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Showing posts with label Prozac. Show all posts
Showing posts with label Prozac. Show all posts

Tuesday, 6 November 2018

When is an SSRI not an SSRI? Low dose SSRIs as Selective Brain Steroidogenic Stimulants (SBSSs) via Allopregnanolone modifying GABAa receptors and neonatal KCC2 expression


Today’s post might seem to have a very complicated tittle, but to regular readers it is really just another take on what we have seen time and time again.
Today we see how another steroid imbalance in autism – low levels of allopregnenolone in this case – affects the neurotransmitter GABA and indeed the chloride transporter KCC2.

Putting Prozac/Zoloft to a better use?

I did report previously on a trial in adults with autism where pregnenolone was used.


Recall that disturbed hormonal homeostasis is a key feature of autism. What matters is the level of each hormone inside the brain (i.e. centrally), not in your blood. The only way to get a reliable idea of what is going on would be to take a sample of spinal fluid.



Today we look at boosting allopregnenolone not with a steroid hormone, but with a 1/10th dose of Prozac (Fluoxetine) or indeed Zoloft (Sertraline). Prozac is a selective serotonin reuptake inhibitor (SSRI) when given at the usual dose of 20-80mg, but at 2.5mg it does not function as an SSRI.
At regular doses selective serotonin reuptake inhibitors (SSRI) drugs like Prozac are well known to cause problems, as do benzodiazepines like Clonazepam.
Thanks to Professor Catterall we saw in earlier posts how tiny doses of Clonazepam have an effect on one particular sub-unit of GABAA receptors. By fine tuning the response of this receptor we saw how a cognitive improvement can be achieved, in some people. The dose is so low there appear to be no long term side effects. At least one other professor of medicine, I am in contact with, has been treating his son with autism with low dose clonazepam for years.
Many adults and children with autism are prescribed Prozac for anxiety. Even Temple Grandin has said she takes Prozac.
At low, non-serotonergic doses, some drugs like Prozac show a different mode of action, they potently, positively, and allosterically modulate GABA action at GABAA receptors. These drugs achieve this by increasing the amount of the steroid hormone allopregnanolone.
Neurosteroid biosynthesis down‐regulation and changes in GABAA receptor subunit composition are a feature of several neurological conditions, including some autism.
Stimulating allopregnenalone biosynthesis will have multiple effects including on TSPO and endocannabinoid receptors.


Brain principal glutamatergic neurons synthesize 3α-hydroxy-5α-pregnan-20-one (Allo), a neurosteroid that potently, positively, and allosterically modulates GABA action at GABAA receptors. Cerebrospinal fluid (CSF) Allo levels are decreased in patients with posttraumatic stress disorder (PTSD) and major depression. This decrease is corrected by fluoxetine in doses that improve depressive symptoms. Emotional-like behavioral dysfunctions (aggression, fear, and anxiety) associated with a decrease of cortico-limbic Allo content can be induced in mice by social isolation. In socially isolated mice, fluoxetine and analogs stereospecifically normalize the decrease of Allo biosynthesis and improve behavioral dysfunctions by a mechanism independent from 5-HT reuptake inhibition. Thus, fluoxetine and related congeners facilitate GABAA receptor neurotransmission and effectively ameliorate emotional and anxiety disorders and depression by acting as selective brain steroidogenic stimulants (SBSSs).                               
When the results of these in vitro studies are compared to those of our in vivo studies, it becomes evident that in mice the doses of fluoxetine and norfluoxetine that cause a rapid increase in brain Allo levels do not exceed brain concentrations in the low nanomolar range, whereas the fluoxetine concentrations that directly activate 3a-HSD in vitro are in the micromolar range. Moreover, the high potency and stereospecificity of fluoxetine and norfluoxetine in decreasing aggressive behavior and normalizing brain Allo content during social isolation (see Table 1, and Figure 3) support the notion that these compounds facilitate the action of 5a-R type I or 3a-HSD by an unidentified indirect mechanism, which is most probably perturbed by protracted social isolation.

