Serotonin, Stress, and Autism – Biocast 014
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In this podcast I’m going to look at endotoxin, serotonin, stress, development, and autism. It is building on the base of the last few podcasts on endotoxin and serotonin, you should listen to those first if you haven’t already.
My website is resonantfm.com, where you can find links to content and social media, transcripts and references on resonantfm Patreon page. Previously we’ve seen that endotoxin can cause all sorts of problems, this is a bacterial byproduct that can get into the circulation and adipose tissue from the gastrointestinal system when the gut barrier function is lowered. It seems that the immune response to this senses it as a live bacterial infection and increaseses inflammation to deal that . It is this inflammation that causes problems like diabetes, obesity, liver disease, dementias and so on. Endotoxin also increases serotonin production the gastrointestinal system which leads to increased serotonin in the peripheral circulation, that is it picked up by the platelets around the gastrointestinal system increasing circulation of serotonin in the platelets in general, though not generally thought to cross the blood brain barrier. Endotoxin administration to the brain in experimental models increases serotonin, and increased endotoxin in general circulation seems to increase the synthesis of serotonin in the brain. The final point to catch up on is that serotonin itself is centrally implicated in causing many of the symptoms and behaviours that are roughly classified as depression.
There seem to be different ways to assess levels of serotonergic activity, and these seem to be specific to certain tissues or regions also. There are associations with mood disorders, low IQ, and increased violence from increased whole blood serotonin, and peripheral serotonin is seen to cause inflammatory, metabolic and fibrotic problems with it is released from the platelets. The term peripheral is generally a description of serotonin that is outside of the brain in this context. Inside the brain the assessment of serotonergic activity is a little bit more difficult especially in humans, sometimes the serotonin leaving the brain is sampled along with its metabolite 5-HIAAA, seems a marker of serotonin turnover, also more recent pet scans have been used to track various serotonin -related markers.
I’m going to look at some of the associations with endotoxin and autism, and serotonin and autism, then stress and serotonin, prenatal use of serotonin modulating drugs and developmental changes, and alteration of social deficit categorised behaviours by substances that might be said to block the effect of serotonin.
The effect of LPS on emotions and social behavior.
For the first section here I’m going to be using references from a site called microbial influence, which has a lot of interesting links on endotoxin, this site generally uses the other name for endotoxin LPS which is an acronym for lipopolysaccharide. There is a pretty well accepted correlation between autism spectrum disorders and gastrointestinal disorders, so it should not be a surprise that there is bacterial and immune aspect to this. Microbial influences lists references showing that injection of endotoxin into mice shows a decrease in markers of social behaviour. Endotoxin administration to a subtype of mice called Lurcher mice showed even more pronounced effects on behaviour than on normal or wild-type mice. Lurcher mice are known to be more susceptible to inflammation than normal mice. The social inhibition behaviours induced by endotoxin in this experiment reversed after the endotoxin was removed from the system. I think perhaps a longer exposure to endotoxin would increase serotonin activity in the brain and this would tend to reinforce itself. This page has references showing endotoxin induces anxiety in rodent models, effects on endogenous opioid peptides from endotoxin which are thought to be centrally connected to autism spectrum disorder along with the effects on depression and mood modulating states and behaviours.
Low-grade endotoxemia in patients with severe autism.
A 2010 paper assessing the levels of endotoxin and some inflammatory cytokines which are increased by endotoxin looked at 22 people with severe autism and 28 control subjects. They found significantly increased levels of the inflammatory cytokines IL-1 , IL-6, while the average levels of circulating endotoxin in people with severe autism were approximately double what was found in the controls. The paper suggests that endotoxin may play an inflammatory role in neurodevelopment for autism spectrum disorder. The paper also found that endotoxin was an independent predictor of socialisation according to a couple of autism -related diagnostic tests. The paper also mentioned that endotoxin was not an absolute predictor of autism -like behaviours, and I think that it may be one in a number of factors that increase inflammatory or serotonergic activity.
Autistic children and their first-degree relatives: relationships between serotonin and norepinephrine levels and intelligence
Whole blood serotonin has been consistently shown to be elevated in children with autism spectrum disorder. Severely retarded children have also been shown to have high whole blood serotonin. Hyperserotonemia, which is a clinical characterisation of pathologically high serotonin is found in 30% to 50% of children with either autism spectrum disorder or mental retardation. Previous studies referenced in the article show that higher blood serotonin is correlated with decrease measures of full-scale IQ, verbal IQ and developmental quotient in children with psychosis. Including number of links on whole blood serotonin levels and autism.
Origin of the blood hyperserotonemia of autism
Hyperserotonemia and amine metabolites in autistic and retarded children.
The hyperserotonemia of autism.
Hyperserotonemia in adults with autistic disorder.
Elevated Serotonin Levels in Autism: Association with the Major Histocompatibility Complex
Maternal serotonin transporter genotype affects risk for ASD with exposure to prenatal stress.
