Showing posts with label ADHD. Show all posts
Showing posts with label ADHD. Show all posts

Monday, 11 December 2017

Cognitive Loss/Impaired Sensory Gating from HCN Channels - Recovered by PDE4 Inhibition or an α2A Receptor Agonist

Today we have a complex dysfunction, but we have a plausible understanding of the detailed biological underpinnings and several therapeutic options. It is relevant to people with autism who have impaired sensory gating (they find noises like a clock ticking annoying), and perhaps those who struggle with complex thought. It is very likely to be disturbed in some people with ADHD and many with schizophrenia.

Trouble in the Pre-Frontal Cortex

For a recap on sensory gating, here is an earlier post:-

Sensory Gating in Autism, Particularly Asperger's

Today’s dysfunction relates to HCN channels located on those tiny dendritic spines in a part of the brain called the pre-frontal cortex. These are a type of voltage gated potassium channel found in your brain and heart, there are 4 types, it looks to me that HCN2 is the key one today.
The pre-frontal cortex (PFC) is seen as the part of the brain most affected by mental illness (schizophrenia, bipolar, ADHD etc.), although medicine’s current understanding looks rather medieval to me.
These HCN channels can open when they are exposed to cAMP (cyclic adenosine monophosphate). When open, the information can no longer flow into the cell, and thus the network (created by numerous interacting neurons) is effectively disconnected.
By keeping these channels closed, it is thought that you can improve working memory and reducing distractibility. Now you might think distractibility is an odd word, and it is not a word I expected to encounter, what it really means is impaired sensory gating. This is a core feature of Asperger’s, ADHD and schizophrenia.
One of the key risk genes for schizophrenia, DISC1, also affects HCN channels and this may account for some of the cognitive deficit found in schizophrenia. High level thinking is particularly affected.  It is thought that loss of DISC1 function in the PFC would likely prevent proper PDE4 function, leading to a dysregulated build-up of cAMP in dendritic spines resulting in excessive opening of HCN channels

I did wonder how nicotine fits in, since in earlier post we saw that α7 nAChR agonists, like nicotine, improve sensory gating and indeed that people with schizophrenia tend to be smokers. It turns out that nicotine is also an HCN channel blocker. For a change, everything seems to fit nicely together. There are different ways to block HCN channels, some of which are indirect. One common ADHD drug, Guanfacine, keeps these channels closed, but in a surprising way.
Alpha-2A adrenergic receptors near the HCN channels, on those dendritic spines, inhibit the production of cAMP and the HCN channels stay closed, allowing the information to pass through into the cell, connecting the network. These Alpha-2A adrenergic  receptors are stimulated by a natural brain chemical norepinephrine, or by drugs like Guanfacine.
Stress appears to flood PFC neurons with cAMP, which opens HCN channels, temporarily disconnects networks, and impairs higher cognitive abilities.
This would explain why stress makes people’s sensory gating problems get worse. So someone with Asperger’s would get more distracted/disturbed at exam time at school for example, or when he goes for a job interview. Reducing stress is another method to improve sensory gating and indeed cognition. In Monty, aged 14 with ASD, the only time he exhibits significantly impaired sensory gating, is when he has stopped all his Polypill therapies for several days. I think stress/anxiety is what has changed and this opens those HCN channels. Then even the sound of someone eating food next to him makes him angry.
Excessive opening of HCN channels might underlie many lapses in higher cognitive function.
While the researchers at Yale patented the idea of HCN blockers to improve cognition, we can see how other existing ideas to improve cognition may indeed have the same mechanism, most notably PDE4 inhibitors.
The University of Maastricht holds patents on the use of Roflumilast, a PDE4 inhibitor, to improve cognition; most interestingly, this takes effect at one fifth of the COPD dosage, for which it is an approved drug. At high doses PDE4 inhibitors have annoying side effects, but at low doses they tend to be trouble-free.
One effect of a PDE4 inhibitor is that it reduces cAMP. So a PDE4 inhibitor acts indirectly like an HCN blocker.
Not surprisingly recent research showed that low doses of Roflumilast improves sensory gating in those affected by this issue.
So rather than waiting for a brain selective HCN blocker, the potential exists to use a one fifth dose of Roflumilast today. This is something that should indeed be investigated across different types of cognitive dysfunction.
There are numerous dysfunctions that can impair cognition and they can occur in different diagnosis. For example impaired autophagy is a key feature of Huntington’s, impaired remyelination defines multiple sclerosis, low levels of nerve growth factor are a key feature of Rett syndrome. Less severe dysfunctions of these processes occur in entirely different conditions.
It is thought that people with Alzheimer’s might benefit from PDE4 inhibition. If it was me, I would try it in all types of dementia or cognitive loss of any kind.

PDE4 Inhibitors
There have been many mentions of PDE4 inhibitors elsewhere in this blog. They are broadly anti-inflammatory and anti-oxidant, but currently only widely used to treat asthma in Japan and COPD in Western countries. COPD is a kind of very severe asthma.
Traditionally a PDE4 inhibitor is thought of as drug used to block the degradative action of phosphodiesterase 4 (PDE4) on cyclic adenosine monophosphate (cAMP). That all sound complicated, just think of it as increasing cAMP.
Now cAMP is a messenger in many biological processes, one of which relates to PKA (Protein Kinase A). In autism we know that PKA, PKB and PKC are often disturbed. These PKs are very important because they have the ability to literally change the function of thousands of proteins in your body. This is similar to how epigenetic tags can switch on or switch off a particular gene. PKs, via a different mechanism we will look at in another post, change the function of proteins, so it is very important that you have the correct level of PKA, PKB and PKC.
We saw in a recent post that the Pitt Hopkins gene TCF4 is regulated by PKA and that under-expression of TCF4 is also a feature of some ID and schizophrenia. So more PKA, please.

You can use a PDE4 inhibitor to increase cAMP, which then increases PKA.

Other effects of PDE4 inhibitors
Today’s post is about sensory gating and the effect here of PDE4 inhibitors is via the effect of cAMP on those HCN channels in your tiny dendritic spines.
There are numerous other effects of PDE4 that may also be therapeutic. One interesting effect is that inhibition of PDE4 can mimic calorie restriction by activating AMPK/SIRT1 pathway.
Calorie restriction has just been shown in a large trial to be able to reverse type 2 diabetes, if initiated with a few years of the disease developing.
Humans have evolved based to periods of feast and famine. Periods of fasting may be therapeutic for many modern conditions.
Not surprisingly one side effect of PDE4 inhibitors is weight loss. Many psychiatric drugs cause troubling weight gain.

Acute administration of Roflumilast enhances sensory gating in healthy young humans in a randomized trial. 




Sensory gating is a process involved in early information processing which prevents overstimulation of higher cortical areas by filtering sensory information. Research has shown that the process of sensory gating is disrupted in patients suffering from clinical disorders including attention deficit hyper activity disorder, schizophrenia, and Alzheimer's disease. Phosphodiesterase (PDE) inhibitors have received an increased interest as a tool to improve cognitive performance in both animals and man, including sensory gating.


