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Showing posts with label Depression. Show all posts
Showing posts with label Depression. Show all posts

Thursday 2 August 2018

Turmeric/Curcumin – clinically effective in humans after all? SLC6A15 Amino Acid Transporter


Turmeric powder, only in food, modified the SLC6A15 gene

I know that most readers of this blog want to treat autism with supplements and/or diet.
Many supplements and herbal medicines do show promise in the laboratory, when tests are conducted in vitro, but very often when tests are made in humans the results are much weaker, or just not present.  Turmeric/Curcumin is a perfect example; in the test tube it has a wide range of potent benefits, but due to low absorption into humans (bioavailability) it does not show such conclusive results in human studies.
One researcher a while back did send me a study that reviewed all the turmeric/curcumin trials and it concluded that curcumin has no beneficial effect in humans.
In modern medicine anecdotal evidence does not count. Some anecdotes are genuine, but some are coincidence and some are placebo. 

Mini trial of Turmeric at three UK Universities
There is a remarkably good medical program produced by the BBC in the UK, called Trust me I’m a Doctor, where the doctor presenters team up with universities to test practical medical hypotheses.
In one study they took 100 people to assess whether turmeric has any measurable medical benefit. They teamed up with Newcastle University, Leeds University and a clever genetic researcher at University College London (UCL).

They showed that eating turmeric in your food modified a specific gene (SLC6A15) associated with certain cancers, asthma/eczema and depression.
Taking turmeric as a supplement pill or taking a placebo pill had no effect on the gene.
The researcher at UCL was measuring the epigenetic tags attached to the genes. He showed that methylation of this gene was increased by dietary turmeric. Changing the methylation of this gene will change when it turns on/off.
Anecdotally, we know that people who eat a lot of turmeric tend to have less cancer, less asthma and less eczema.
Given that this gene is also associated with depression, you might expect big eaters of turmeric to have either less, or more, depression. Probably nobody has researched this.  

SLC6 Gene Family
It is true that asthma and eczema (atopic dermatitis) are common in people with autism, but variations in the broader SLC6 family of genes are known to affect people with ADHD, Fragile X, Tourette’s and broad autism.
SLC transporters encompass approximately 350 transporters organized into 55 families. The SLC6 family is among the largest SLC families, containing 20 genes that encode a group of highly similar transporter proteins. These proteins perform transport of amino acids and amino acid derivatives into cells. 


In humans, the SLC6 family of transporters defines one of the most clinically relevant protein groups with links to orthostatic intolerance, attention deficit hyperactivity disorder (ADHD), addiction, osmotic imbalance, X-linked mental retardation , Hartnup disorder, hyperekplexia, Tourette syndrome, schizophrenia, Parkinson disease (PD), autism  and mood disorders such as depression, anxiety, obsessive compulsive disorder (OCD), and post-traumatic stress disorder (PTSD).
This review will focus on the structure-function aspects of the mammalian SLC6 transporters, their regulation by both classical as well as emerging epigenetic/transgenerational mechanisms and what impact these properties may have on disease and the use of biomarkers to detect these proteins in disease states  

The functional impact of SLC6 transporter genetic variation.


Solute carrier 6 (SLC6) is a gene family of ion-coupled plasma membrane cotransporters, including transporters of neurotransmitters, amino acids, and osmolytes that mediate the movement of their substrates into cells to facilitate or regulate synaptic transmission, neurotransmitter recycling, metabolic function, and fluid homeostasis. Polymorphisms in transporter genes may influence expression and activity of transporters and contribute to behavior, traits, and disease. Determining the relationship between the monoamine transporters and complex psychiatric disorders has been a particular challenge that is being met by evolving approaches. Elucidating the functional consequences of and interactions among polymorphic sites is advancing our understanding of this relationship. Examining the influence of environmental influences, especially early-life events, has helped bridge the gap between genotype and phenotype. Refining phenotypes, through assessment of endophenotypes, specific behavioral tasks, medication response, and brain network properties has also improved detection of the impact of genetic variation on complex behavior and disease. 

Amino acids are very important and it is not just that you need them, but you need them in the right place at the right time.
It appears that one of the many effects of defective amino acid/derivative transport into cells is on behaviour.
Improving amino acid transmission is therefore a potential therapy to correct aberrant behaviour, including depression but likely much more. 

