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Friday, 8 April 2016

Mirtazapine and Folate for Idiopathic Schizophrenia, but for which Autism?


 China, where things tend to be big, even their clinical trials


A short while ago we looked at the possible mechanisms behind a reader’s successful experience in use of Mirtazapine (Remeron) in autism, then being prescribed to increase appetite.

Mirtazapine is a tricyclic antidepressant, meaning it is very closely related to first generation antihistamines, but it has numerous other effects;  more of that later.

Folate is vitamin B9.  Folic acid is synthetically produced, and used in fortified foods and supplements on the theory that it is converted into folate, which may not be the case.

It appears that in both schizophrenia and autism there is a family of possible folate dysfunctions that range from minor to severe.  The mild dysfunction responds to a small supplement of folate, while the severe dysfunction requires a much larger supplement of folate.

Roger, another reader of this blog has the more severe dysfunction called Cerebral Folate Deficiency (CFD) and this condition is best studied by Vincent Ramaekers  (Department of Pediatric Neurology and Center of Autism, University Hospital Liege) and Richard Frye at the Arkansas Children’s Hospital.

Cerebral folate deficiency as diagnosed by Ramaekers/Frye is extremely rare.

In a previous post we looked at Biotin (vitamin B7) and we saw that while biotin/biotinidase deficiency is technically extremely rare, a partial deficiency seems to exist in about 5% of people with autism.  

Both severe biotin/biotinidase deficiency and partial biotin/biotinidase deficiency responds well to high dose biotin supplementation.

Without going into the details of Folate Receptor Autoantibodies (FRAs), it is clear that Ramaekers has found the same condition in both Schizophrenia and Autism.

The milder folate dysfunction is very well known in schizophrenia.


The Chinese Trial

On the basis that bigger is better, a clinical trial is underway in China on 330 subjects with Schizophrenia to measure the benefit of Mirtazapine and/or folate as an add-on therapy.




I was quite surprised to come across this trial.



Today’s Post

Today’s post will look at the known effects of Mirtazapine and folate in schizophrenia and also the role folate plays in human biology.

There are lab tests that you could make to check for Folate dysfunction, just as there are for Biotin dysfunction. 

The standard therapy for Cerebral Folate Deficiency is the prescription drug leucovorin, normally used in cancer therapy.  There is also a supplement called Metafolin (Levomefolate calcium) that should have a very similar, if not identical, effect. Metafolin is produced by Merck and sold to supplement companies on the basis that it is only sold in low doses.  Metafolin appears more than your average “supplement”.

Another producer of Levomefolate calcium, is Pamlab; they sell it as a treatment for memory loss and peripheral neuropathy.  Pamlab was purchased by Nestlé Health Science in 2013; the Swiss tend to know what they are doing.



Schizophrenia

Schizophrenia overlaps significantly with autism in terms of its genetic origin.
Interestingly, people with schizophrenia may have a high rate of irritable bowel syndrome, but they often do not mention it unless specifically asked.

To better understand the clinical trials you need to know that the schizophrenia is a spectrum like autism with three main problem areas:-

Positive symptoms
These are symptoms that most individuals do not normally experience but are present in people with schizophrenia. They can include delusions, disordered thoughts and speech, and tactile, auditory, visual, olfactory and gustatory hallucinations, typically regarded as manifestations of psychosis. Hallucinations are also typically related to the content of the delusional theme. Positive symptoms generally respond well to medication.

Negative symptoms
These are deficits of normal emotional responses or of other thought processes, and are less responsive to medication. They commonly include flat expressions or little emotion, poverty of speech, inability to experience pleasure,lack of desire to form relationships, and lack of motivation. Negative symptoms appear to contribute more to poor quality of life, functional ability, and the burden on others than do positive symptoms. People with greater negative symptoms often have a history of poor adjustment before the onset of illness, and response to medication is often limited.

 

Cognitive dysfunction


The extent of the cognitive deficits an individual experiences is a predictor of how functional an individual will be, the quality of occupational performance, and how successful the individual will be in maintaining treatment.  The presence and degree of cognitive dysfunction in individuals with schizophrenia has been reported to be a better indicator of functionality than the presentation of positive or negative symptoms


Effective psychiatric drugs only exist for the positive symptoms, they do not exist for the negative symptoms or the cognitive dysfunction.