The current study investigated the effects of the PDE4 inhibitor Roflumilast in a sensory gating paradigm in 20 healthy young human volunteers (age range 18-30 years). We applied a placebo-controlled randomized cross-over design and tested three doses (100, 300, 1000 μg).


Results show that Roflumilast improves sensory gating in healthy young human volunteers only at the 100-μg dose. The effective dose of 100 μg is five times lower than the clinically approved dose for the treatment of acute exacerbations in chronic obstructive pulmonary disease (COPD). No side-effects, such as nausea and emesis, were observed at this dose. This means Roflumilast shows a beneficial effect on gating at a dose that had no adverse effects reported following single-dose administration in the present study.


The PDE4 inhibitor Roflumilast has a favourable side-effect profile at a cognitively effective dose and could be considered as a treatment in disorders affected by disrupted sensory gating.

Background Information
Selective phosphodiesterase (PDE) inhibition has been considered as a very promising target for cognition enhancement.
Roflumilast is a PDE4 inhibitor that has been developed by Takeda for Chronic Obstructive Pulmonary Disease (COPD). In recent year, Maastricht University has been collaborating with Takeda to develop Roflumilast for cognitive impairments
In 2015 Takeda sold COPD indication of Roflumilast to AstraZeneca, and ownership of IP for treatment of cognitive impairment returned to Maastricht University.
Compelling clinical results
A single administration of Roflumilast improves episodic memory in mice, and in young and elderly healthy subjects at a non-emetic dose
As shown in the figure, healthy (A) and memory impaired (B) elderly subjects showed better performances in the delayed recall of the Verbal Learning Task after roflumilast

Key Features and Advantages
Opportunities to reposition a clinically-proven safe compound with a well-established pharmacology.
Compelling preclinical and clinical evidences showing that Roflumilast effectively deliver to the brain to produce robust cognitive enhancement.
Pro-cognitive effects at low dose (5 times lower than COPD indication), which allows to circumvent the emetic effects commonly observed with other PDE4 inhibitors
Maastricht University has a strong IP protection extending to at least 2033.

PDE inhibitors in psychiatry--future options for dementia, depression and schizophrenia?

Author information


Phosphodiesterases are key enzymes in cellular signalling pathways. They degrade cyclic nucleotides and their inhibition via specific inhibitors offers unique 'receptor-independent' opportunities to modify cellular function. An increasing number of in vitro and animal model studies point to innovative treatment options in neurology and psychiatry. This review critiques a selection of recent studies and developments with a focus on dementia/neuroprotection, depression and schizophrenia. Despite increased interest among the clinical neurosciences, there are still no approved PDE inhibitors for clinical use in neurology or psychiatry. Adverse effects are a major impediment for clinical approval. It is therefore necessary to search for more specific inhibitors at the level of different PDE sub-families and isoforms.

The current study found that brain cells in PFC contain ion channels called hyperpolarization-activated cyclic nucleotide-gated channels (HCN) that reside on dendritic spines, the tiny protrusions on neurons that are specialized for receiving information. These channels can open when they are exposed to cAMP (cyclic adenosine monophosphate). When open, the information can no longer flow into the cell, and thus the network is effectively disconnected. Arnsten said inhibiting cAMP closes the channels and allows the network to reconnect.
Guanfacine can strengthen the connectivity of these networks by keeping these channels closed, thus improving working memory and reducing distractibility," she said. "This is the first time we have observed the mechanism of action of a psychotropic medication in such depth, at the level of ion channels."
Arnsten said the excessive opening of HCN channels might underlie many lapses in higher cognitive function. Stress, for example, appears to flood PFC neurons with cAMP, which opens HCN channels, temporarily disconnects networks, and impairs higher cognitive abilities.
The study also found alpha-2A adrenergic receptors near the channels that inhibit the production of cAMP and allow the information to pass through into the cell, connecting the network. These receptors are stimulated by a natural brain chemical  norepinephrine or by medications like guanfacine.
 “Guanfacine can strengthen the connectivity of these networks by keeping these channels closed, thus improving working memory and reducing distractibility,” she said. “This is the first time we have observed the mechanism of action of a psychotropic medication in such depth, at the level of ion channels.”
Yale has submitted a patent application on the use of HCN blockers for the treatment of PFC cognitive deficits based on the data reported in the Cell paper.

The full Yale paper:

The prefrontal cortex (PFC) is among the most evolved brain regions, contributing to our highest order cognitive abilities. It regulates behavior, thought, and emotion using working memory. Many cognitive disorders involve impairments of the PFC. A century of discoveries at Yale Medical School has revealed the neurobiology of PFC cognitive functions, as well as the molecular needs of these circuits. This work has led to the identification of therapeutic targets to treat cognitive disorders. Recent research has found that the noradrenergic α2A agonist guanfacine can improve PFC function by strengthening PFC network connections via inhibition of cAMP-potassium channel signaling in postsynaptic spines. Guanfacine is now being used to treat a variety of PFC cognitive disorders, including Tourette’s Syndrome and Attention Deficit Hyperactivity Disorder (ADHD). This article reviews the history of Yale discoveries on the neurobiology of PFC working memory function and the identification of guanfacine for treating cognitive disorders.

Molecular modeling suggests that, similarly to ZD 7288, nicotine and epibatidine directly bind to the inner pore of the HCN channels. It is therefore likely that nicotine severely influences rhythmogenesis and high cognitive functions in smokers.

Modulation of HCN channels in lateral septum by nicotine

I think many people stand to benefit from the drugs mentioned in today’s post, but for different biological reasons. A person with Pitt Hopkins may benefit from Roflumilast because it will upregulate PKA and then increase expression of their remaining TCF4 gene.
In a person with schizophrenia there are multiple reasons these drugs might help them and it will depend on which genes they have that are misexpressed (TCF4, DISC1 etc.).
In a person with idiopathic Asperger’s and impaired sensory gating it looks like the effect on HCN channels is what is important.
I think low dose Roflumilast has great potential for many. The Japanese drug Ibudilast very likely will provide similar benefits, but at what dosage?
PDE4 inhibitors do have side effects at higher doses in part because there are several different types of PDE4 (PDE4A, PDE4B, PDE4C etc) and different drugs effect different subtypes differently.
Ibudilast is used as a daily drug therapy for asthma in Japan and is being studied as a therapy for Multiple Sclerosis (MS) in the US.
Roflumilast is sold by Astra Zeneca as Daxas/Daliresp but at a high dose of 500mcg to treat flare ups of COPD (Chronic Obstructive Pulmonary Disease) it does cause troubling side effects, but it reduces your chance of dying from COPD.
The cognitive dose used in research is 100mcg. Higher doses had no cognitive/sensory gating benefit.
Further investigation of the ADHD drug Guanfacine should be made, because some of the people who benefit from a PDE4 inhibitor might get a similar effect from Guanfacine. People with Pitt Hopkins would not be in this category. A person with Asperger’s and impaired sensory dating should respond to Guanfacine, a cheap drug.
At the end of the day, choice of therapy will come down to side effects and cost. In the US, Roflumilast is expensive ($330), seven times more expensive than in some other countries; in the UK the price of the same 30 tablets is $50. One pack would be enough for 5 months at the suggested dose.