Conclusion
Modern clinical trials are often hugely expensive, but as the BBC keeps showing with its TV series, you can carry out very meaningful research without breaking the bank.
You would think that cancer researchers would now look at the modified versions of turmeric that claim higher bioavailability and see if these pills can also modify this cancer gene, since they can easily repeat the UCL laboratory analysis. I doubt this will happen any time soon.
It has long been known that turmeric is not well absorbed, but just one teaspoon a day added to food was enough to modify the gene.
Indians have a low incidence of cancer and a high consumption of turmeric. Turmeric should particularly limit breast cancer.

Source: https://vizhub.healthdata.org/gbd-compare/

The above chart, where blue is best, shows India does well, as do some other turmeric eating countries (South Asia and the Middle East). Clearly longevity and quality of healthcare also matter, so beware Africa. Europe, Russia, Argentina, Uraguay, Oz, NZ and North American might want to up their turmeric intake.

We can say that turmeric is a potential epigenetic therapy for at least one important gene (SLC6A15) and possibly more, because turmeric does not just affect methylation. It has several other better documented epigenetic properties. 

Epigenetic regulation, which includes changes in DNA methylation, histone modifications, and alteration in microRNA (miRNA) expression without any change in the DNA sequence, constitutes an important mechanism by which dietary components can selectively activate or inactivate gene expression. Curcumin (diferuloylmethane), a component of the golden spice Curcuma longa, commonly known as turmeric, has recently been determined to induce epigenetic changes. This review summarizes current knowledge about the effect of curcumin on the regulation of histone deacetylases, histone acetyltransferases, DNA methyltransferase I, and miRNAs. How these changes lead to modulation of gene expression is also discussed. We also discuss other nutraceuticals which exhibit similar properties. The development of curcumin for clinical use as a regulator of epigenetic changes, however, needs further investigation to determine novel and effective chemopreventive strategies, either alone or in combination with other anticancer agents, for improving cancer treatment.
Only a few reports have so far investigated the effect of curcumin on DNA methylation. Molecular docking of the interaction between curcumin and DNMT1 suggested that curcumin covalently blocks the catalytic thiolate of DNMT1 to exert its inhibitory effect on DNA methylation. However, a more recent study showed no curcumin-dependent demethylation, which suggested that curcumin has little or no pharmacologically relevant activity as a DNMT inhibitor. To clarify these contradictions, more research is urgently needed.
Given that 5-azacitidine and decitabine, two FDA-approved hypomethylating agents for treating myelodysplastic syndrome, have a demonstrated ability to sensitize cancer cells to chemotherapeutic agents, it would be worthwhile to explore whether the hypomethylation effect of curcumin can also induce cancer cell chemosensitization. Interestingly, a phase 1 trial with curcumin administered several days before docetaxel in patients with metastatic breast cancer resulted in 5 partial remissions and stable disease in 3 of 8 patients. This unexpected high response might have resulted from the clever sequential delivery of these two agents, which capitalized on and maximized curcumin’s epigenetic activity for cancer treatment.


Docetaxel is a 20 year old chemotherapy drug produced using extracts from the leaves of the European yew tree, perhaps best taken with root (rhizome) of the Asian Curcuma Longa plant. 
The main mode of therapeutic action of docetaxel is the suppression of microtubule dynamic assembly and disassembly. It exhibits cytotoxic activity on breast, colorectal, lung, ovarian, gastric, renal and prostate cancer cells.



Wednesday 10 February 2016

More Failed Autism Trials and (28 million) thoughts as to why



Two autism therapies mentioned in this blog have recently failed in their clinical trials.

The selective mGluR5 antagonist mavoglurant failed in two trials funded by Roche and Coronado Biosciences threw in the towel with its Trichuris suis ova (“TSO”) program.  TSO are parasites that are introduced to the gut to modify the immune response, they are thought to help conditions like ulcerative colitis and some autism.



"Coronado Biosciences (NASDAQ: CNDO) has decided to no longer pursue the development of its Trichuris suis ova (“TSO”) program. The Company is terminating all on-going TSO trials, including the Company’s Phase 2A clinical trial of TSO in pediatric patients with autism spectrum disorder. A preliminary analysis of data from this trial failed to demonstrate any signal of activity."