One of the main trends in research now is looking for genetically determined causes of disease. A paper from Queens University Ontario attempted to find an effect of stress on genetic expression related to autism. The authors were going on previous associations showing that psychological stress during gestation could cause neuropsychiatric conditions including autism spectrum disorder, associations that were stronger around the end of the second beginning of the third trimester. This paper looked at the genetic variation of a serotonin transporter gene, this gene they say is involved affecting stress tolerance and could play a role in variable responses to environmental stressors in risks for autism.
This paper looked at surveys from mothers regarding their prenatal environment and experience, and also at their variants for this serotonin transporter gene. The idea is that certain genes encode for different processes in the body but these genes can have slightly different variants and these variants lead to altered levels of the processes, so a gene with lower ability to do the prescribed process could lead to different outcomes. The mothers with the shorter allele variant of this gene had memories of a greater number of stressors, and these stressors were of increased severity. Mothers who did not have this allegedly high stress inducing variant of the gene reported less stress during pregnancy. Mothers who had this variant and a high stress pregnancy during gestation of a child with autism reported less stress during pregnancy with siblings that did not have autism spectrum disorder.
A transient placental source of serotonin for the fetal forebrain
The next reference I included shows that serotonin during gestation in mice can be synthesised from maternal tryptophan, this is an amino acid and precursor to serotonin. The paper shows serotonin from this source can accumulate in the forebrain and hindbrain of rodents, showing a pathway modulating brain development through tryptophan and serotonin.
Fetal, maternal, and placental sources of serotonin and new implications for developmental programming of the brain.
Another paper showing similar data in rodents points to important role for maternal placental fetal interactions and tryptophan in adult mental disorders.
Maternal inflammation boosts serotonin and impairs fetal brain development in mice
Inflammation increases serotonin affecting placental/fetal concentrations going forward
Maternal Inflammation Disrupts Fetal Neurodevelopment via Increased Placental Output of Serotonin to the Fetal Brain.
A paper furthering this line of investigation used an immune stimulant on pregnant rodents. It found that the inflammatory effect of due in part, to increase the serotonin producing enzyme tryptophan hydroxylase TPH. leading to accumulation of serotonin in the forebrain of the fetus and altering axonal growth in the same region. A drug used to inhibit tryptophan hydroxylase prevented this, showing that altered serotonin metabolism would disrupt certain fetal neuro development processes.
The findings show that the brain activity of newborns of mothers who took anti-depressants indicate less -organized communication between the brain hemispheres. The cortical rhythms of the same newborns also show weaker synchronization.
“”Since the changes did not correlate with the mother’s psychiatric symptoms, we have assumed that they resulted as a side effect of maternal drug treatment.” another article from vanhatalo
Newborn Brain Function Is Affected by Fetal Exposure to Maternal Serotonin Reuptake Inhibitors.
The next paper looks at the effects of serotonin reuptake inhibitors, drugs normally thought to inhibit the serotonin transporter SERT. It looks at the effects on newborns of mothers who had or had not used SRI drugs. It gives theories of SRI use in pregnancy of between 5 and 8%. The paper lists a number of previous papers containing reasons for doing the current experiment, paper suggesting that SRIs may affect early brain development, distorting various structures. Previous animal studies had shown clear effects from fetal SRI exposure, and the paper proposed to use a type of brain analysis called newborn scalp electro encephalography, which are referred to from here on in as EEG, due in part to rapid advancement of the analytical and recording capacity of the technology and in part due to the fact that it’s very difficult to otherwise get this kind of data.
The paper aimed to see whether they could find measurable changes in electrical activity in the brains of newborns from prenatal SRI exposure, to assess any differences between EEGs in different stages of development which might give information on how long the effects from SRIs might last after exposure, this was pretty short term though with recordings taken at 1 and 2 weeks, enough to assess something equivalent to acute withdrawal, and finally to assess the potential confounding effect of maternal stress or depression.
They ruled out a lot of other psychiatric medications and exclude and infants born preterm. 22 pregnant women were recruited who were at the time being treated with SRIs, the SRI free control group consisted of 62 pregnant women.
Mothers using the SRI medications were found to be more often suffering from an anxiety disorder at the time of assessment, were also more likely to have a previous diagnosis of anxiety disorder or major depressive disorder. Rates of breastfeeding were similar in both groups at the time of the EEG recordings and clinical examinations.
Clinical data between the groups was similar, and no evidence of drug withdrawal was found when the babies were tested at an average of nine days post birth. Neurological examinations showed some alteration in the SRI group including signs of tremor, hand and toe posture, and startle reaction.
The EEG recordings showed significant differences between groups in the ability to sustain local periodic oscillatory bouts, the measure of cross frequency integration was altered in SRI group, the measures of inter hemispheric connectivity showed lower integration in the SRI group, this difference remained for the second test also, further significant alterations were found in measures of the global average of spectral amplitudes. The spatial analysis showed significant differences concentrated into the frontal brain regions.
The paper reports that their assessment of the analysis of the effect of medication versus maternal mood or anxiety indicated more likely that the effects were due to SRI exposure or an interaction with the medication and mood alterations. It mentions that early developmental changes in the expression of the serotonin transporter are thought to be altered by these medications.