Friday, 3 March 2017

Polygenic Disorders that Overlap – Autism(s), Schizophrenia(s), Bipolar(s) and ADHD(s) – Creativity & Intelligence

Blogs are inevitably rather jumbled up and lack a clear structure; today’s post really should be at the beginning.
One clear message from the more sophisticated research into neuropsychiatric disorders is that they are generally associated with variances in the expression of numerous different genes, making them polygenic.
What I find interesting is that there is a substantial overlap in the genes that are miss-expressed across different neuropsychiatric disorders.  This is further proof, if it was needed, that the observational diagnoses used by psychiatrists are rather primitive.
So individual people will have a near unique set of genetic variances that make their symptoms slightly different to everyone else.  However it is highly likely that discrete biological dysfunctions will exist across the diagnoses.  So for example elevated intracellular chloride will be found in some autism and some schizophrenia. A calcium channelopathy affecting Cav1.2 would be found in some autism and some bipolar.
Eventually you would dispose of the old observational diagnoses like bipolar and give the biological diagnoses.  Then you will have the same drugs being used in a person with “bipolar” and another with “autism”.  When all this will happen is no time soon. 
In the meantime people interested in autism can benefit from the research into the other neuropsychiatric disorders.  These other disorders can be much better researched, partly because they usually concern adults who are fully verbal and have typical IQ.  In many cases there are both hypo and hyper cases in these disorders.   
Also of interest is that the same unusual gene expression in schizophrenia/bipolar is linked to creativity and the autism genes to intelligence. This is put forward as an explanation as to why evolution has conserved rather than erased neuropsychiatric disorders.

Height is polygenic 

Let’s start will a simple example.
There is no single gene that determines your height. Some school books suggest 3 or 4 genes, so let’s assume that is correct for now.
Traits are polygenic when there is wide variation. For example, humans can be many different sizes. Height is a polygenic trait, controlled by at least three genes with six alleles. If you are dominant for all of the alleles for height, then you will be very tall. There is also a wide range of skin colour across people. Skin colour is also a polygenic trait, as are hair and eye colour.

Polygenic inheritance often results in a bell shaped curve when you analyze the population. Most people fall in the middle of the phenotypic range, such as average height, while very few people are at the extremes, such as very tall or very short. At one end of the curve will be individuals who are recessive for all the alleles (for example, aabbcc); at the other end will be individuals who are dominant for all the alleles (for example, AABBCC). Through the middle of the curve will be individuals who have a combination of dominant and recessive alleles (for example, AaBbCc or AaBBcc).

There may be 4 or 6 or more alleles involved in the phenotype. At the left extreme, individuals are completely dominant for all alleles, and at the right extreme, individuals are completely recessive for all alleles. Individuals in the middle have various combinations of recessive and dominant alleles.
Unfortunately the real world is a bit more complex than high school biology. 

“Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.

Genes vs the Environment 
The spectrum of human diseases are caused by a multitude of genetic and environmental factors acting together. In certain conditions such as Down syndrome , genetic factors predominate, while in infections for example, environmental factors predominate. Most chronic non-communicable conditions such as schizophrenia and diabetes as well as congenital malformations are caused by an interaction of both genetic and environmental factors.

The environment and epigenetic change
Some environmental influences, like smoking or pollution, can also become genetic in that heritable epigenetic markers can become tagged to a specific gene.  This impacts whether it is turned on or off.  

Multifactorial vs Polygenic Inheritance 
Multifactorial inheritance diseases that show familial clustering but do not conform to any recognized pattern of single gene inheritance are termed multifactorial disorders. They are determined by the additive effects of many genes at different loci together with the effect of environmental factors.

These conditions show a definite familial tendency but the incidence in close relatives of affected individuals is usually around 2-4%, instead of the much higher figures that would be seen if these conditions were caused by mutations in single genes (25-50%).
Examples of disorders of multifactorial inheritance

·        asthma

·        schizophrenia

·        diabetes mellitus

·        hypertension

Polygenic inheritance involves the inheritance and expression of a phenotype being determined by many genes at different loci, with each gene exerting a small additive effect. Additive implies that the effects of the genes are cumulative, i.e. no one gene is dominant or recessive to another.

According to the liability/threshold model, all of the factors which influence the development of a multifactorial disorder, whether genetic or environmental, can be considered as a single entity known as liability.
The liabilities of all individuals in a population form a continuous variable, which can be exemplified by a bell shaped curve.

Individuals on the right side of the threshold line represent those affected by the disorder. 
In autism the threshold keeps being moved, because the definition of the disease keeps being widened.

Liability curves of affected and their relatives
The liability curve is relevant to the question posed by parents who have autism in the family and want to know whether it will occur again and also to grown up siblings of those with autism.

The curve for relatives of affected will be shifted to the right; so the familial incidence is higher than the general population incidence.

So the biggest future autism risk is likely to be a previous occurance. 
There are ways to actively promote protective factors and shift the curve back to the left; but a risk will remain. 

Evidence that Autism is Polygenic 
This is a paper from 2016 that looks at how the genetic risks are additive.

Autism spectrum disorder (ASD) risk is influenced by both common polygenic and de novo variation. The purpose of this analysis was to clarify the influence of common polygenic risk for ASDs and to identify subgroups of cases, including those with strong acting de novo variants, in which different types of polygenic risk are relevant. To do so, we extend the transmission disequilibrium approach to encompass polygenic risk scores, and introduce with polygenic transmission disequilibrium test. Using data from more than 6,400 children with ASDs and 15,000 of their family members, we show that polygenic risk for ASDs, schizophrenia, and educational attainment is over transmitted to children with ASDs in two independent samples, but not to their unaffected siblings. These findings hold independent of proband IQ. We find that common polygenic variation contributes additively to ASD risk in cases that carry a very strong acting de novo variant. Lastly, we find evidence that elements of polygenic risk are independent and differ in their relationship with proband phenotype. These results confirm that ASDs' genetic influences are highly additive and suggest that they create risk through at least partially distinct etiologic pathways.

Summary and Conclusions
Autism and related conditions are highly heritable disorders. Consequently, gene discovery promises to help elucidate the underlying pathophysiology of these syndromes and, it is hoped, eventually improve diagnosis, treatment, and prognosis. The genetic architecture of autism is not yet known. What can be said from the studies to date is that writ large, autism is not a monogenic disorder with Mendelian inheritance. In many, but clearly not all individual cases, it is likely to be a complex genetic disorder that results from simultaneous genetic variations in multiple genes. The CDCV hypothesis predicts that the risk alleles in Autism and other complex disorders will be common in the population. However, recent evidence both with regard to autism and other complex disorders, raises significant questions regarding the overall applicability of the theory and the extent of its usefulness in explaining individual genetic liability. In addition, considerable evidence points to the importance of rare alleles for the overall population of affected individuals as well as their role in providing a foothold into the molecular mechanisms of disease. Finally, there is debate regarding the clinical implications of autism genetic research to date. Most institutional guidelines recommend genetic testing or referral only for idiopathic autism if intellectual disability and dysmorphic features are present. However, recent advances suggest that the combination of several routine tests combined with a low threshold for referral is well-justified in cases of idiopathic autism.