Folate Deficiency in Schizophrenia

Folate treatment in schizophrenia is linked to improvement in the negative symptoms that are normally untreatable.

Studies are mixed, but subgroups clearly exist in schizophrenia where folate supplementation improved well-being.

The rare severe dysfunction which is Cerebral Folate Deficiency is shown to exist in schizophrenia. 



Folate and vitamin B12 supplementation reduces disabling schizophrenia symptoms in patients with specific gene variants


Participants were all taking antipsychotic medications – which have been shown to alleviate positive symptoms, such as hallucinations and delusions, but not negative symptoms – and were randomized to receive daily doses of either folate and vitamin B12 or a placebo for 16 weeks. Every two weeks their medical and psychiatric status was evaluated, using standard symptom assessment tools along with measurements of blood levels of folate and homocysteine, an amino acid that tends to rise when folate levels drop. Nutritional information was compiled to account for differences in dietary intake of the nutrients. Participants' blood samples were analyzed to determine the variants they carried of MTHFR and three other folate-pathway genes previously associated with the severity of negative symptoms of schizophrenia. 

Among all 140 participants in the study protocol, those receiving folate and vitamin B12 showed improvement in negative symptoms, but the degree of improvement was not statistically significant compared with the placebo group. But when the analysis accounted for the variants in the genes of interest, intake of the two nutrients did provide significant improvement in negative symptoms, chiefly reflecting the effects of specific variants in MTHFR and in a gene called FOLH1. Variants in the other two genes studied did not appear to have an effect on treatment outcome.

  

Folate and vitamin B12 status in schizophrenic patients

CONCLUSIONS:
This study showed that folate deficiency is common in schizophrenic patients; therefore, it is important to pay attention to folate levels in these patients.


Folinic acid treatment for schizophrenia associated with folate receptor autoantibodies



  
The Role of Folate/vitamin B9 in Human Biology

Vitamin B9 is essential for numerous bodily functions. Humans cannot synthesize folates de novo; therefore, folic acid has to be supplied through the diet to meet their daily requirements. The human body needs folate to synthesize DNA, repair DNA, and methylate DNA as well as to act as a cofactor in certain biological reactions.

Folic acid is synthetically produced, and used in fortified foods and supplements on the theory that it is converted into folate.  To be used it must be converted to tetrahydrofolate (tetrahydrofolic acid) by dihydrofolate reductase (DHFR). Increasing evidence suggests that this process may be slow in humans.

Note betaine below, which is also used to treat Cerebral Folate Deficiency, along with NAC.













Folic Acid, Folinic Acid and Folate

The terminology is confusing; what we want is folate, but there are several ways to get it.  Folic acid does not appear to be a good way.  Folinic acid, Levomefolic acid and Levomefolate calcium look to be the most effective supplements.

Here is a brief summary from Wikipedia:_

Folinic acid  or leucovorin, generally administered as the calcium or sodium salt (calcium folinate, sodium folinate, leucovorin calcium, leucovorin sodium), is an adjuvant used in cancer chemotherapy involving the drug methotrexate. It is also used in synergistic combination with the chemotherapy agent 5-fluorouracil.

Folinic acid (also called 5-formyltetrahydrofolate) was first discovered in 1948 as citrovorum factor and occasionally is still called by that name. Folinic acid should be distinguished from folic acid (vitamin B9). However, folinic acid is a vitamer for folic acid, and has the full vitamin activity of this vitamin.


Levomefolic acid is the primary biologically active form of folic acid used at the cellular level for DNA reproduction, the cysteine cycle and the regulation of homocysteine. It is also the form found in circulation and transported across membranes into tissues and across the blood-brain barrier. In the cell, L-methylfolate is used in the methylation of homocysteine to form methionine and tetrahydrofolate (THF). THF is the immediate acceptor of one carbon units for the synthesis of thymidine-DNA, purines (RNA and DNA) and methionine. The un-methylated form, folic acid (vitamin B9), is a synthetic form of folate, and must undergo enzymatic reduction by methylenetetrahydrofolate reductase (MTHFR) to become biologically active.

