief that we can enable and enhance the treatment of common brain disorders with OptiNose delivery technology.”
The company says that it is initiating a Phase 2 trial of OPN-300 in autism patients in Norway. OptiNose is also developing intranasal fluticasone for chronic sinusitis and recently reported positive results from a Phase 3 trial of that product.
Read the OptiNose press release.
Read the Translational Psychiatry article.




Conclusion

Some parents already use the Syntocinon version of oxytocin for autism; some tried it in one of the earlier clinical trials and found it did not help.  There is nothing surprising in that. 

The people at OptiNose seem to be a bit more motivated than some of the other oxytocin researchers, in relaxed leafy universities, to actually get to the finishing line.  They are initiating Phase 2 trials of OPN-300 in autism patients in Norway.  Some of the other studies have been going on for several years and are still not finished.

Hopefully we will soon have some data on what percentage of people with “autism” respond to OPN-300 and then we could compare that to the response to Syntocinon.

As we have seen several times before, it seems that smaller doses of oxytocin are more effective than larger doses.  Larger doses seem to change (reduce) vasopressin levels, which will also affect social behavior.

One you start changing the level of one hormone, like oxytocin, you are very likely to affect others.  There are many interrelations and feedback loops.  

Oxytocin may well be part of the solution for some people with autism, but I expect in others it may make them worse.  Hopefully in the later trial(s) they will try and indentify biomarkers for the responder group.








Friday 6 February 2015

Tuning GABAa receptors, plus Oxytocin

Today’s post will hopefully not get too complicated.

As has been mentioned in this blog, and also at leading institutions like MIT, it does seem possible to fine-tune certain receptors in the brain that have become dysfunctional in autism.  In the case of MIT they were “tuning” a receptor called mGluR5, which they suggested was either hypo or hyper, in other words too much or too little, depending on what the underlying disease variant was.


This was done with something called an allosteric modulator, either a positive one called PAM, or a negative one called NAM.

They found that a particular glumate receptor, called mGluR5, was dysfunction in many autism-like conditions.  But the nature of the dysfunction varied, so different people would require different treatments to return the receptor performance back to normal (top dead center).   So it really becomes like tuning your car engine. 
As I have progressed in my review of the literature it becomes clear that numerous receptors are “out of tune”; so a better analogy is tuning something like a piano.

  



"Tuning" the shape (but not number) of dendritic spines also appears not to be as fanciful as it sounds.


Back to GABAA

Regular readers will know that one of the key dysfunctional receptors in autism is called GABAA.




This subject is very complicated.  In effect what appears to have happened in autism is that the neurons have not matured as they should, and so GABAA receptors continue to function in their “normal” immature state.  The concentration of chloride remains high since the NKCC1 transporter continues to exist, whereas KCC2/3 should have developed.  The result is that when the receptor is stimulated, instead of causing an inhibitory/calming effect it causes an excitatory effect.





This is fortunately treatable by inhibiting the flow of chloride into the cells, through NKCC1, using a drug called Bumetanide.

However this is not the end of the story.


At least 11 binding sites on GABAA receptors

As you can learn from Wikipedia:-


The active site of the GABAA receptor is the binding site for GABA and several drugs such as muscimol, gaboxadol, and bicuculline. The protein also contains a number of different allosteric binding sites which modulate the activity of the receptor indirectly. These allosteric sites are the targets of various other drugs, including the benzodiazepines, nonbenzodiazepines, barbiturates, ethanol, neuroactive steroids, inhaled anaesthetics, and picrotoxin, among others.

We are particularly interested in the allosteric binding sites.
The only one that is usually referred to, in any depth, is the site for benzodiazepines, but there are at least 11 different binding sites.

Abstract
gamma-Aminobutyric acid (GABA)a receptors for the inhibitory neurotransmitter GABA are likely to be found on most, if not all, neurons in the brain and spinal cord. They appear to be the most complicated of the superfamily of ligand-gated ion channels in terms of the large number of receptor subtypes and also the variety of ligands that interact with specific sites on the receptors. There appear to be at least 11 distinct sites on GABAA receptors for these ligands.




These sites include:-

·        GABA Binding Site
·        Benzodiazepine Binding Site
·        Neurosteroid Binding Site
·        Convulsant Binding Site
·        Barbiturate Binding Site
·        b Subunit Binding Site(s)


In an earlier post I highlighted the discovery by Professor Catterall, that tiny doses of a particular Benzodiazepine drug called Clonazepam had a strange effect on the GABAA receptor.