So What is Autism? 
Most people’s autism is of unknown cause (idiopathic) and this is most likely to be polygenic, but highly likely to have some environmental influences making it multifactorial.

What is interesting and potentially relevant to therapy is that the polygenic footprint of autism overlaps with those causing other neuropsychiatric diseases like bipolar, schizophrenia and even ADHD.

As you broaden the definition of autism and so move the threshold you will eventually diagnose everyone as having autism; because we all have some autism genes.

This does then start to be ridiculous, but in some ways we are now at the point where quirky but normal has become quirky autistic.
This same questionable position of where to draw the threshold applies to all such disorders (bipolar, ADHD etc.).  At what point does a difference become a disorder?
Where things currently stand more than 10% of the population have an autism-gene-overlapping diagnosis.  That is a lot and suggests that things are getting a little out of control.  Perhaps better to raise the threshold for where difference become disorder?

 Percent of the population affected by various disorders genetically overlapping to strictly define autism (SDA). Estimates of prevalence vary widely by country and study.

If you raise the threshold for how severe autism has to be, you soon lose the quirky autism. A stricter approach to diagnosing ADHD would mean losing the people that will naturally “grow out of it” and leave a much smaller group that might genuinely benefit from medical intervention. We saw in an earlier post that the percentage of kids with ADHD given drugs varies massively among developed countries, with the US at the top and France at the bottom. Here is another article on this subject.

Autism overlapping with Schizophrenia, Bipolar ADHD etc.
There are now numerous different studies showing how the large number of genes that underlie each observational diagnosis overlap with each other.

One Sentence Summary: Autism, schizophrenia, and bipolar disorder share global gene expression patterns, characterized by astrocyte activation and disrupted synaptic processes.
Recent large-scale studies have identified multiple genetic risk factors for mental illness and indicate a complex, polygenic, and pleiotropic genetic architecture for neuropsychiatric disease. However, little is known about how genetic variants yield brain dysfunction or pathology. We use transcriptomic profiling as an unbiased, quantitative readout of molecular phenotypes across 5 major psychiatric disorders, including autism (ASD), schizophrenia (SCZ), bipolar disorder (BD), depression (MDD), and alcoholism (AAD), compared with carefully matched controls. We identify a clear pattern of shared and distinct gene-expression perturbations across these conditions, identifying neuronal gene co-expression modules downregulated across ASD, SCZ, and BD, and astrocyte related modules most prominently upregulated in ASD and SCZ. Remarkably, the degree of sharing of transcriptional dysregulation was strongly related to polygenic (SNP-based) overlap across disorders, indicating a significant genetic component. These findings provide a systems-level view of the neurobiological architecture of major neuropsychiatric illness and demonstrate pathways of molecular convergence and specificity.

We observe a gradient of synaptic gene down-regulation, with ASD > SZ > BD. BD and SCZ appear most similar in terms of synaptic dysfunction and astroglial activation and are most differentiated by subtle downregulation in microglial and endothelial modules. ASD shows the most pronounced upregulation of a microglia signature, which is minimal in SCZ or BD. Based on these data, we hypothesize that a more severe synaptic phenotype, as well as the presence of microglial activation, is responsible for the earlier onset of symptoms in ASD, compared with the other disorders, consistent with an emerging understanding of the critical non-inflammatory role for microglia in regulation of synaptic connectivity during neurodevelopment (39, 66). MDD shows neither the synaptic nor astroglial pathology observed in SCZ, BD. In contrast, in MDD, a striking dysregulation of HPA-axis and hormonal signalling not seen in the other disorders is observed. These results provide the first systematic, transcriptomic framework for understanding the pathophysiology of neuropsychiatric disease, placing disorder-related alterations in gene expression in the context of shared and distinct genetic effects.


Several of the variants lie in regions important for immune function and associated with autism. This suggests that both disorders stem partly from abnormal activation of the immune system, say some researchers.

The study builds on previous work, in which Arking’s team characterized gene expression in postmortem brain tissue from 32 individuals with autism and 40 controls2. In the new analysis, the researchers made use of that dataset as well as one from the Stanley Medical Research Institute that looked at 31 people with schizophrenia, 25 with bipolar disorder and 26 controls3.
They found 106 genes expressed at lower levels in autism and schizophrenia brains than in controls. These genes are involved in the development of neurons, especially the formation of the long projections that carry nerve signals and the development of the junctions, or synapses, between one cell and the next. The results are consistent with those from previous studies indicating a role for genes involved in brain development in both conditions.

“On the one hand, it’s exciting because it tells us that there’s a lot of overlap,” says Jeremy Willsey, assistant professor of psychiatry at the University of California, San Francisco, who was not involved in the work. “On the other hand, these are fairly general things that are overlapping.”
Full paper

Schizophrenia/Bipolar linked to Creativity? Autism linked to Intelligence?

Since we see that neuropsychiatric disorders are substantially polygenic, the question arises why they have been evolutionarily conserved. Over thousands of years why have these traits not just faded away?
That question was raised, and answered again, in a recent autism study at Yale.  The same wide cluster of genes that may lead trigger autism are again seen to be linked to higher intelligence. You may get autism, higher intelligence, both or indeed neither, but people with those genes have a higher likelihood of autism and/or a higher IQ.

Previous studies have linked bipolar/schizophrenia to creativity, so you would expect artists and stage actors to have a higher incidence of those disorders.
In terms of evolutionary selection, clearly creativity and intelligence have been valued and so the associated disorders did not fade away over thousands of years.

“It might be difficult to imagine why the large number of gene variants that together give rise to traits like ASD are retained in human populations — why aren’t they just eliminated by evolution?” said Joel Gelernter, the Foundations Fund Professor of Psychiatry, professor of genetics and of neuroscience, and co-author. “The idea is that during evolution these variants that have positive effects on cognitive function were selected, but at a cost — in this case an increased risk of autism spectrum disorders. 