Thus, these drugs, which were originally termed ‘SSRI’ antidepressants, may be beneficial in psychiatric disorders because in doses that are inactive on 5-HT reuptake mechanisms, they increase the bioavailability of neuroactive GABAergic steroids. On the basis of these considerations, we now propose that the term ‘SSRIs’ should be changed to the more appropriate term ‘selective brain steroidogenic stimulants’ (SBSSs), which more accurately defines the pharmacological mechanisms expressed by fluoxetine and its congeners.

Conclusions

The pharmacology of the S stereoisomers of fluoxetine and norfluoxetine appears to be prototypic for molecules that possess specific neurosteroidogenic activity. The doses of S-fluoxetine and S-norfluoxetine required to normalize brain Allo content downregulation, pentobarbital action, aggressiveness, and anxiety in socially isolated mice are between 10-fold to 50-fold lower than those required to induce SSRI activity. However, the precise mechanisms of action by which S-fluoxetine and S-norfluoxetine increase neurosteroids remain to be investigated.

Derivatives of S-fluoxetine and S-norfluoxetine, acting with high potency and specificity on brain neurosteroid expression at doses devoid of significant action on brain 5-HT reuptake mechanisms, may represent a new class of pharmacological tools important for the management of anxiety, related mood disorders, dysphoria, fear, and impulsive aggression.

On the basis of these data, new drugs devoid of SSRI activity but that are potent neurosteroidogenic agents should be developed for the treatment of psychiatric disorders that result from the downregulation of neurosteroid expression, including major depression, and in the prevention of PTSD.

France often gets very negative comments about how it treats people with autism, but in the case studies below it looks like some innovative work is going on in some of their day hospitals, where boys and girls with severe autism are sent to pass their time. 

The system in England has recently been highlighted as being pretty appalling, where over 2,000 people with autism are currently detained in Assessment and Treatment Units (ATUs), privately run secure residential "hospitals", at great cost paid for by the State. Those inside might enter with the approval of their family to stay for 3 weeks for respite care, but end up being detained for 3 years, or even longer. The State assumes their guardianship and the individual and parents are powerless. The individuals are kept in prison-like conditions and not surprisingly get worse not better, the worse they get, the harder it is ever to be released. Hard to believe this is still happening.  If you live in England, best not to hand your child over to the State. Someone has even written a book about escaping from such a unit. This is no better than the old State Hospitals in the US, that finally were closed down in the 1970s, that warehoused mentally disabled people, until their premature death.


Autism Spectrum Disorder (ASD) is defined by the copresence of two core symptoms: alteration in social communication and repetitive behaviors and/or restricted interests. In ASD children and adults, irritability, self-injurious behavior (SIB), and Attention Deficit and Hyperactivity Disorders- (ADHD-) like symptoms are regularly observed. In these situations, pharmacological treatments are sometimes used. Selective Serotonin Reuptake Inhibitors- (SSRI-) based treatments have been the subject of several publications: case reports and controlled studies, both of which demonstrate efficacy on the symptoms mentioned above, even if no consensus has been reached concerning their usage. In this article four clinical cases of children diagnosed with ASD and who also present ADHD-like symptoms and/or SIB and/or other heteroaggressive behaviors or irritability and impulsivity treated with low doses of fluoxetine are presented.
Case 1 
An 8-year-old girl (19 kg) had an ASD diagnosis according to the DSM-5 and ADI-R criteria based on information provided by parents. She also had significant mental retardation, with severe SIB (banging her head against objects and biting her hands), forcing her entourage to maintain a daily and permanent physical restraint. She spends most of her time in a day hospital. She received the following pharmacological treatment: risperidone 2 mg/d and cyamemazine 80 mg/d without modifications to her SIB and at the price of a major slowing down and a manifestation of a tendency toward blunting. The CGI severity of illness score was at five (markedly ill). We decreased and stopped risperidone and started valproic acid. After four weeks of valproic acid 400 mg/d in combination with cyamemazine (60 mg/day), SIBs did not improve. Then, we added fluoxetine 2.5 mg/d and increased it after one week to 5 mg/d and to 10 mg/d in the third week. After one week, the CGI improvement scale (CGI-I) was at two; after three weeks, it lowered to 1 (very much improved). We also observed a significant decrease in anxiety as well as the disappearance of SIB (disappearance of the behavior consisting of the banging and rubbing her head against objects). However, it should be noted that the entourage kept the bandages on her hands because she continued to bite them, even if she did it with less intensity than before. There were no side effects. After three months of fluoxetine, her clinical state remains stable.