Clonazepam is a known Positive Allosteric Modulator (PAM) of the GABAA site.  In mature neurons it amplifies the calming effect when the GABA binding site is stimulated.  In mouse models of autism (we assume therefore immature neurons)   where GABA is still excitatory, the tiny dose seemed to switch it to inhibitory.

This suggests a new function, rather than a PAM, the effect was to invert the function entirely.

Now it appears that similar things may indeed also be possible at some of the other 9+ binding sites (I exclude GABA Binding Site itself)

As complicated as this subject may sound, it actually gets even more complicated since the GABA receptors are made up of sub-units.  It appears that mutations in these subunits may be a cause of some epilepsies and, I propose, some “oddities” in autism.

Recent studies have again shown that many genetic dysfunctions found in autism relate to GABA, this short article is not so recent, but gives a nice summary:-


GABA is the major inhibitory neurotransmitter in the brain. It essentially acts as a brake for brain activation. Several aspects of GABA regulation have been linked to ASD, from early brain development to adult brain function.
Variations in GABA receptor subunits have been strongly associated with ASD. GABA receptors come in two major forms: fast, “ionotropic” GABAA receptors let negatively charged chloride ions flow into the neuron, and slow, “metabotropic” GABAB receptors produce chemical messages inside the neuron. GABAA receptors, the most common form in the brain, contain five subunits that shape their properties. Genome-wide association studies have linked the GABAA receptor subunit genes GABRA4 (α4 subunit), GABRB1 (β1 subunit), and GABRB3 (β3 subunit) to autism.[1][2] In addition, deletion of a chromosomal region that contains a cluster of a variety of GABA receptor genes (region 15q11-13) causes Angelman Syndrome.[3][4]
Genes controlling the development of GABA-releasing neurons have also been associated with ASD. Autism-linked variations in the ARX and DLX family of transcription factors interfere with proper expression of GABA.[5][6][7] Absence of such GABA-releasing neurons would negatively affect early brain development as well as adult brain stability.

Notably, variations in other ASD-linked genes affect GABA signaling. New evidence shows that the gene MECP2, the mutation of which causes Rett Syndrome, is critical for normal function of GABA-releasing neurons.[8] When MECP2 expression was blocked in GABAergic neurons of mice, GABA expression and release were reduced and the mice exhibited autistic behaviors.

ASD is a complex disorder that is likely to be caused by a combination of mutations in a variety of genes. GABA receptors are a promising therapeutic target because of their important role in monitoring brain excitation. Identification and exploration of autism-linked mutations in other GABA-related genes could shed light on the pathogenesis of autism.


Over to Switzerland

At the University of Bern a small research group is looking  at the world of  GABAA receptors, here is what they say:-

“Many scientists and companies are put off by the complexity of the field of GABAA receptors, but it is exactly this complexity that offers numerous possibilities of fine-tuned pharmacological interventions.” 


Here is one of their recent papers, that shows both what is known and how very much remains unknown.




Ion Conductance
The GABAA receptors are generally GABA-gated anion channels selective for Cl ions, with some permeability for bicarbonate anions (49). Exceptionally, in C. elegans, a cation-selective GABA-gated channel has been discovered (50). Excitatory neurotransmitters increase the cation conductance to depolarize the membrane, whereas inhibitory neurotransmitters increase the anion conductance to tendentially hyperpolarize the membrane. However, if the gradient for Cl ions decreases due to down-regulation of KCC2 chloride ion transporters, opening of GABAA receptors may cause an outward flux of these anions, leading to depolarization of the membrane and thereby to excitation. This phenomenon has been implicated in neuropathic pain (51). During early development (52) and in neuronal subcompartments (53), GABA similarly confers excitation. 
Although it is relatively simple to address questions at the level of individual receptor subunit isoforms, we can only speculate how many GABAA receptors are expressed in our brain and what their subunit composition is, not to mention subunit arrangement.


Conclusions
Many scientists and companies are put off by the complexity of the field of GABAA receptors, but it is exactly this complexity that offers numerous possibilities of fine-tuned pharmacological interventions.

It may be anticipated that genetic alterations of subunits of the GABAA receptor affect any of the above mentioned processes and thereby contribute to inherited human diseases. A start has been made with the analysis of point mutations that cause epilepsy






Why is all this relevant ?

We have in recent posts discovered that at least two anti-convulsants (carbamazepine and phenytoin) appear to modulate GABAA receptors in unexpected ways when given in tiny doses.