The original user of TSO in autism documented his case here:-

http://autismtso.com/

It has been a long time since the father updated his site. Does he still give TSO to his son?

This adds to a growing list of very expensive failures.

The good news is that people are beginning to wonder why these, and all the previous trials, "failed".  Perhaps some were not failures, rather narrowly selective successes.  A new initiative is underway called Autism Biomarkers Consortium for Clinical Trials to try to develop more objective measures both for diagnosing autism in young children and for tracking changes.


"The Autism Biomarkers Consortium for Clinical Trials (ABC-CT) is a multicenter research study based at Yale that spans Duke University, Boston Children’s Hospital, the University of Washington/Seattle Children’s Research Institute and the University of California, Los Angeles. The aim of the consortium is to develop reliable and objective measurements of social function and communication in people with autism."
  

NIH provides $28M to study autism biomarkers via its Biomarkers Consortium


That is a lot of money.



I wish them well.

I do not think they fully realize the task facing them.  There are hundreds of “autisms” and many are dynamic, so changing over time.  Even if you find a responder to a therapy, if you tested the same person six months later he might not respond positively. 

It is highly unlikely that any single therapy can target all the symptoms in any case of autism.  So multiple therapies will be needed.

For many people, autism is a moving target, any kind of allergy, tooth issue or other inflammation could cause a false negative.



Single Gene vs Idiopathic Autism

It should be much easier to develop treatment for single gene autisms, like Fragile X, than for the idiopathic (“we have no clue what causes it”) autisms.  The above trials by Roche were in Fragile-X, where at least you know that all the subjects in the trial started with the same single gene dysfunction. 

But do they have other genetic/epigenetic dysfunctions?  Do they all have the same downstream dysfunctions? 

Fragile X is caused by a lack of the FRMP protein, perhaps the only time to correct this is very early in life.  Thereafter you have the downstream consequences, some of which overlap with ideopathic autism, some of these may well be treatable. 


 Autism Case Reports and Anecdotal Evidence

A good source of information remains published case reports.  These are documented pieces of anecdotal evidence showing what appeared to help a particular person. Here is one highlighted recently by Agnieszka, a reader of this blog.

Beta-Lactam Antibiotics as A Possible Novel Therapy for Managing Epilepsy and Autism, A Case Report and Review of Literature



The index patient is a 9 year old boy with autism spectrum disorder diagnosed according to Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). He suffered from generalized tonic-clonic epilepsy from age 4. He had taken multiple different medications such as phenobarbital, sodium valporate, and carbamazepine with sufficient dosages and durations without favorable control of his epilepsy. According to his parents’ reports, the patient took cefixime 200mg/day to control diarrhea about 2 years ago. The seizure episodes were dramatically decreased 3 days after starting the medication while the there was no change in his anti-epileptic medication regime. The seizure episodes were controlled for about 5 months, after which the number of seizure episodes again increased. His highly educated parents administered cefixime 200mg/day to control seizure again. They reported that seizure attacks were controlled markedly after taking cefixime for three days. The patient was not febrile while the medication trials were administered. Both parents reported that they repeated this trial for several times to control the seizure episodes in the recent years. The epilepsy was controlled in all of the trials after taking cefixime for 3 to 5 days. Then, they discontinued cefixime after 7 days. They reported that there was a marked decreased in the number of seizure attacks as well as aggressive behaviors.


You cannot read too much into any one case report, other than to note how many totally unrelated interventions seem to benefit unique cases of autism.  This only goes to show that totally unrelated dysfunctions can manifest themselves as “autism”.

If you grouped all the anecdotal evidence together you would have some interesting reading.  If someone actually followed up on these anecdotes and did some additional investigation on each case we might learn very much more.



Previous Autism Clinical Trials

When I read the original clinical trials of NAC and Bumetanide in Autism, the results seemed good enough to me to warrant my own trial.

I do not see why there has not yet been a follow up of Stanford’s trial of NAC.  There was a patent (below) and then nothing.  It clearly works in many people, but most clinicians will not prescribe it until it is “evidence based”.  Those granted the patent should then go and collect some more evidence.