Case 2 
A 12-year-old boy (70 kg), with DSM-5 criteria for an ASD and ADI-R confirming this diagnosis, exhibited extreme irritability, violence, and impulsiveness as well as SIB (he had thrown seven television sets out of the window). The CGI severity illness scoring was at six (severely ill). In the day hospital where he spent most of his time, it was difficult for staff to manage his impulsivity and unpredictability. His treatment included risperidone 4 mg/d as well as loxapine 80 mg/d. Despite this pharmacological treatment, episodes of aggression and SIBs continued. This treatment induced a significant weight gain (8 kg in 5 months). Treatment with fluoxetine 2.5mg/d was introduced and increased to5mg/d after one week and to 10 mg/d at the beginning of the third week. After one week, there was a CGI-I score of three, which decreased to two after two weeks of treatment and to one after three weeks. Such a positive clinical response allowed for a reduction in risperidone to 2mg/d and in loxapine to 60 mg/d. The treatment was tolerated well by the patient, and he began to lose weight (4 kg). After two months off luoxetine, his clinical state remains stable.

Case 3
 A 6-year-old male child (30 kg) with DSM-5 criteria and ADI-R for an ASD exhibited problems of SIB and repetitive behaviors (washing his hands for more than 30 minutes at least two to three times per day), severe irritability, frequent crying, social withdrawal, and inappropriate speech. Treatment with risperidone 2mg/d had improved irritability and partially the SIB, but it had also produced significant weight gain (four kg in three months). A decrease in the risperidone dosage seemed necessary. Treatment with fluoxetine2.5mg/d was begun, which quickly led to a reduction in inappropriate behavior (for example, impulsive crawling on the ground in the classroom). After one week, the CGI-I scoring was at two. The dosage was gradually increased to 5 mg/d the second week and to 7.5mg/d the third week. The repetitive behaviors gradually subsided. After three weeks the CGI-I score was at one, and it remained stable for nine weeks. The risperidone dosage could be decreased to 0,5 mg/day and the patient’s weight remained the same.
Case 4 
A 12-year-old boy (62kg) withDSM-5 and ADI-R criteria for a severe case of ASD, including severe ADHD-like symptoms, often required physical restraint and did not improve despite a long-term treatment of risperidone 3 mg/d as well as melaton in 4mg at bedtime. The CGI severity illness scoring was at 6 (severely ill). The behavioral pattern included irritability, marked agitation, crying, severe hyperactivity, and other behaviors typical of this disorder. He was also anxious, rendering the situation at his day hospital where he spent most of his time all the more difficult. A prescription of fluoxetine 2.5mg/d was initiated with an immediate and complete improvement of ADHD-like symptoms:CGI-I at one week of treatment was at a one, making this case the most remarkable of the four presented here. Treatment with fluoxetine was continued with a dosage increase up to 5 mg/d to allow for a decrease in the risperidone dose to 1 mg/d. CGI-I score remained stable at one for the duration of the nine weeks.

Our reader Mira, whose son has FXS, recently referred to Dr Hagerman’s trial of low dose Sertaline/Zoloft in Fragile X. GABAA malfunction appears to be a feature of Fragile X, but it is not necessarily the identical malfunction to those with idiopathic autism who respond to bumetanide.

Objective

Observational studies and anecdotal reports suggest sertraline, a selective serotonin reuptake inhibitor (SSRI), may improve language development in young children with fragile X syndrome (FXS). We evaluated the efficacy of six months of treatment with low-dose sertraline in a randomized, double-blind, placebo-controlled trial in 52 children with FXS ages 2–6 years.


Results

Eighty-one subjects were screened for eligibility and 57 were randomized to sertraline (27) or placebo (30). Two subjects from the sertraline arm and three from the placebo arm discontinued. Intent-to-treat analysis showed no difference from placebo on the primary outcomes: the Mullen Scales of Early Learning (MSEL) expressive language age equivalent and Clinical Global Impression-Improvement (CGI-I). However, analyses of secondary measures showed significant improvements, particularly in motor and visual perceptual abilities and social participation. Sertraline was well tolerated, with no difference in side effects between sertraline and placebo groups. No serious adverse events occurred.