Cognitive impairment is common among individuals diagnosed with autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD). It has been suggested that some aspects of intelligence are preserved or even superior in people with ASD compared with controls, but consistent evidence is lacking. Few studies have examined the genetic overlap between cognitive ability and ASD/ADHD. The aim of this study was to examine the polygenic overlap between ASD/ADHD and cognitive ability in individuals from the general population. Polygenic risk for ADHD and ASD was calculated from genome-wide association studies of ASD and ADHD conducted by the Psychiatric Genetics Consortium. Risk scores were created in three independent cohorts: Generation Scotland Scottish Family Health Study (GS:SFHS) (n=9863), the Lothian Birth Cohorts 1936 and 1921 (n=1522), and the Brisbane Adolescent Twin Sample (BATS) (n=921). We report that polygenic risk for ASD is positively correlated with general cognitive ability (beta=0.07, P=6 × 10(-7), r(2)=0.003), logical memory and verbal intelligence in GS:SFHS. This was replicated in BATS as a positive association with full-scale intelligent quotient (IQ) (beta=0.07, P=0.03, r(2)=0.005). We did not find consistent evidence that polygenic risk for ADHD was associated with cognitive function; however, a negative correlation with IQ at age 11 years (beta=-0.08, Z=-3.3, P=0.001) was observed in the Lothian Birth Cohorts. These findings are in individuals from the general population, suggesting that the relationship between genetic risk for ASD and intelligence is partly independent of clinical state. These data suggest that common genetic variation relevant for ASD influences general cognitive ability.
Given the overlap between so many neuropsychiatric disorders it might be helpful if psychiatrists were more aware of the limitations of their observational diagnoses.
There is no singular schizophrenia like there is no single autism. They are all intertwined.  A mood disturbance in Asperger’s may have plenty in common with one in schizophrenia and respond to the same therapy.  Not surprisingly an off-label treatment in autism may work wonders for someone who is bipolar.
Probably the tighter you define autism the more there will be biological overlaps with bipolar/schizophrenia.
While there are overlaps there are other areas where autism is the opposite of bipolar and/or schizophrenia.
From a therapeutic perspective, since schizophrenia therapies have been more deeply researched than those of autism, it is always well work checking schizophrenia research for evidence.
The multifactorial approach does help explain the increasing incidence of more severe autism as environmental insults increase in modern life and we accumulate epigenetic damage.  The studies linked autism/schizophrenia with immunity genes and there is has been a continuing rise in other auto-immune, disease like asthma.
The ever sliding diagnosis threshold substantially explains much of the great increase in mild autism.
You can also use this framework to work out how to reduce the incidence of autism in future generations, but it seems that human nature continues to work in the opposite way.

Environmental factors are simple to modify, reducing risk factors and increasing protective factors.

If you think like Knut Wittkowski you might look at the tail of autism liability curve and try to identify those future people. Those people are likely to have some of the 700 autism risk genes over/under expressed and might benefit from some preventative therapy to minimize the coming developmental damage.  Knut thinks that Mefanemic acid will do the job. There are numerous other ideas.

Sunday, 26 February 2017

Secondary Monoamine Neurotransmitter Disorders in Autism – Treatment with 5-HTP and levodopa/carbidopa?

This post is about monoamine neurotransmitter disorders in Autism, that are usually a down-stream consequence of other miscellaneous dysfunctions, which makes them “secondary” dysfunctions.

There was a post on this blog way back in 2013 on catecholamines:

Classical monoamine is a broader term and encompasses:-

       ·          Classical Tryptamines:

Drugs used to increase or reduce the effect of monoamines are sometimes used to treat patients with psychiatric disorders, including depression, anxiety, and schizophrenia.

This blog does go on rather ad nauseam about histamine, so today it will skip over it.  It does not cause autism, but it certainly can make it much worse in some people.

Tryptophan is a precursor to the neurotransmitters serotonin and melatonin.  For years it has been known that odd things are going on in some people with autism regarding tryptophan, serotonin and indeed melatonin. This research does not really lead you anywhere.

Other than being converted to serotonin and melatonin, tryptophan has the potential to be converted in the gut into some very good things and some bad ones; this all depends on what bacteria are present. People lucky enough to have Clostridium sporogenes will produce a super potent, but apparently very safe, antioxidant called 3-Indolepropionic acid (IPA), which is seen as an Alzheimer’s  therapy.  To be effective you would need a constant supply of IPA, and that is exactly what you get from the right bacteria living in your gut.

Some people with autism have high levels of serotonin in their blood and so do their parent(s). It is known that in the brain many people with autism have low levels of serotonin.  Various mechanisms have been proposed to explain this using the body’s feedback loops, including mother to child.

Many people with autism take 5-HTP which is an  intermediate in the synthesis of both serotonin and melatonin from tryptophan.

Serotonin itself does not cross the blood brain barrier (BBB).

Too much serotonin in your brain has a negative effect and so taking too much 5-HTP supplement produces negative effects.

Many people take melatonin at small doses for sleep. At larger doses it has many other beneficial effects that range from resolving GI problems to reducing oxidative stress in mitochondria. 

Of the Catecholamines, it is dopamine that gets the most attention in neuro-psychiatric disorders and schizophrenia in particular.

There is a dopamine hypothesis for schizophrenia, but there is also a glutamate hypothesis of schizophrenia. 

If you read the research, it is actually ADHD that has the strongest connection to dopamine.  When you look closer still, you will see that even that connection is quite weak.

The conclusion is that ADHD, just like autism and schizophrenia is usually multigenic, meaning that numerous little things went awry, rather than one single dysfunction.

Tourette's syndrome and related tic disorders may be associated with either too much dopamine or overly sensitive dopamine receptors. 

It is fair to say that secondary monoamine neurotransmitter disorders can occur in autism, ADHD and indeed schizophrenia.

There is a long list of primary monoamine neurotransmitter disorders and much is known about them.

Monoamine Neurotransmitter Disorders  

I found an excellent paper that tells you pretty much all you could want to know about monoamine neurotransmitter disorders.  It also has nice graphics to explain what is going on.

Most people with autism are unlikely to have a primary disorder, but if they did, treating it should have a big impact on them.

BH4 =tetrahydrobiopterin. TH-D=tyrosine hydroxylase deficiency. AADC-D=aromatic L-amino acid decarboxylase deficiency. DTDS=dopamine transporter deficiency syndrome. PLP-DE=pyridoxal-phosphate-dependent epilepsy. P-DE=pyridoxine-dependent epilepsy. AD GTPCH-D=autosomal dominant GTP cyclohydrolase 1 deficiency. SR-D=sepiapterin reductase deficiency. AR GTPCH-D=autosomal recessive GTP cyclohydrolase 1 deficiency. PTPS-D=6-pyruvoyltetrahydropterin synthase deficiency. DHPR-D=dihydropteridine reductase deficiency. HIE=hypoxic ischaemic encephalopathy. PKAN=pantothenate kinase associated neurodegeneration. DNRD=dopa non-responsive dystonia. PKD=paroxysmal kinesogenic dyskinesia.

People with a secondary disorder would typically be identified by testing their spinal fluid for the metabolites of the monoamine.  So for serotonin you measure  5-HIAA (5-hydroxyindoleacetic acid) and for dopamine you measure  HVA (homovanillic acid).