We also found out that valproate also seems to possess such qualities.  The exact mode of action of valproate is not known and perhaps it also acts a modulator of one of the many binding sites on the GABAA receptors.

We do think that valproate is working somehow via GABA.



It turns out that Carbamazepine has also been shown to potentiate GABA receptors made up of alpha1, beta2, and gamma2 subunits.

I have already established that the effect of tiny doses of Valproate is not the same as tiny doses of Clonazepam.

The next step would be to look at the effect of tiny doses of carbamazepine, phenytoin and potentially anything else that modulates those mysterious  GABAAsites.  They are clearly all there for a reason.  It seems that their role goes beyond just the allosteric modulation (amplification/reduction) of GABA’s effect.  It is likely much more subtle and they affect emotional behaviour.

Given the difficulty/impossibility of research on human brains, in the end we may need to revert to the medical world’s often used “scientific” discovery methods known as trial and error, and stumbled upon.

For the moment that will be left to Professors Sigel and Catterall and their mice, and Dr Bird, in Australia, with his human subjects.




Oxytocin and Bumetanide share the same mode of action in autism


Whilst on the subject of GABAA, I should come back to Oxytocin.



The conclusion of this Ben-Ari paper from last year is that Oxytocin and Bumetanide share the same effect in autism; they lower the level of chloride within the neurons and help switch GABA back to inhibitory.

It seems that oxytocin from the mother may be the signal to the developing brain to lower Cl levels.  Oxytocin has many other functions in the body.

Small doses of oxytocin/Syntocinon, have been shown to be effective in some people with autism.  One reader from Portugal has written on this blog how effective it has been in his young son.

Oxytocin/Syntocinon is not available everywhere, but is being reintroduced to the US.



I am wondering if in some people, who are not responders, bumetanide/oxytocin lowers the level of chloride, but not enough to show any benefit.  People using Bumetanide, which has a short half-life, comment that the effect fades through the day and that splitting the same daily dose 3 times a day is beneficial over 2 times a day.  This might suggest that combining Oxytocin with Bumetanide might give better results, by maintaining the downward pressure on chloride levels and keeping GABA more inhibitory and for longer.

In the longer term, an analog of Bumetanide is needed without the diuretic effect and with a delayed release, to maintain a constant effective level.  This is known to the researchers, but would require a big financial investment.

Larger doses of oxytocin are likely to produce effects elsewhere in the body.

If anyone tries the combination of Bumetanide + oxytocin, let me know.





Tuesday 2 September 2014

GABA’s role in Neurodevelopment – Oxytocin and Bumetanide



This is a very brief post to direct those of you interested in the role of GABA, the neurotransmitter, towards a very recent open access review paper by Ben Ari.

In particular, people considering Oxytocin or Bumetanide to treat autism may find it interesting.








Monday 4 November 2013

Central Serotonergic Hypoactivity in Autism & Degradation of Tryptophan

 
Today’s post has an impressive title and a year ago I would not have understood it, but it summarizes exactly what may be going on inside the autistic brain.  It fits into the wider puzzle of hormonal imbalances in autism that then manifest themselves into behaviours ranging from qwerky to extreme self-injury.


Human emotions and behaviours are influenced by parallel signals from the nervous system (i.e. the brain) and the endocrine system.  The two systems are interconnected and so your state of mind in controlled by hormones that you cannot directly control and the nervous system which you can learn to control.  For example, you can make yourself happy, unhappy, or depressed with the power of your mind.  You can train yourself to overcome fear.  Some people are clearly very much better at doing this than others; but the potential to do so lies within all of us, autistic or neurotypical.  This also explains why singing makes you happy and rapidly reduces cortisol, your stress hormone, as we learnt in an earlier post.
So on the one hand we need to understand any in-built hormonal disturbances in autism and then see how to best tackle them using the hormonal system and the nervous system.  This may sound like fantasy but the more you learn about it, the more plausible it becomes.

Serotonin
Most people have heard of Serotonin; it is frequently thought of as the “happy hormone”.