It is synthesized in the absorptive cells of the small intestine from polyglutamylated dietary folate. It is a methylated derivative of tetrahydrofolate. Levomefolic acid is generated by MTHFR from 5,10-methylenetetrahydrofolate (MTHF) and used to recycle homocysteine back to methionine by 5-methyltetrahydrofolate-homocysteine methyltransferase(MTR) also known as methionine synthase (MS).
Levomefolic acid (and folic acid in turn) has been proposed for treatment of cardiovascular disease and advanced cancers such as breast and colorectal cancers. It bypasses several metabolic steps in the body and better binds thymidylate synthase with fDump, a metabolite of the drug fluorouracil.


Levomefolate calcium, a calcium salt of levomefolic acid, is sold under the brand names Metafolin (a registered trademark of Merck KGaA) and Deplin (trademark of Pamlab, LLC). Methyl folate can be bought at online stores or in some chemists though without a prescription.

A good choice seems to be Metafolin, like in this product:-





Folate and Autism

We know from Roger and Frye/Ramaekers that the rare condition condition Cerebral folate deficiency (CFD) exists in autism, but what about the more widespread milder dysfunction like that found in schizophrenia?

As usual the level of knowledge in autism is less than that in schizophrenia.  The paper below concludes that when it comes to autism, not much is known.

Folic acid and autism: What do we know?

 

Autism spectrum disorders (ASD) consist in a range of neurodevelopmental conditions that share common features with autism, such as impairments in communication and social interaction, repetitive behaviors, stereotypies, and a limited repertoire of interests and activities. Some studies have reported that folic acid supplementation could be associated with a higher incidence of autism, and therefore, we aimed to conduct a systematic review of studies involving relationships between this molecule and ASD. The MEDLINE database was searched for studies written in English which evaluated the relationship between autism and folate. The initial search yielded 60 potentially relevant articles, of which 11 met the inclusion criteria. The agreement between reviewers was κ = 0.808. The articles included in the present study addressed topics related to the prescription of vitamins, the association between folic acid intake/supplementation during pregnancy and the incidence of autism, food intake, and/or nutrient supplementation in children/adolescents with autism, the evaluation of serum nutrient levels, and nutritional interventions targeting ASD. Regarding our main issue, namely the effect of folic acid supplementation, especially in pregnancy, the few and contradictory studies present inconsistent conclusions. Epidemiological associations are not reproduced in most of the other types of studies. Although some studies have reported lower folate levels in patients with ASD, the effects of folate-enhancing interventions on the clinical symptoms have yet to be confirmed.


Given the anecdotal evidence, including from our reader Seth, and the close biological relationship between autism and schizophrenia it seems pretty clear that a sub-group of people with autism do have a folate dysfunction that should respond to supplementation.  

How big this subgroup is remains to be seen.  For biotin it is about 5%, for vitamin B12 it about 10%.  Given it is known that MTHFR mutations are very common in autism, for example 23% were found to have the homozygous mutation 677CT allele (see the study below), it is very likely to be a sizeable group.  MTHFR is only one of the genes that could cause a folate problem.




A trial of metafolin could be a rewarding experience for some.





Back to the second half of that big Chinese Trial - Mirtazapine

There is a wealth of research that looks into the benefit of Mirtazapine in schizophrenia.  I choose to highlight a study from Finland because it is extremely comprehensive.




It has been reported earlier, from another part of this study, that clear-cut differences in all PANSS subscales and a large effect size of 1,00 (CI95% 0,23-1,67) on the PANSS total scores resulted from mirtazapine treatment when compared with a placebo in both within group and between group analyses during the double-blind phase (Joffe et al. 2009). In the open label phase, patients who switched to mirtazapine treatment demonstrated a clinical improvement in the same manner as their mirtazapine-treated counterparts in the double-blind phase. Prolonged treatment with mirtazapine led to more prominent improvements in clinical parameters than short-term treatment. A trend towards improvement was seen in all measured parameters, therefore providing more evidence of mirtazapine’s beneficial effect on schizophrenia symptoms.