Figure 2: The monoamine neurotransmitter biosynthesis pathway BH4 is synthesized in four enzymatic steps from GTP. BH4 is a necessary cofactor for TrpH and TH, the rate limiting enzymes in monoamine synthesis. Tryptophan is converted to 5-HTP by TrpH. Tyrosine is converted to L-dopa by TH. The conversion of 5-HTP to serotonin and of L-dopa to dopamine is catalyzed by AADC and its cofactor PLP.  When BH4 acts as a cofactor for TH and TrpH, it is converted to PCBD, which in turn is converted to BH4 (in the BH4 regeneration pathway) by a two-step process involving PCD and DHPR. After synthesis, uptake of monoamine neurotransmitters into the synaptic secretory vesicles requires the vesicular monoamine transporter VMAT (not shown).⁶ After synaptic transmission, serotonin and dopamine are metabolised through similar pathways, which involve MAO enzymes and COMT. Presynaptic reuptake of the monoamines is facilitated by DAT and SERT (not shown).⁷ Metabolic pathway of BH4 synthesis is shown in light blue, monoamine synthesis in light green, monoamine catabolism in dark blue, and BH4 regeneration in red. The biogenic amines are illustrated in light green circles and the cofactors (BH4 and PLP) are represented by light blue circles. Enzymes in the monoamine neurotransmitter pathway are underlined. GTPCH=GTP cyclohydrolase 1. H₂NP₃=dihydroneopterin triphosphate. PTPS=6-pyruvoyltetrahydropterin synthase. 6-PTP=6-pyruvoyltetrahydropterin. AR=aldose reductase. SP=sepiapterin. SR=sepiapterin reductase. BH4 =tetrahydrobiopterin. TrpH=tryptophan hydroxylase. TH=tyrosine hydroxylase. DHPR=dihydropteridine reductase. PCBD=tetrahydrobiopterin-α-carbinolamine. PCD=pterin-4αcarbinolamine dehydratase. qBH₂=(quinonoid) dihydrobiopterin. 5-HTP=5-hydroxytryptophan. L-dopa=levodihydroxyphenylalanine. COMT=catechol-O-methyltransferase. 3-OMD=3-ortho-methyldopa. VLA=vanillactic acid. AADC=aromatic L-amino acid decarboxylase. PLP=pyridoxal phosphate. DBH=dopamine β hydroxylase. PNMT=phenylethanolamine N-methyltransferase. MAO=monoamine oxidase. AD=aldehyde dehydrogenase. 3-MT=3-methoxytyramine. DOPAC=3,4-dihydroxyphenylacetic acid. 5-HIAA=5-hydroxyindoleacetic acid. HVA=homovanillic acid. MHPG=3-methoxy-4-hydroxylphenylglycol. VMA=vanillylmandelic acid.

The paper is very clear about what to:-

Secondary neurotransmitter disorders

Neurotransmitters abnormalities indicative of dopamine or serotonin depletion are becoming increasingly recognized as secondary phenomena in several neurological disorders. Concentrations of HVA and 5-HIAA in CSF in such patients are mostly within the range deemed abnormal for primary neurotransmitter disorders, but generally do not reach the lowest levels.

A secondary reduction in HVA is reported in perinatal asphyxia, disorders of folate metabolism, phenyl ketonuria, Lesch-Nyhan disease, mitochondrial disorders, epilepsy (and infantile spasms), opsoclonus-myoclonus, pontocerebellar hypoplasia, leukodystrophies, Rett’s syndrome, and some neuropsychiatric disorders.  Many patients who have no specific diagnosis but who present with neuromuscular or dystonic symptoms have low HVA concentrations in CSF, which suggests dopaminergic depletion. These patients also often present with dyskinesia, tremor, and eye-movement disorders similar to those seen in many of the primary monoamine neurotransmitter disorders. Cortical atrophy is associated with low levels of 5-HIAA in CSF. Low concentrations of HVA and 5-HIAA have been reported in patients with type 2 pontocerebellar hypoplasia and in a syndrome that involves spontaneous periodic hypothermia and hyperhidrosis.  Whether the latter syndrome is a primary or secondary neurotransmitter disorder is still unclear because the underlying cause is unknown. Patients with neonatal disease onset who have severe motor deficits and abnormalities on brain MRI seem particularly vulnerable to secondary reductions in HVA production. Such disruption of normal brain function is likely to impair biogenic monoamine synthesis, and the resultant neurotransmitter deficiencies in critical periods of neurodevelopment are thought to prevent development of certain brain functions. The possibility of treating such patients with levodopa, 5-hydroxytryptophan, or both should be considered, therefore, to improve brain maturation and neurological outcome.

When you look at autism specifically it is usually 5-HIAA and not HVA that is disturbed.  

Now for two papers by one of our reader Roger’s favourite researchers, Vincent Ramaekers. Ramaekers is one of the specialists for central folate deficiency and even better is a researcher/clinician who replies to my emails. 


Patients with autism spectrum disorder (ASD) may have low brain serotonin concentrations as reflected by the serotonin end-metabolite 5-hydroxyindolacetic acid (5HIAA) in cerebrospinal fluid (CSF).


We sequenced the candidate genes SLC6A4 (SERT), SLC29A4 (PMAT), and GCHFR (GFRP), followed by whole exome analysis.


The known heterozygous p.Gly56Ala mutation in the SLC6A4 gene was equally found in the ASD and control populations. Using a genetic candidate gene approach, we identified, in 8 patients of a cohort of 248 with ASD, a high prevalence (3.2%) of three novel heterozygous non-synonymous mutations within the SLC29A4 plasma membrane monoamine transporter (PMAT) gene, c.86A > G (p.Asp29Gly) in two patients, c.412G > A (p.Ala138Thr) in five patients, and c.978 T > G (p.Asp326Glu) in one patient. Genome analysis of unaffected parents confirmed that these PMAT mutations were not de novo but inherited mutations.

Expression of mutations PMAT-p.Ala138Thr and p.Asp326Glu in cellulae revealed significant reduced transport uptake activity towards a variety of substrates including serotonin, dopamine, and 1-methyl-4-phenylpyridinium (MPP+), while mutation p.Asp29Gly had reduced transport activity only towards MPP+. At least two ASD subjects with either the PMAT-Ala138Thr or the PMAT-Asp326Glu mutation with altered serotonin transport activity had, besides low 5HIAA in CSF, elevated serotonin levels in blood and platelets. Moreover, whole exome sequencing revealed additional alterations in these two ASD patients in mainly serotonin-homeostasis genes compared to their non-affected family members.


Our findings link mutations in SLC29A4 to the ASD population although not invariably to low brain serotonin. PMAT dysfunction is speculated to raise serotonin prenatally, exerting a negative feedback inhibition through serotonin receptors on development of serotonin networks and local serotonin synthesis. Exome sequencing of serotonin homeostasis genes in two families illustrated more insight in aberrant serotonin signaling in ASD.

In this context, we found that isolated low brain serotonin concentration, as reflected by the 5HIAA in the CSF, is associated with PDD-NOS and the functional (heterozygous) c.167G > C (p.G56A) mutation of the serotonin re-uptake transporter gene (SERT/SCL6A4) combined with a homozygous long (L/L) SERT gene-linked polymorphic promoter (5-HTTLPR) region [21]. Moreover, daily treatment with serotonin precursor 5-hydroxytryptophan and aromatic amino acid decarboxylase (AADC) inhibitor carbidopaled to clinical improvements and normalization of the 5HIAA levels in the CSF and urine, indicating that the brain serotonin turnover was normalized [22]. In an attempt to gain some insight into the brain serotonin physiology and underlying mechanisms of abnormal brain metabolism, we report in patients with ASD and low brain 5HIAA mutations in the serotonin transporter SCL29A4, an observation that may provide some bases for improving the application of various therapeutic tools.