Bumetanide has also been patented for autism and the next stage of trials will follow, we are informed.

I will be interested to see whether the phase 3 trials are solid enough to convince mainstream clinicians to actually prescribe it.  "A diuretic for autism, come on, be serious!"

Nothing would surprise me.


Funding for Future Trials

It would be a bold person who invested any profit-seeking capital in autism trials, but they keep coming forward.  Here is another new one, OV101 from start-up Ovid.

The only reliable source is public money and philanthropy.

It looks like the US NIH (National Institutes of Health) still has deep pockets and Jim Simons keeps backing his Foundation.



mGLuR5

Roche may not have succeeded with their mGLuR5 drug, mavoglurant, but mGluR5 remains a target for treating schizophrenia and autism



Receptors in brain linked to schizophrenia, autism



Disruption of mGluR5 in parvalbumin-positive interneurons induces corefeatures of neurodevelopmental disorders





What would a successful Autism Trial look like?

Given the heterogeneous nature of autism, even a really effective drug might not look so good in the data.  Very specific drugs that counter the disorders where there can be both hypo and hyper, will come out with some good responders, some with no effect and a sizable number with a bad effect; so on average not so good.

Drugs that affect the most common down stream effect, oxidative stress, would come out best.  So I the results Hardan obtained in his Stanford trial of NAC will be as good as it gets.  Those results were enough for me, but not so impressive to many.

Now reconsider a long forgotten trial of an anti-depressant drug, developed from a first generation antihistamine.

This trial has a rather eclectic mix of 26 subjects, but 36% were responders, either much improved or very much improved in a wide variety of symptoms including aggression, self-injury, irritability, hyperactivity, anxiety, depression, and insomnia. However the authors judge the trial drug as: 


  "Mirtazapine was well tolerated but showed only modest effectiveness for treating the associated symptoms of autistic disorder" 


What were they hoping for ?






Abstract

OBJECTIVE:

The aim of this study was to conduct a naturalistic, open-label examination of the efficacy and tolerability of mirtazapine (a medication with both serotonergic and noradrenergic properties) in the treatment of associated symptoms of autism and other pervasive developmental disorders (PDDs).
METHODS:

Twenty-six subjects (5 females, 21 males; ages 3.8 to 23.5 years; mean age 10.1 +/- 4.8 years) with PDDs (20 with autistic disorder, 1 with Asperger's disorder, 1 with Rett's disorder, and 4 with PDDs not otherwise specified were treated with open-label mirtazapine (dose range, 7.5-45 mg daily; mean 30.3 +/- 12.6 mg daily). Twenty had comorbid mental retardation, and 17 were taking concomitant psychotropic medications. At endpoint, subjects' primary caregivers were interviewed using the Clinical Global Impressions (CGI) scale, the Aberrant Behavior Checklist, and a side-effect checklist.

RESULTS:

Twenty-five of 26 subjects completed at least 4 weeks of treatment (mean 150 +/- 103 days). Nine of 26 subjects (34.6%) were judged responders ("much improved" or "very much improved" on the CGI) based on improvement in a variety of symptoms including aggression, self-injury, irritability, hyperactivity, anxiety, depression, and insomnia. Mirtazapine did not improve core symptoms of social or communication impairment. Adverse effects were minimal and included increased appetite, irritability, and transient sedation.

CONCLUSIONS:


Mirtazapine was well tolerated but showed only modest effectiveness for treating the associated symptoms of autistic disorder and other PDDs.



I think that was a successful trial that should have been followed up, rather then being forgotten.








Wednesday 17 April 2013

Cortisol, AVP, Oxytocin - Part II Stress Reactivity Model

I think today's post is going to be one of my better efforts.  We are continuing with the theme of Cortisol, depression and stress; but we are going to add two further chemicals, both "social neuropeptides".

The reason than today's post is worth reading is that it will bridge neurobiology and neuropsychology.   For me at least, psychology is light reading whereas biology needs more thought and understanding.  A social neuropeptide is a nice term not invented by me; it seems to come from Dr Stein from the University of Cape Town.

Rather than understand everything about human hormones, we are just trying to understand stress and coping mechanisms, so that we can reduce or  just better manage autistic behaviours. 