As we have learnt in this blog, the human body is not like any man-made invention, it seems to function in quite irrational ways.  Serotonin is found mainly in the intestines and less than 10% is in the brain (and CNS), but it is not the same serotonin.  Serotonin cannot cross the blood brain barrier.  In autism serotonin in the blood (produced in the intestines) tends to be elevated, but the level of serotonin in the brain appears to be reduced.  So there appears to be a failure in the entire serotonin system, the one for the brain and the one for the blood.
Drugs that lower brain serotonin are often used to treat the symptoms of autism.  Even Temple Grandin admits (on her own website) to being on a low dose of Prozac to control her anxiety.  In spite of a long list of side effects, many children with ASD living in the US are prescribed this serotonin lowering drug.  Prozac is a heavily prescribed antidepressant drug and is a selective serotonin reuptake inhibitor (SSRI).

Somewhat bizarrely, Prozac is linked to an increase in suicidal tendencies.  As is often the case, many drugs have secondary or tertiary modes of action; you will experience all of them.
In the language of your doctor, low brain serotonin would be called central serotonergic hypoactivity, but don’t go asking him to test it, because he cannot.  All he can do is measure the level of serotonin in the blood or urine, and probably tell you that it is slightly elevated and not to worry.

Researchers have known about this serotonin paradox in autism for many years.  To my surprise a researcher at Yale University even made a mathematical model to better understand it. 

Since the early 1960s, the most consistent pathophysiological finding in autistic individuals has been their statistically elevated blood 5-hydroxytryptamine (5-HT, serotonin) levels. However, many autistic individuals have normal blood 5-HT levels, so this finding has been difficult to interpret. The serotonin transporter (SERT) controls 5-HT uptake by blood platelets and has been implicated in autism, but recent studies have found no correlation between SERT polymorphisms and autism. Finally, autism is considered a brain disorder, but studies have so far failed to find consistent serotonergic abnormalities in autistic brains. A simple mathematical model may account for these paradoxes, if one assumes that autism is associated with the failure of a molecular mechanism that both regulates 5-HT release from gut enterochromaffin cells and mediates 5-HT signaling in the brain. Some 5-HT receptors may play such a dual role. While the failure of such a mechanism may lead to consistent abnormalities of synaptic transmission with no alteration of brain 5-HT levels, its effects on blood 5-HT levels may appear paradoxical.

 The figure below sums up what appears to be going wrong.
 


A great all-in-one overview
If you only want to read one paper on serotonin and autism, and one that is not too science heavy, the one for you is:-


If you have more interest, then read on …

Research on Serotonin in the Autistic Brain
A recurring problem in all brain research is the lack of physical samples.  You cannot just open up someone's head and take a brain biopsy.  Research is either carried out on the tiny number of autistic brains donated to medical research, or it is non-invasive (MRIs and EEGs etc.), or it is very indirect.  An example of this latter type is the following paper from Belgium, home of kriek, a beer made from cherries and French fries served with mayonnaise.

"Some studies have suggested that disorders in the central serotonergic function may play a role in the pathophysiology of autistic disorder. In order to assess the central serotonergic turnover in autism, this study examines the cortisol and prolactin responses to administration of L-5-hydroxy-tryptophan (5-HTP), the direct precursor of 5-HT in 18 male, post-pubertal, Caucasian autistic patients (age 13-19 y.; I.Q.>55) and 22 matched healthy volunteers. Serum cortisol and prolactin were determined 45 and 30 minutes before administration of 5-HTP (4 mg/kg in non enteric-coated tablets) or an identical placebo in a single blind order and, thereafter, every 30 minutes over a 3-hour period. The 5-HTP-induced increases in serum cortisol were significantly lower in autistic patients than in controls, whereas there were no significant differences in 5-HTP-induced prolactin responses between both study groups. In baseline conditions, no significant differences were found in serum cortisol and prolactin between autistic and normal children. The results suggest that autism is accompanied by a central serotonergic hypoactivity and that the latter could play a role in the pathophysiology of autism."
 
Tryptophan and DHEA
Just to complicate things a little further, I now introduce you to Tryptophan and DHEA.

Tryptophan is an essential amino acid, meaning that it is essential for human life, cannot be synthesized by the organism, and therefore must be part of your diet.
Tryptophan functions as a biochemical precursor for the following compounds:

The disorders fructose malabsorption and lactose intolerance cause improper absorption of tryptophan in the intestine, reduced levels of tryptophan in the blood and depression

What you will not find on Wikipedia, is that perhaps Tryptophan is in fact also a bona fide neurotransmitter in its own right.

Tryptophan as an evolutionarily conserved signal to brain serotonin: molecular evidence and psychiatric implications.