Whole blood serotonin and platelet serotonin content are increased in about 25 to 30% of the ASD population and their first-degree relatives. Because the fetal blood–brain barrier during pregnancy is not yet fully formed, the fetal brain will be exposed to high serotonin levels, leading through a negative-feedback mechanism to a loss of serotonin neurons and a limited outgrowth of their terminals. This hypothesis has been confirmed by rat studies using the serotonin agonist 5-methoxytryptamine between gestational days 12 until postnatal day 20 [42].

Tryptophan hydroxylase (TPH; EC catalyzes the first rate-limiting step of serotonin biosynthesis by converting l-tryptophan to 5-hydroxytryptophan. Serotonin controls multiple vegetative functions and modulates sensory and alpha-motor neurons at the spinal level. We report on five boys with floppiness in infancy followed by motor delay, development of a hypotonic-ataxic syndrome, learning disability, and short attention span. Cerebrospinal fluid (CSF) analysis showed a 51 to 65% reduction of the serotonin end-metabolite 5-hydroxyindoleacetic acid (5HIAA) compared to age-matched median values. In one out of five patients a low CSF 5-methyltetrahydrofolate (MTHF) was present probably due to the common C677T heterozygous mutation of the methylenetetrahydrofolate reductase (MTHFR) gene. Baseline 24-h urinary excretion showed diminished 5HIAA values, not changing after a single oral load with l-tryptophan (50-70 mg/kg), but normalizing after 5-hydroxytryptophan administration (1 mg/kg). Treatment with 5-hydroxytryptophan (4-6 mg/kg) and carbidopa (0.5-1.0 mg/kg) resulted in clinical amelioration and normalization of 5HIAA levels in CSF and urine. In the patient with additional MTHFR heterozygosity, a heterozygous missense mutation within exon 6 (G529A) of the TPH gene caused an exchange of valine by isoleucine at codon 177 (V177I). This has been interpreted as a rare DNA variant because the pedigree analysis did not provide any genotype-phenotype correlation. In the other four patients the TPH gene analysis was normal. In conclusion, this new neurodevelopmental syndrome responsive to treatment with 5-hydroxytryptophan and carbidopa might result from an overall reduced capacity of serotonin production due to a TPH gene regulatory defect, unknown factors inactivating the TPH enzyme, or selective loss of serotonergic neurons.

Carbidopa is a drug given to people with Parkinson's disease in order to inhibit peripheral metabolism of levodopa. This property is significant in that it allows a greater proportion of peripheral levodopa to cross the blood–brain barrier for central nervous system effect.

L-DOPA/levodopa is the precursor to the neurotransmitters dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline) collectively known as catecholamines. Furthermore, L-DOPA itself mediates neurotrophic factor release by the brain and CNS. As a drug, it is used in the clinical treatment of Parkinson's disease.


Based upon the hypothesis that brain monoamine metabolism is disorganized in some children with an autistic disorder, we tried low dose levodopa therapy (0.5 mg/kg/day) proposed by Segawa, et al. We treated 20 patients with an autistic disorder diagnosed according to DSM-IV, and evaluated the effectiveness. A double blind cross over method was applied in this study because of the small number of patients. Drug effects were observed carefully by the psychologists and pediatric neurologists using an evaluation sheet consisting of twenty items. No significant effectiveness was observed in this study, although four cases (20%) showed some improvement. In conclusion, administration of low dose levodopa to autistic children resulted in no clear clinical improvements of autistic symptoms.

A team led by Wen-Hann Tan,  of the Genetics Program at Children’s, is completing a phase I clinical trial examining the safety and dosing of levodopa, a drug commonly used for Parkinson disease, in patients with Angelman syndrome. The results will inform a planned phase II treatment trial, to be conducted in collaboration with University of California San Francisco, University of California San Diego, Vanderbilt University, Baylor College of Medicine and Greenwood Genetic Center. [For more information on Angelman research and events, check out this Facebook page.]

Research suggests that levodopa may increase the activity of an important brain enzyme known as CaMKII, which is involved in learning and memory, and that may be decreased in Angelman syndrome. In a mouse model of Angelman syndrome, low activity of CaMKII is associated with neurologic defects. Levodopa reverses the chemical modification that underlies decreased CaMKII activity. When this same modification is reversed in mice by genetic means, they show improvement in neurologic deficits, and it’s hoped that levodopa can do the same in humans.

Parkinson's disease

We saw in an earlier post that people with Down Syndrome are prone to early onset Alzheimer’s. In the case of lack of dopamine the risk might be towards Parkinson's disease (PD). 

There was a recent post on PANS/PANDAS/Tourette’s which like PD results from dysfunction in the basal ganglia region of the brain.

The basal ganglia, a group of brain structures innervated by the dopaminergic system, are the most seriously affected brain areas in PD. The main pathological characteristic of PD is cell death in the substantia nigra, where greatly reduced activity of dopamine-secreting cells caused by cell death.

When a decision is made to perform a particular action, inhibition is reduced for the required motor system, thereby releasing it for activation. Dopamine acts to facilitate this release of inhibition, so high levels of dopamine function tend to promote motor activity, while low levels of dopamine function, such as occur in PD, demand greater exertions of effort for any given movement. Thus, the net effect of dopamine depletion is to produce hypokinesia, an overall reduction in motor output. Drugs that are used to treat PD, conversely, may produce excessive dopamine activity, allowing motor systems to be activated at inappropriate times and thereby producing dyskinesias.

The drugs used in PD only treat some of the symptoms and are not curative, but do offer effective ways to increase dopamine levels.

High rates of Parkinsonism in adults with autism? Or is it partly drug-induced Parkinsonism

There is a study suggesting high rates of Parkinsonism in adults with autism.  I think some of this is more likely to be drug-induced Parkinsonism, either caused by currently taken drugs, or those taken in earlier years, which is not mentioned in the study. 


While it is now recognized that autism spectrum disorder (ASD) is typically a life-long condition, there exist only a handful of systematic studies on middle-aged and older adults with this condition.

We first performed a structured examination of parkinsonian motor signs in a hypothesis-generating, pilot study (study I) of 19 adults with ASD over 49 years of age. Observing high rates of parkinsonism in those off atypical neuroleptics (2/12, 17 %) in comparison to published population rates for Parkinson’s disease and parkinsonism, we examined a second sample of 37 adults with ASD, over 39 years of age, using a structured neurological assessment for parkinsonism.
Twelve of the 37 subjects (32 %) met the diagnostic criteria for parkinsonism; however, of these, 29 subjects were on atypical neuroleptics, complicating interpretation of the findings. Two of eight (25 %) subjects not taking atypical neuroleptic medications met the criteria for parkinsonism. Combining subjects who were not currently taking atypical neuroleptic medications, across both studies, we conservatively classified 4/20 (20 %) with parkinsonism.
We find a high frequency of parkinsonism among ASD individuals older than 39 years. If high rates of parkinsonism and potentially Parkinson’s disease are confirmed in subsequent studies of ASD, this observation has important implications for understanding the neurobiology of autism and treatment of manifestations in older adults. Given the prevalence of autism in school-age children, the recognition of its life-long natural history, and the recognition of the aging of western societies, these findings also support the importance of further systematic study of other aspects of older adults with autism.