The actual mechanism for a potential neurocognitive enhancing effect of mirtazapine in schizophrenia remains unknown, but it may be elucidated from its receptor binding profile. Like most SGAs, mirtazapine could also increase prefrontal dopaminergic and noradrenergic activity via 5-HT2A or 5-HT2C receptor blockade, as demonstrated in animal models (Liegeois et al. 2002; Meneses 2007; Zhang et al. 2000), and thus improve neurocognitive performance. Secondly, 5-HT3 receptor modulation by mirtazapine could also improve neurocognition (Akhondzadeh et al. 2009), presumably through increased release of acetylcholine (Ramirez et al. 1996). Thirdly, mirtazapine might improve neurocognition as a result of the indirect agonism of 5-HT1A receptors (Sumiyoshi et al. 2007). Moreover, mirtazapine is a more potent alpha-2 receptor antagonist than clozapine, which may explain its additional neurocognition-enhancing effect, even if it is added to clozapine (as in the study reported by Delle Chiae et al. 2007). The alpha-2 receptors remain an important target for neurocognitive research and its down-regulation may enhance neurocognition through a noradrenaline-mediated modulation of response to environmental stimuli (Friedman et al. 2004). Furthermore, alpha-2 receptor antagonism seems to boost hippocampal neurogenesis (Rizk et al. 2006). Also, mirtazapine may actually boost levels of brain-derived neurotrophic factor (BDNF) Rogoz et al. 2005), which is a major mediator of neurogenesis 62 and neuroplasticity. Correspondingly, those who suffer from schizophrenia often have abnormally low BDNF serum levels (Rizos et al. 2008).

During the 6-week extension phase, patients who had previously received six weeks of mirtazapine and those on placebo both showed significant improvement on several neurocognitive tests. Twelve-week mirtazapine treatment demonstrated better neurocognitive outcome than just six weeks of mirtazapine treatment, as evaluated by Stroop Dots time and TMT-B, number of mistakes, which are associated with general improvement in mental speed/attention control and executive functions. Twelve-week mirtazapine add-on to antipsychotic treatment indicated additional neurocognitive improvements of just six weeks, which demonstrates a progressive therapeutic effect.


In earlier posts on Mirtazapine/Remeron I raised various possible modes of action and other readers added their further ideas.

The table below lists some of the possible modes of action.  I declare a bias towards the importance of histamine, but clearly many more things are involved.








Mirtazapine has been trialed for a vast range of conditions:

A Review of Therapeutic Uses of Mirtazapine in Psychiatric and Medical Conditions


Mirtazapine is an effective antidepressant with unique mechanisms of action. It is characterized by a relatively rapid onset of action, high response and remission rates, a favorable side-effect profile, and several unique therapeutic benefits over other antidepressants. Mirtazapine has also shown promise in treating some medical disorders, including neurologic conditions, and ameliorating some of the associated debilitating symptoms of weight loss, insomnia, and postoperative nausea and vomiting.


And even Fibromyalgia, which I did suggest was the “almost autism” for females:-


In a 6-week open-label trial of mirtazapine, 54% of the 26 fibromyalgia patients who completed the study demonstrated a clinically significant reduction in pain intensity and in mean weekly dosage of acetaminophen. Additionally, there was a significant improvement in sleep quality and somatic symptoms, including cold extremities, dry mouth, sweating, dizziness, and headache. Of note, the magnitude of reduction in major fibromyalgia symptoms was significantly correlated with the magnitude of reduction in depression



Mirtazapine in Autism

In the new trial of Mirtazapine in autism they have chosen to focus on anxiety.  That looks odd to me given the very wide scope of benefits seen in schizophrenia and the feedback of our reader who asked why Remeron was working wonders with his child.

As is often the case, this trial at Massachusetts General Hospital uses doses that are extremely high.  Given the numerous effects of this drug it is highly likely that the effect may be completely different at higher/lower doses.



This study will determine the effectiveness of mirtazapine in reducing anxiety in children with autistic disorder, Asperger's disorder and Pervasive Developmental Disorder.

The starting dose for subjects is 7.5 mg daily. The maximum daily dose will be 45 mg.


I am very much in agreement with the readers of this blog using Mirtazapine at a lower dose.

As the schizophrenia trial showed, the effect grows over time, so better to try a low dose of 5mg for two months than race up to 45mg. 