Abstract

The role of serotonin (5-HT) in psychopathology has been investigated for decades. Among others, symptoms of depression, panic, aggression and suicidality have been associated with serotonergic dysfunction. Here we summarize the evidence that low brain 5-HT signals a metabolic imbalance that is evolutionarily conserved and not specific for any specific psychiatric diagnosis. The synthesis and neuronal release of brain 5-HT depends on the concentration of free tryptophan in blood and brain because the affinity constant of neuronal tryptophan hydroxylase is in that concentration range. This relationship is evolutionarily conserved. Degradation of tryptophan, resulting in lower blood levels and impaired cerebral production and release of serotonin, is enhanced by inter alia inflammation, pregnancy and stress in all species investigated, including humans. Consequently, tryptophan may not only serve as a nutrient, but also as a bona fide signaling amino acid. Humans suffering from inflammatory and other somatic diseases accompanied by low tryptophan levels, exhibit disturbed social behaviour, increased irritability and lack of impulse control, rather than depression. Under particular circumstances, such behaviour may have survival value. Drugs that increase brain levels of serotonin may therefore be useful in a variety of psychiatric disorders and symptoms associated with low availability of tryptophan. 

This paper is open access, it gets quite technical but here is a summary of the conclusion. 
 

Our findings support a possible mitochondrial dysfunction as a result of impaired tryptophan metabolism in cells from patients with ASDs
Although approximately 99% of the dietary tryptophan intake is metabolized via the kynurenine pathway, tryptophan is also the main precursor for both serotonin and melatonin
Melatonin plays a critical role in the regulation of the circadian rhythm, and anomalies of this rhythm have been associated with some of the signs in the autistic spectrum, like seizures or sleep disorders
Serotonin is a neurotransmitter involved in multiple aspects of brain functions, ranging from the regulation of mood to the control of appetite and social interactions and its production has been reported as deficient in ASD brains.
Tryptophan levels have been demonstrated to directly influence central nervous system (CNS) serotonin levels and behavior, and altered tryptophan transport has been described in fibroblasts from boys with attention deficit/hyperactivity disorder (ADHD)
Patients with ASDs, on average, are less capable of utilizing tryptophan as an energy source than controls.
Decreased tryptophan metabolism in patients with ASDs may alter metabolic pathways involved in the regulation of the early stages of brain development (first month of gestation), mitochondrial homeostasis and immune system activity in the brain.
Disruption of such pathways can primarily be caused either by insufficient serotonin production by placental cells, mitochondrial dysfunction and/or impaired balance between quinolinic and kynurenic acid in fetal cells. The combined effects of these events could lead to abnormal organization of neurons , particularly in specific brain regions, determining the imbalance between the short- and long-term circuitry that has been considered to be one of the fundamentals of the ASD neuropathology
Even though the ideal target tissue, brain, could not be investigated, our observation of decreased tryptophan metabolism in cells from patients with ASDs may provide a unifying model that could help explain the genetic heterogeneity of ASDs.
Tryptophan is a precursor of important compounds, such as serotonin, quinolinic acid, and kynurenic acid, which are involved in neurodevelopment and synaptogenesis. In addition, quinolinic acid is the structural precursor of NAD+, a critical energy carrier in mitochondria. Also, the serotonin branch of the tryptophan metabolic pathway generates NADH. Lastly, the levels of quinolinic and kynurenic acid are strongly influenced by the activity of the immune system. Therefore, decreased tryptophan metabolism may alter brain development, neuroimmune activity and mitochondrial function. Our finding of decreased tryptophan metabolism appears to provide a unifying biochemical basis for ASDs and perhaps an initial step in the development of a diagnostic assay for ASDs.

DHEA
DHEA  (didehydroepiandrosterone) It is the most abundant circulating steroid in humans, importantly for us to know it is also produced in the brain.  It has a variety of potential biological effects in its own right, binding to an array of nuclear and cell surface and acting as a neurosteroid.

Faulty serotonin--DHEA interactions in autism: results of the5-hydroxytryptophan challenge test. 

Abstract

BACKGROUND:


Autism is accompanied by peripheral and central disorders in the metabolism of serotonin (5-HT). The present study examines plasma dehydroepiandrosterone-sulphate (DHEA-S) and the cortisol/DHEA-S ratio following administration of L-5-hydroxytryptophan (5-HTP), the direct precursor of 5-HT, to autistic patients.

METHODS:


Plasma DHEA-S levels were determined both before and after administration of 5-HTP or placebo, on two consecutive days in a single blind order in 18 male autistic patients and 22 matched healthy controls.