Drug induced Parkinsonism

Any drug that blocks the action of dopamine (referred to as a dopamine antagonist) is likely to cause parkinsonism. Drugs used to treat schizophrenia and other psychotic disorders such as behaviour disturbances in people with dementia, known as neuroleptic drugs, are possibly the major cause of drug-induced parkinsonism worldwide. Parkinsonism can occur from the use of any of the various classes of neuroleptics.
The atypical neuroleptics – clozapine (Clozaril) and quetiapine (Seroquel), and to a lesser extent olanzapine (Zyprexa) and risperidone (Risperdal) – appear to have a lower incidence of extrapyramidal side effects, including parkinsonism. These drugs are generally best avoided by people with Parkinson’s, although some may be used by specialists to treat symptoms such as hallucinations occurring with Parkinson’s.
For people with Parkinson’s, anti-sickness drugs such as domperidone (Motilium) or ondansetron (Zofran) are the drugs of choice for nausea and vomiting.
As well as neuroleptics, some other drugs can cause drug-induced parkinsonism. These include some medications for dizziness and nausea such as prochlorperazine (Stemetil); and metoclopromide (Maxalon), which is used to stop sickness and in the treatment of indigestion.
Calcium channel blocking drugs used to treat high blood pressure, abnormal heart rhythm, angina pectoris, panic attacks, manic depression and migraine may occasionally cause drug-induced parkinsonism. Calcium channel blocking drugs are, however, widely used to treat angina and high blood pressure, and it is important to note that most common agents in clinical use probably do not have this side effect. These drugs should never be stopped abruptly without discussion with your doctor.
A number of other agents have been reported to cause drug-induced parkinsonism, but clear proof of cause and effect is often lacking. Amiodarone, used to treat heart problems, causes tremor and some people have been reported to develop Parkinson’s-like symptoms. Sodium valproate, used to treat epilepsy, and lithium, used in depression, both commonly cause tremor which may be mistaken for Parkinson’s.

Dopamine Receptors vs Dopamine as Dysfunctions 

We saw in great detail with the neurotransmitter GABA that the autism dysfunctions are usually related to the function and make-up of the neurotransmitter receptors, rather than the amount of GABA itself. Targeting these dysfunctions does indeed deliver results for many people with autism and Asperger’s.

Potentially this might be the case with dopamine, but it looks much less likely.

I did look at the following paper which seeks to link the genes of dopamine receptors (DRD1, DRD2, DRD3, DRD4, DRD5), dopamine-synthesizing enzyme DDC, dopamine transporter (DAT) and dopamine-catabolizing enzymes COMT and MAO to the several hundred known autism genes.

Using bioinformatics, in some they found a link and in others they did not.

The graphic below looks nice, but I am not sure it tells us much useful.  To me it looks much better to go direct to the autism gene and then see how to selectively modulate it. I do not think you can assume that the associated dopamine gene/receptor is the unifying problem across dysfunctional autism genes.  It would be great if it was.  

Autism spectrum disorder (ASD) is a debilitating brain illness causing social deficits, delayed development and repetitive behaviors. ASD is a heritable neurodevelopmental disorder with poorly understood and complex etiology. The central dopaminergic system is strongly implicated in ASD pathogenesis.

Genes encoding various elements of this system (including dopamine receptors, the dopamine transporter or enzymes of synthesis and catabolism) have been linked to ASD. Here, we comprehensively evaluate known molecular interactors of dopaminergic genes, and identify their potential molecular partners within up/down-steam signaling pathways associated with dopamine. These in silico analyses allowed us to construct a map of molecular pathways, regulated by dopamine and involved in ASD. Clustering these pathways reveals groups of genes associated with dopamine metabolism, encoding proteins that control dopamine neurotransmission, cytoskeletal processes, synaptic release, Ca2+ signaling, as well as the adenosine, glutamatergic and gamma-aminobutyric systems. Overall, our analyses emphasize the important role of the dopaminergic system in ASD, and implicate several cellular signaling processes in its pathogenesis.

Fig. 3. Reconstruction of biomolecular pathways related to dopaminergic genes associated with ASD (also see Fig. 2 and Table 2 for details). Known biological interactions between protein products of various genes are shown as complexes or denoted by arrows (sharp – activation, dull – inhibition). Proteins encoded by genes associated with ASD are marked with red (other colors are used here for illustration purposes only, to better distinguish visually between multiple different proteins within the dopaminergic pathways). Clustering of proteins into distinct functional groups is shown by dashed lines.

The strongest evidence for the role of dopamine genes in neuropsychiatric disorders is not in schizophrenia or autism, but in ADHD. As you can see in the paper below, even there the association is weak.


Although twin studies demonstrate that ADHD is a highly heritable condition, molecular genetic studies suggest that the genetic architecture of ADHD is complex. The handful of genome-wide scans that have been conducted thus far show divergent findings and are, therefore, not conclusive. Similarly, many of the candidate genes reviewed here (i.e. DBH, MAOA, SLC6A2, TPH-2, SLC6A4, CHRNA4, GRIN2A) are theoretically compelling from a neurobiological systems perspective, but available data are sparse and inconsistent. However, candidate gene studies of ADHD have produced substantial evidence implicating several genes in the etiology of the disorder. The literature published since recent meta-analyses is particularly supportive for a role of the genes coding for DRD4, DRD5, SLC6A3, SNAP-25, and HTR1B in the etiology of ADHD.

Yet, even these associations are small and consistent with the idea that the genetic vulnerability to ADHD is mediated by many genes of small effect.


In the ideal world you would take a sample of spinal fluid and measure 5-HIAA, to look for low brain serotonin and measure HVA for low brain dopamine.

For low serotonin you would give 5-HTP, with Dr Ramaekers suggesting 1mg/kg.

For low dopamine you would give levodopa or carbidopa.

In the real world even blood draws can be problematic so most people will never have their spinal fluid analyzed. Perhaps one day in the future this will be standard practice after an autism diagnosis, with numerous test being run at the same time and justifying this invasive procedure.   Many blood tests tell you little about brain disorders because the blood brain barrier means that the levels outside the brain will be completely different to those inside the brain. Measuring spinal fluid should be a good proxy for inside the brain.

The research suggests that 1mg/kg of 5-HT could have a long term beneficial effect, particularly if given from a very early age, in those with low serotonin in their brains, which is a large group of autism.

There are 5 types of dopamine receptors and in some genetic disorders the receptors’ response can be up/down regulated.  That would trigger a chain reaction with the non dopamine neurotransmitter receptors that are known to interact with that type of dopamine receptor.

There are associations between some autism genes and some dopamine genes, but it looks much more fruitful to target the autism genes themselves.

Avoid drug induced Parkinson’s Disease and other drug induced disorders, by very selective use of drugs.