Conclusion

This randomized controlled trial of six-months of sertraline treatment showed no primary benefit with respect to early expressive language development and global clinical improvement. However, in secondary, exploratory analyses there were significant improvements seen on motor and visual perceptual subtests, the Cognitive T score sum on the MSEL, and on one measure of Social Participation on the Sensory Processing Measure–Preschool. Further, post hoc analysis found significant improvement in early expressive language development as measured by the MSEL among children with ASD on sertraline. Treatment appears safe for this 6-month period in young children with FXS, but we do not know the long-term side effects of this treatment. These results warrant further studies of sertraline in young children with FXS using refined outcome measures, as well as longer term follow-up studies to address long-term side effects of low-dose sertraline in early childhood.


Neurosteroid biosynthesis down‐regulation and changes in GABAA receptor subunit composition: a biomarker axis in stress‐induced cognitive and emotional impairment

By rapidly modulating neuronal excitability, neurosteroids regulate physiological processes, such as responses to stress and development. Excessive stress affects their biosynthesis and causes an imbalance in cognition and emotions. The progesterone derivative, allopregnanolone (Allo) enhances extrasynaptic and postsynaptic inhibition by directly binding at GABAA receptors, and thus, positively and allosterically modulates the function of GABA. Allo levels are decreased in stress-induced psychiatric disorders, including depression and post-traumatic stress disorder (PTSD), and elevating Allo levels may be a valid therapeutic approach to counteract behavioural dysfunction. While benzodiazepines are inefficient, selective serotonin reuptake inhibitors (SSRIs) represent the first choice treatment for depression and PTSD. Their mechanisms to improve behaviour in preclinical studies include neurosteroidogenic effects at low non-serotonergic doses. Unfortunately, half of PTSD and depressed patients are resistant to current prescribed 'high' dosage of these drugs that engage serotonergic mechanisms. Unveiling novel biomarkers to develop more efficient treatment strategies is in high demand. Stress-induced down-regulation of neurosteroid biosynthesis and changes in GABAA receptor subunit expression offer a putative biomarker axis to develop new PTSD treatments. The advantage of stimulating Allo biosynthesis relies on the variety of neurosteroidogenic receptors to be targeted, including TSPO and endocannabinoid receptors. Furthermore, stress favours a GABAA receptor subunit composition with higher sensitivity for Allo. The use of synthetic analogues of Allo is a valuable alternative. Pregnenolone or drugs that stimulate its levels increase Allo but also sulphated steroids, including pregnanolone sulphate which, by inhibiting NMDA tonic neurotransmission, provides neuroprotection and cognitive benefits. In this review, we describe current knowledge on the effects of stress on neurosteroid biosynthesis and GABAA receptor neurotransmission and summarize available pharmacological strategies that by enhancing neurosteroidogenesis are relevant for the treatment of SSRI-resistant patients. Linked Articles This article is part of a themed section on Pharmacology of Cognition: a Panacea for Neuropsychiatric Disease? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.19/issuetoc.

Too little allopregnanalone can induce autism.


Results
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with core symptoms of social impairments and restrictive repetitive behaviors. Recent evidence has implicated a dysfunction in the GABAergic system in the pathophysiology of ASD. We investigated the role of endogenous allopregnanolone (ALLO), a neurosteroidal positive allosteric modulator of GABAA receptors, in the regulation of ASD-like behavior in male mice using SKF105111 (SKF), an inhibitor of type I and type II 5α-reductase, a rate-limiting enzyme of ALLO biosynthesis. SKF impaired sociability-related performance, as analyzed by three different tests; i.e., the 3-chamber test and social interaction in the open field and resident-intruder tests, without affecting olfactory function elucidated by the buried food test. SKF also induced repetitive grooming behavior without affecting anxiety-like behavior. SKF had no effect on short-term spatial working memory or long-term fear memory, but enhanced latent learning ability in male mice. SKF-induced ASD-like behavior in male mice was abolished by the systemic administration of ALLO (1mg/kg, i.p.) and methylphenidate (MPH: 2.5mg/kg, i.p.), a dopamine transporter inhibitor. The effects of SKF on brain ALLO contents in male mice were reversed by ALLO, but not MPH. On the other hand, SKF failed to induce ASD-like behavior or a decline in brain ALLO contents in female mice. These results suggest that ALLO regulates episodes of ASD-like behavior by positively modulating the function of GABAA receptors linked to the dopaminergic system. Moreover, a sex-dependently induced decrease in brain ALLO contents may provide an animal model to study the main features of ASD.