Prenatal SSRI exposure: Effects on later child development.
A 2014 review paper on the effects of prenatal SSRI exposure found that there were no negative effects on cognitive function found in early development, however in association with later development found some cognitive difficulties, and behavioural problems correlating with SSRI exposure
Effects of prenatal maternal stress on serotonin and fetal development
A 2015 paper on the effects of maternal stress and serotonin on fetal development concluded that prenatal stress could induce alterations in serotonin synthesis and these alterations could lead to increased risk of psychiatric diseases later in life. I will point out that many of the arguments made in this paper however are not entirely in agreement with the interpretations of serotonin’s activity and role described so far in this podcast.
Social Behavioral Deficits Coincide with the Onset of Seizure Susceptibility in Mice Lacking Serotonin Receptor 2c
5-HT2cR antagonist reverses social deficits in mice
A somewhat confusing paper on very strains of mutant mice showed that a specific serotonin receptor antagonist drug, antagonist to the 5-HT 2C receptor, could reverse social deficit behaviours in mice. In rodents with Pten mutations the serotonin receptor antagonist drug decreased behaviours of social deficit, seizures and spontaneous death was decreased compared to the Pten rodents without the antagonist. Pten is believed to play a role in some cases of autism. This paper a little confusing because we also have a separate experiment in this showing that adult, but not juvenile rodents with a generic knockout of the serotonin receptor previously mentioned exhibit social deficits and increased seizures.
Effects of the 5HT antagonist cyproheptadine on neuropsychological function in chronic schizophrenia
Cyproheptadine is an older drug that was primarily used as an antihistamine, it was and still is commonly used for emergency cases of serotonin syndrome, it’s a serotonin 5-HT 2C antagonist which shows some efficacy for schizophrenia and a very large range of other conditions, many of them probably linked with high serotonin. I will link to a forum discussion that references papers on those conditions.
Cyproheptadine – A Wonder Drug?
Cyproheptadine in treatment of autism
A paper in 2002 looked at two case reports of the effect of cyproheptadine in autism. In the first report of 16-year-old female was treated with 12 mg increasing to 20 mg per day of cyproheptadine. The parents reported a dramatic decline in the frequency and severity of some of the behaviours. This patient had Rett syndrome, and some of the spasticity associated with this condition was decreased during treatment. Signs of depression and social withdrawal became evident that for months and lowering the dose to 4 mg per day relieved the depression and unfortunately some of the improvement was also curtailed. Cyproheptadine as many effects, so it’s difficult to gauge what was the cause of the negative side-effects, it may have been to do with an effect on dopamine receptors.
The second was a case of regression at 30 months in which the patient had a very prominent response to cyproheptadine at 24 mg per day.
Cyproheptadine in the treatment of autistic disorder: a double-blind placebo-controlled trial.
A couple of years after that paper was published another was published with a double-blind placebo controlled study on cyprpheptadine in the treatment of autism. This study lasted for eight weeks and was confounded by the inclusion of another drug in the cyproheptadine group. This drug was haloperidol, is a dopamine antagonist with some antagonist and agonist effects on various serotonin receptors. 40 patients between the ages of three and 11 years old were ascribed to either of two groups. The first group was cyproheptadine and haloperidol, and the second was haloperidol alone. The dose of cypro was titrated up to 0.2 mg per kilogram per day. All subjects were also given the drug biperiden.
A couple of different rating scales were used to assess the efficacy of the drugs, by the ABC-C rating scale there were some improvements with both groups. Quantification of the aberrant behaviours went from about 28 to 25 on average in the group without cyproheptadine, in the cyproheptadine group these words went from 26 to 15. Similar effects were seen using the childhood autism rating scale. The conclusion was that treatment with cyproheptadine and the antipsychotic drug was superior to the anti psychotic alone, and that larger randomised controlled trials are needed.
[Ritanserin in autistic children].
A 1993 paper investigating the effect of the serotonin antagonist Ritanserin on autism and Rett’s Syndrome concluded that Ritanserin had a positive effect on children with Rett’s syndrome and children with autistic syndrome and mental retardation. The most marked effect was observed in reduction of psychomotor instability, impaired concentration of attention and partly also in autism.
That is where I’m going to leave this podcast. I have a number of papers here to go through on the topic of LSD, Serotonin, and Autism and I’ll probably put out an article on Patreon about the time this podcast gets released on the the iTunes feed. I need to generate more income for the time put into these podcasts if they are to continue, so much as I’d like to put everything out for free I’m going to have to put more content for Patreon only supporters or there may be no content at all. I’m currently writing articles on reducing endotoxin and related inflammation on the Patreon page. I’d like to thank all the Patreon supporters for their help. My website is resonantfm.com, which has all the relevant links to social media and the Patreon page. I normally post some other studies a few times a week on the resonant fm facebook page. I have put up a site index on the homepage which lists all the content in some order from across the various sites and that is linked in the pinned post n the Patreon page also for easier navigation.
Thanks for listening.