RESULTS:


The 5-HTP-induced DHEA-S responses were significantly higher in autistic patients than in controls. In baseline conditions, the cortisol/DHEA-S ratio was significantly higher in autistic patients than in controls. Discussion: The results suggest that autism is accompanied by a major disequilibrium in the serotonergic system. The increased Cortisol (neurotoxic) versus DHEA-S (neuroprotective) ratio suggests that an increased neurotoxic potential occurs in autism.

CONCLUSIONS:


It is concluded that disequilibrium in the peripheral and central turnover of serotonin and an increased neurotoxic capacity by glucocorticoids are important pathways in autism.
 
Mice Studies
For the mice lovers amongst you, they also get their vitamin P (Prozac).

Serotonin Defects Identified in "Autistic" Mice

 
Serotonin modulators mitigate some BTBR behaviors
The researchers tested the effects of acute doses of fluoxetine (Prozac) (an SERT blocker), risperidone (a 5-HT2A receptor antagonist), and buspirone (a partial 5-HT1A receptor agonist) on social and repetitive behaviors of BTBR mice. These three compounds regulate serotonin activity and have inconsistent, limited, and sometimes harmful effects in rodent models of and people with autism. Only buspirone and fluoxetine were found to make BTBR mice significantly more social: treated mice spend proportionally more time socializing with a strange mouse than do saline-treated controls. Interestingly, BTBR mice treated with either buspirone or fluoxetine show a reduced interest in social novelty: when introduced to a second stranger mouse, they do not show a preference for either stranger. In contrast, the saline-treated controls spend more time investigating the newer mouse. Compared to either buspirone- or fluoxetine-treated mice and saline-treated controls, Risperidone-treated mice spend less time investigating strange mice and novel surroundings.
Regardless of treatment, BTBR mice spend comparable amounts of time burying marbles (an index of repetitive behavior). However, eliminating from the analysis one saline-treated control that did not bury any marbles suggests that risperidone-treated mice bury significantly fewer marbles than the saline-treated controls.
In summary, Daws and her team concluded that the autism-like behaviors of BTBR mice are likely due in part to an altered hippocampal SERT serotonin transporter and/or an altered 5-HT1A serotonin receptor. These findings may lead to the identification of additional therapeutic targets for treating human autism.
 
Conclusion
There was a lot of science in this post and it was clear that the mechanisms involved are only very partially understood by researchers.
It is clear that interventions increasing central (brain) serotonin levels are likely to reduce autistic behaviours.  Prozac was mentioned, but there is a much wider class of drugs called serenic, many of which could potentially be helpful.  As mentioned earlier, the big problem with most of the drugs created for psychiatrists is side effects.  Autism is supposed to be very common, but you would not think so by looking at way new drugs are developed.  As a result, the drugs currently used in ASD and the majority of those in the pipeline are ones developed for other conditions (depression, bi-polar, psychosis , anxiety, ADHD, schizophrenia, Alzheimer’s etc.) many of which share some similar characteristics, but are essentially different conditions, with the exception of ADHD.  It is akin to trying to fix your Ford car with a parts bin filled with Toyota components; it is possible, but not a wise idea.
In my opinion, all the hormone dysfunctions in autism can eventually be traced back to damage caused by oxidative stress and neuroinflammation.  The brain has just adjusted to find a new homeostasis, which happens to be an autistic one.  The list of metabolic disturbances in autism is long and getting longer; but they are just consequences.  I very much doubt it is ever going to be possible to go hormone by hormone, neurotransmitter by neurotransmitter “correcting” them.   I think the best solution is to go further back up the chain and look at how hormones and neurotransmitters themselves are jointly regulated.  I do not believe anyone fully understands the molecular basis on which this is carried out, but as I have pointed out earlier in this blog, you can get the right answer for the wrong reasons and also without showing your workings.  As long as it works, perhaps understanding why does not matter.  A much less intellectual approach might indeed prove effective.
I will continue with my problem solving, but less intellectual, approach and see where it leads.

 
P.S.
 
Just to show how all the hormones are interrelated, I added the paper below from Japan.  They investigate the relationship between Oxytocin and Serotonin:


Evidence That Oxytocin Exerts Anxiolytic Effects via Oxytocin Receptor Expressed in Serotonergic Neurons in Mice

"It is thus possible that oxytocin modulates not only anxiety-related behavior but also social behavior via serotoninergic transmission. These observations may provide new insights into psychiatric disorders associated with disruptions in social and emotional behavior, including autism, anxiety disorders, and depression."