Results
Some steroids, whose levels are raised in autism (allopregnanolone, androsterone, pregnenolone, dehydroepiandrosterone and their sulfate conjugates) are neuroactive and modulate GABA, glutamate, and opioid neurotransmission, affecting brain development and functioning. These steroids may contribute to autism pathobiology and symptoms such as elevated anxiety, sleep disturbances, sensory deficits, and stereotypies among others.

Tuning the Brain
I did write a post a while back to show the effect of tuning GABAa receptors.




The effect of allopregnanolone of KCC2 expression and hence the level of chloride within neurons.

Neonatal allopregnanolone or finasteride administration modifies hippocampal K(+) Cl(-) co-transporter expression during early development in male rats.

Abstract

The maintenance of levels of endogenous neurosteroids (NS) across early postnatal development of the brain, particularly to the hippocampus, is crucial for their maturation. Allopregnanolone (Allop) is a NS that exerts its effect mainly through the modulation of the GABAA receptor (GABAAR). During early development, GABA, acting through GABAAR, that predominantly produces depolarization shifts to hyperpolarization in mature neurons, around the second postnatal week in rats. Several factors contribute to this change including the progressive increase of the neuron-specific K(+)/Cl(-) co-transporter 2 (KCC2) (a chloride exporter) levels. Thus, we aimed to analyze whether a different profile of NS levels during development is critical and can alter this natural progression of KCC2 stages. We administrated sustained Allop (20mg/kg) or Finasteride (5α-reductase inhibitor, 50mg/kg) from the 5th postnatal day (PD5) to PD9 and assessed changes in the hippocampal expression of KCC2 at transcript and protein levels as well as its active phosphorylated state in male rats. Taken together data indicated that manipulation of NS levels during early development influence KCC2 levels and point out the importance of neonatal NS levels for the hippocampal development.                                                                                                                           
Conclusion

Add very low dose Prozac to the long list of possible SIB therapies, more practical than electroconvulsive therapy (ECT), that is for sure!

This post was long waiting in my “to-complete” pile. I thought it would be a short one, but it kept growing.  It does draw together several interesting issues and shows there is a pattern developing in all these blog posts.
The majority of psychiatric drugs have such severe drawbacks that the great majority of children are better off without them.  However, there are many existing drugs that have little known neurological effects that can be highly beneficial and are known to be safe to use long term.
Psychiatric drugs that can be repurposed at lower dosages for different purposes may indeed be free of the major drawbacks encountered at higher doses.
It looks like humans with Fragile X Syndrome (FXS) are leading the way with low dose SSRI therapy to modulate GABA.  It would seem highly plausible that other idiopathic autism might also benefit and the French case studies in this post are examples of those who did benefit.
I think this is another example of fine-tuning the brain to optimize its functioning. It probably will not produce miracles, but the science shows that allopregnenalone can be tuned to vary mood in humans.  Low levels of allopregnenalone can produce autistic-like behaviours in mouse models.
The effect of allopregnenalone on KCC2 expression may only be present in tiny babies, if it continues into childhood that would be another reason to consider it as a target for modulation.  If that were the case, then Finasteride the cheap generic drug for prostate enlargement, should be investigated.
As is always the case in autism, both extremes are likely to exist; some people will likely benefit from low dose SSRIs but it will make some others worse (anxiety, SIB etc). If you start with elevated allopregnenalone, you would want less, not more.
Repurposing existing drugs has huge unrealized potential.
The OTC antihistamine Clemastine, which I highlighted in an earlier post as being a Positive Allosteric Modulator (PAM) of P2X7, and so helps remyelination, is yet another example of repurposing a safe drug.  Reportedly, it has this effect even below the regular dosage for allergy; at the high dosage usage in MS trials it will send you to sleep and risk some other side effects. As MS is not a singular condition, it seems that some people respond much more so than others. It also seems to have a benefit is some psychiatric disorders; not bad for a cheap OTC antihistamine.