15 comments:

  1. Sorry again for this being off-topic but a huge genetics paper came out today with respect to autism that you may or may not have had a chance to look at:

    http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0153329

    The most important findings are that the MAPK signaling and calcium signaling pathways were strongly associated with ASD's. Not that there has not been a lot of research suggesting this already, but these findings may improve the signal to noise ratio of where researchers need to look next for usable therapies that get at the root of some ASD's (Timothy Syndrome which you covered a few weeks ago was one suggestion they made).

    I did a quick readup on MAPK signaling as I am much more familiar with calcium signaling and came across this:

    "RAF-ERK pathway is also involved in the pathophysiology of Noonan's Syndrome, a polymalformative disease, where Simvastatin was proposed as a way to improve CNS-cognitive symptoms of the disorder." - https://en.wikipedia.org/wiki/MAPK/ERK_pathway

    Symptoms of Noonan syndrome of course parallel many of the peripheral symptoms of many ASD's to varying degrees. What is interesting was the mention of simvastatin which you have covered here on your blog in great detail already.

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    1. Thanks Tyler, statins certainly show effect for our type of autism and from the first pill.

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    2. BTW, are you doing both atorvastatin and verapamil concurrently right now? I know verapamil is) your choice of calcium channel blocker, but simvastatin was mentioned as a modulator of MAPK (my post above). I recall you saying you only used verapamil for allergy related flare-ups (I could be wrong). Statins and calcium channel blockers are generally contraindicated so how do you (or your doctor) approach this problem specifically if you give them both concurrently. I have thought about verapamil for quite a while, but the long-term effects (depending on dosage of course) I am a little bit iffy about at the moment.

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    3. Tyler, there is indeed an interaction between different statins and verapamil. It is well documented:-

      "If you are taking verapamil with lovastatin or simvastatin, your body may not process your cholesterol medicine correctly.If you are taking atorvastatin and verapamil, your body may not process verapamil correctly.

      What might happen:

      If you are taking verapamil with lovastatin or simvastatin, the amount of cholesterol medicine in your blood may increase and cause muscle problems.If you are taking atorvastatin and verapamil, the amount of verapamil in your blood may increase and cause more side effects than normal."

      Atorvastatin is the best tolerated of all the statins, including the interaction with verapamil.

      I am using the lowest standard dose of atorvastatin (10mg) and a daily dose of <= 60mg verapamil, which is 1.5mg/kg/day, a very low dose.

      There have been no side effects from either drug and we have been using them together for a long time. I have no doubt that at higher doses things might be different.

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    4. Great! Thanks for the clarification on all of that.

      Also, I came across this paper today (first link is a description of the paper) that discusses a newly discovered mechanism glial cells use to control the shape of neurons. What might interest you is that the mechanism (in C Elegans though) is a cation chloride co-transporter called KCC-3. What this shows is that glial cells can communicate with neurons and instruct them to change their shape based upon chloride ion signaling. How this works in humans is obviously unclear but it suggests the way we think about chloride levels in neurons and what all the complexity that entails in terms of cell functioning may change in the future when more followup work ensues (hopefully).

      http://neurosciencenews.com/glial-cells-kcc-3-nerve-cells-4015/

      Here is the actual paper:

      http://www.cell.com/cell/abstract/S0092-8674(16)30322-1?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867416303221%3Fshowall%3Dtrue

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    5. Tyler, KCC-3 looks like it may be very relevant.

      The following paper gets rather complex, but shows the interaction between NKCC1, KCC3 etc. It raises the idea of the "activation of the KCC3 switch" and "dephosphorylation of the homologous residues in KCC2 (Thr906/Thr1107) might also be a novel method of stimulating KCC2 in diseased neurons to promote Cl− extrusion and restore GABAergic inhibition.

      http://journal.frontiersin.org/article/10.3389/fncel.2015.00255/full

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    6. So the obvious question now is what mechanisms/interventions perturb glial cells to release or else inhibit the release of chloride ions onto the cell membranes of neurons since it may be an indirect way of activating KCC2?