Cortisol

Cortisol is a hormone that is very easy to measure; saliva samples will do just fine.  Cortisol levels, or changes in cortisol levels, tell us about how the body is coping with emotion stress.  We are not talking about oxidative stress, but clearly there is direct linkage between the two.

We know that cortisol is a hormonal body clock (it maintains diurnal rhythms), cortisol levels should peak 30 minutes after waking, decline rapidly in the morning and then reach its lowest level in the evening.  This is well illustrated in the figure below, from an excellent study by Vahdettin Bayazit from Turkey.  He was studying the effect of exercise and stress on cortisol levels.


 

Children with ASD are known to have atypical response to stress and some have dysregulation of diurnal rhythms and abnormally high evening cortisol levels.  Among children with ASD there are significant individual differences, so the level of dysregulation is variable.  Note that many children with ASD have sleeping disorders; not surprising really if their body clock is malfunctioning.


 
In Bayazit's study he comments:-
"The more unexpected finding was that the evening values (of cortisol) for the children with autism tended to be consistently elevated in comparison with the neurotypical group."
I do not find this result surprising; in fact I would expect it.
 
He goes on to tell us that it is known that older children with depression have altered hormone levels, including hypersecretion of cortisol in the evening.
 
Now back to a stressful event.  In Turkey, a group of high functioning children with ASD were given a public speaking task; their heart rates and saliva cortisol were measured, before, after and during this "stressful event".
 
 
 
 
All we need to note is that the stress tended to cause a spike in cortisol level.


Stress Reactivity Model

Now we combine biology with psychology.  I took an existing model from an excellent book called "The neuropsychology of Autism".  Chapter 22 has a paper by Suma Jacob et al; she provided the biology and I just added the psychology (the opposite of what you might have expected)
 
 
 
 


This model shows how the equilibrium in managing stress is hopefully maintained.

The two little interlopers on the chart above, oxytocin and AVP are social neuropeptides.  Oxytocin is seen as beneficial; it reduces stress levels and gives a feeling of wellbeing.  AVP (Arginine Vasopressin) works in conjunction with CRH (Cortisol Releasing Hormone) to control the release of cortisol.  AVP seems to work in a "bad" way, in that it exaggerates/magnifies natural changes in cortisol.  So if you have a lot of AVP, a small spike in cortisol would become a big spike in cortisol.

Both AVP and cortisol have numerous other functions in the body. For example AVP is also known as the antidiuretic hormone (ADH) and a version of it is used in therapy in extreme cases of bedwetting by children. Whoever designed the human body was either short of chemicals, or likes to play practical jokes.

We already learned in Part I, that you can reduce your own level of cortisol just by singing.  It is reassuring to know that you do not always need drugs.  There are in fact other ways that you can maintain your own homeostatis and reduce cortisol.

A clever clinical psychologist from the University of Zurich, called Markus Heinrichs,  has provided us with an excellent study that compares the effect of social support vs oxytocin as regulators of stress.  What he did was to create two groups of people, in one group each subject brought along their best friend; the other group all came alone.  Then each subject was put through this stressful process:-


"During the introduction to the TSST (Trier Social Stress Test) they were then told that they would be required to give a 5-min mock job interview to an unknown panel (consisting of one man and one woman) on personal suitability for a job and to enumerate their strengths and qualifications in an unstructured manner, followed by 5 min of mental arithmetic performed out loud. To increase task engagement, the job description was matched to each participant, taking into consideration his own individual goals and aspirations. The panel of evaluators were presented as experts in the evaluation of nonverbal behavior."

The subjects were typical males in their early 20s.  Half the subjects had social support of a friend being present, and then each group had either a placebo or had a dose of oxytocin.  Here are the results:-







The base case is the "No social support + placebo".  This shows the highest increase in cortisol (i.e. stress).  The calmest group had "social support + oxytocin".  Of great interest is that the "social support + placebo" ended up less stressed than the "no social support + oxytocin".

This experiment showed the clear positive effect of both social support and oxytocin.

So in the stress reactivity model (the blue one up top) I decided to add social support and singing.  Clearly there are plenty of other social/psychological strategies that would likely have a similar cortisol reducing effect. 


Another dose of cortisol will come shortly in Part III.