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."





 

Monday, 23 September 2013

Autism Biomarkers – Serotonin: LSD, SSRIs & Cyproheptadine/Periatin


Researchers are always looking for biomarkers of autism as a diagnostic tool; I am more interested in biomarkers as an indicator of might be going wrong and hence, perhaps, an indicator of what to do about it.

Going back more than half a century, just such a biomarker was found.  Increased platelet levels of 5-HT (5-Hydroxytryptophan) were found in 30-40% of the autistic population.  5-HTP increases the production of the neurotransmitter serotonin and so it was suggested that hyperserotonemia may be a factor in autism.
  

Hyperseratonemia (Serotonin syndrome)

Hyperseratonemia is not treated by reducing the amount of serotonin, rather by using a receptor antagonist that in effect blocks the serotonin effect.
  

SSRIs and other anti-depressants

Several classes of drugs target the 5-HT system including  anti-depressants, antipsychotics, anxiolytics, antiemetics, and antimigraine drugs, as well as the psychedelic drugs and empathogens.

In you live in the US, you will have heard of Prozac (vitamin P) which is a very widely prescribed anti-depressant.  It is in a class of drug called Selective Serotonin Re-uptake Inhibitors or SSRI.  Many autistic children in the US are prescribed SSRIs like Prozac. In Japan Prozac is illegal.

SSRIs are believed to increase the extracellular level of serotoinin by inhibiting its reuptake.  Excessive use of SSRIs is known to lead to hyperseratonemia.  If you are already prone to hyperserotonemia, like 40% of autistic kids, it would seem that SSRIs could be potentially dangerous drugs.

A good deal of research does exist on the use of SSRIs in autism and it pretty much shows that they do not do much good, (and they certainly can have nasty side effects).  Look at page 6, in the review paper below that included all kinds of drugs trialled in autism.



LSD and other serotonin antagonists

LSD is a banned substance in the US and Europe, but in the time before I was born, it was being used to treat autism.  LSD, among other things, is a serotonin antagonist.  There are indeed several papers published on its use in autism and other conditions.

I was quite surprised to see Ivaar Lovaas, the “father” of Applied Behavioural Analysis (ABA) was merrily giving autistic children LSD at UCLA in the early 1960s.


These old studies are quite interesting and if you want more just click here.

I am not suggesting you take your child to Amsterdam, but if you look on Google you will see that adults with ASD are indeed using LSD therapy.

It now appears that after being banned from use decades ago, medical research with LSD has been restarted.

Fortunately, there are other serotonin antagonists that are available and will not land you in trouble.  The one that attracted my attention is Cyproheptadine or Periactin.

Cyproheptadine in Research

There has been just one study published on autism and Cyproheptadine and that was in 2004.  It is not exactly what we need, since it was being trialed as an adjunct therapy to haloperidol.  Haloperidol is an antipsychotic.

If you live in the US you will be familiar with Risperidone, which is another antipsychotic shown to be effective in autism. In the UK, only specialists such as child psychiatrists can prescribe risperidone for children with autism.  Risperidone can cause side effects like uncontrollable shaking.

So the trial was in effect to see the effect of the antipsychotic + Cyproheptadine vs antipsychotic + placebo.  This is not exactly what we want, but better than nothing.

As you will see in the charts below, the addition of Cyproheptadine did indeed make a marked improvement.  Sadly this research has not been followed up on.



    

Serotonin and Emotional Response

There was a recent study looking at how the emotional response of adults with autism was affected by lowering serotonin levels, I could not find the full version.


Conclusion

Elevated blood levels of serotonin may or may not be a “red herring” in autism research.  The evidence is far from complete and it is not going to be a magic bullet.  Nonetheless, I suspect lowering serotonin levels may have far more impact than those expensive high EPA Omega 3 pills many parents are feeding to their kids.

The latest research does actually indicate that genetic differences cause the high levels of 5-HT in autism.  100% conclusive research does not exist showing the value of counteracting this genetic difference.  A safe, cheap, serotonin antagonist, Cyproheptadine /Periactin does exist; and it is available OTC in some countries.


Autism gene variant causes hyperserotonemia, serotonin receptor hypersensitivity, social impairment and repetitive behavior