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    7. Tyler, have a read of this:-

      The WNK-SPAK/OSR1 pathway: Master regulator of cation-chloride cotransporters

      https://www.researchgate.net/profile/Thomas_Hochdoerfer/publication/263971634_The_WNK-SPAKOSR1_pathway_Master_regulator_of_cation-chloride_cotransporters/links/00b4953c7d57a4177d000000.pdf

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    8. Well I read the paper but it doesn't say anything about glial cells just it discusses CCC's in general with respect to all types of cells which express them. I guess what I was originally trying to say was that rather than just focus on NKCC1 and KCC2 regulators and future drugs and their effect in neurons, that perhaps focusing on the indirect route (via glial to neuron mechanisms of passing chloride ions between them) would be another idea to explore since the best we have right now for reducing chloride in neurons is bumetanide which allegedly is not that great at crossing the blood brain barrier even though it seems enough of it crosses the BBB to improve symptoms in syndromes involving CCC dysregulation.

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  2. I am not sure just how rare Cerebral Folate Deficiency,as described by Ramaekers and Frye is.I will say I have been in an internet group for families with Cerebral Folate Deficiency since 2012,and I will say I have seen families come and go in the last four years.Parents do leave,as their children have been found not to have this condition.While the group of comorbid disorders has expanded a bit since Frye and Rossignol published their first big articles,in 2011-2012,there is a pretty good picture that has formed of low functioning autism (with or without intellectual disability),a family history of serious problems with folate metabolism (My initial tests found me at the lower end of the diagnostic range for Severe MTHFR Deficiency and Homocystinuria.),including mental illness,and often a serious underlying genetic disorder.I have been found to have all this,including mutations for a very rare neurological disease,only twenty five other known cases in the world,that is neither known to exist with autism,nor that I show any of the features of.And then there are all my other medical issues...

    This is very complicated stuff.

    I am trying to be seen by a prominent autism geneticist,whose main interest is autism related to very rare genetic syndromes.


    Cognitive symptoms in autism-CFD are every bit as severe as schizophrenia or dementia.Rapid cognitive decline is often the first sign my leucovorin is wearing off,even before the return of autistic behaviour.

    I have read a couple of other articles about CFD in relation to schizophrenia,and I wish I could get my sister tested.My sister has a diagnosis of high functioning autism,not Asperger's,and severe bipolar disorder,with some signs of psychosis.

    I like this diagram of the folate cycle better.It's more detailed.

    http://smpdb.ca/view/SMP00053?hc_location=ufi

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  3. Hi Peter,

    As usual you have written another great post on an important topic. I had the privilege of interviewing Dr. Frye about his cerebral folate deficiency research and other topics related to treating autism. He is an intelligent and very generous guy. I have posted a transcript of the interview here: https://autismrc.com/2016/03/19/autism-research-connections-1-a-conversation-with-dr-richard-e-frye/. There is also a link to a podcast with the audio.

    Interestingly Dr. Frye told me he favored folinic over methylfolate for autism as there is more on it in the medical literature. I agree with you that methylfolate intuitively sounds like a better choice for most with autism as under methylation is often an issue in autism. Also in experiments on myself, folinic gives me a headache at a fairly modest dose, and I have never had this when using methylfolate. To me this suggests that at least for some folinic may have negative side effects that methylfolate does not have.

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  4. Sharing this on Facebook,thanks Seth.

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  5. What about vitamin B6 (or p5p)? I remember it is needed for Glutamate conversion(?), and recommended together with magnesium for kids with ADHD.
    I've also found a lot of people describing aggressiveness as a side effect of the epilepsy medicine Keppra (parents with angry children, unhappy spouses and even one patient who claimed he went to jail because of Keppra). Some of them swear that adding vitamin B6 did relieve the symtoms.

    /Ling

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    1. Ling, some people do use high doses of B6 over many years. A big fan was the late Bernie Rimland. For other people it does nothing and in some it makes things worse.

      All B vitamins are very important, but it seems that giving high doses of one can disturb the others.

      I think it is fair to say that a minority of people will respond to long term supplementation of one B vitamin or another, but for most people it either does nothing, or makes things worse.

      It is not just a case of supplementing a vitamin you are deficient in. Some people are deficient in vitamin D, but respond negatively to a supplement.

      It is a case for responsible trial and error.

      What works for somebody else on the internet on the second day of their trial, may not help you. You have to be open minded, but also critical.

      These vitamins are inexpensive and so it is easy to do your own research.

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