Folate Metabolism, the Folate Trap, and finding the right therapy for your specific autism

  

Most of the folate and folic acid we eat must be converted into the active form, known as L-methylfolate or 5-MTHF. However, some dietary folate is already in the active form when we eat it and therefore does not rely on MTHFR.

In treating autism, folate metabolism is a key area of therapeutic focus. While folate supplementation seems simple on the surface, the biology behind it is complex — and, if misunderstood, you may even worsen symptoms.

This post explains how folate metabolism works, what the methyl folate trap is, and how different folate and B12 formulations affect outcomes in children and adults with autism, especially those with MTHFR, MTR, or MTRR mutations.

The Normal Folate Cycle 

Folate, a B-vitamin, plays a central role in:

• DNA synthesis 
• Methylation 
• Neurotransmitter production (via SAMe) 

Here is how it works, if you like details:  

• 5,10-methylene-THF helps make thymidine (for DNA).
• Some of this is converted to 5-MTHF by MTHFR.
• 5-MTHF donates a methyl group to homocysteine, converting it to methionine, in a process catalyzed by methionine synthase, which requires vitamin B12.
• This regenerates THF, which goes back into the cycle.

 

The Methyl Folate Trap

 

If there is a vitamin B12 deficiency, or methionine synthase (MTR) dysfunction, the conversion of 5-MTHF → THF is blocked. This causes:

·         5-MTHF to accumulate (it’s “trapped”)

·         THF and 5,10-methylene-THF to fall

·         DNA synthesis to halt

·         Elevated homocysteine, and low SAMe

The result:

·         Anemia

·         Neurological symptoms

·         Behavioral worsening in autism

This is known as the methyl folate trap — and it explains why giving high-dose folate without enough B12 can backfire.

In summary, the methyl folate trap occurs when B12 deficiency or methionine synthase dysfunction prevents 5-MTHF from recycling to THF, stalling DNA synthesis and methylation, even if folate levels are high.

  

Could the Folate Trap Cause Aggressive or Behavioral Regression?

Yes. In autism, worsening behaviors (irritability, aggression etc) after high-dose folinic acid may reflect a relative B12 deficiency or impaired methionine synthase, leading to:

·    Folate trapping

·   Disrupted neurotransmitter synthesis (especially dopamine/serotonin)

·    Low SAMe

In these cases, adding B12 (methylcobalamin or hydroxycobalamin) often improves tolerance to folate therapy and reduces side effects.

 

Other reasons for a possible negative reaction to calcium folinate

Folate metabolism is tightly connected to glutamate and GABA balance.

High folate dosing in some sensitive individuals may cause excess glutamate activity (excitatory), triggering aggression or anxiety-like behaviors.

Children with fragile neurochemical balance may not tolerate sudden shifts in methylation or neurotransmitter levels. A rapid increase in serotonin, dopamine, or norepinephrine can destabilize mood or cause agitation/aggression. This is why you start low and gradually increase your folate supplement.

In such children 5-MTHF may work better, but you still B12.

Apparently, some doctors prescribe antipsychotics to treat agitation caused by calcium folinate; I am not sure that is a good idea.

 

 Choosing the Right Folate: Folinic Acid vs 5-MTHF

	Calcium Folinate / Leucovorin	5-MTHF
Form	Precursor to 5-MTHF	Final active form
Requires MTHFR?	Yes	No
Can enter CSF?	Indirectly	Directly
Behavioral reactions?	More common in some	Usually better tolerated

For whom is 5-MTHF better?

1.      Those with MTHFR mutations (esp. C677T)

2.      Those who react negatively to folinic acid

3.      Those needing direct CNS access

Folinic acid /Leucovorin is converted to 5-MTHF (active folate) through a series of enzymatic steps. First, it is converted into 5,10-methylenetetrahydrofolate, and then the enzyme MTHFR  converts it to 5-MTHF.

In people with MTHFR mutations, this final step may be slower or impaired, meaning folinic acid may not fully convert to active folate. Direct supplementation with 5-MTHF is often preferred in those with these genetic variants.

 

  

The Problem with Synthetic Folic Acid

 Status of mandatory folic acid fortification in 2019

 

In countries like the US folic acid is added to many foods such as flour, bread, pasta and rice in addition to products like breakfast cereals. This is to reduce the incidence of neural tube defects like spina bifida that occur when a fetus lacks sufficient folate in the first 28 days of life.

In Europe there is much less mandatory supplementation of folic acid due to the negative effects. In older people folic acid supplementation can mask vitamin B12 deficiency. High intake of synthetic folic acid can correct the anemia caused by B12 deficiency without correcting the neurological damage. This can lead to delayed diagnosis of B12 deficiency, increasing the risk of irreversible nerve damage, cognitive decline, and dementia in the elderly.

Folic acid is synthetic and must be converted by DHFR (slow, limited in humans).

It competes with both folinic acid and 5-MTHF for cellular entry.

High levels of unmetabolized folic acid can block folate receptors and worsen autism symptoms in some.

Some people with autism should avoid folic acid supplements and fortified foods.

 

The Dilemma: One Size Does not Fit All

While folic acid fortification benefits the general population, especially women of childbearing age, it may pose risks for other groups:

·    Elderly: Risk of masking B12 deficiency

·    Children with autism or FRAA: Risk of blocked folate receptors and behavioral regression

·    Those with MTHFR variants. They have reduced ability to activate folic acid because their ability to convert folic acid into the active form, 5-MTHF, is reduced. This can lead to unmetabolized folic acid (UMFA) in the blood, which may interfere with normal folate metabolism. It can lead to blocking the transport of natural folates into the brain.

 

Here is a study showing that folic acid impairs the transport of active folate (5-MTHF) across the blood brain barrier.

 

Folic acid inhibits 5-methyltetrahydrofolate transport across the blood–cerebrospinal fluid barrier:Clinical biochemical data from two cases

Results: Both patients had low CSF 5MTHF before treatment and high-dose FA therapy did not normalize CSF 5MTHF. There was a dissociation between serum total folate and 5MTHF concentrations during FA therapy, which was considered to be due to the appearance of unmetabolized FA. The addition of folinic acid did not improve low CSF 5MTHF in the KSS patient and the cessation of FA resulted in the normalization of CSF 5MTHF. In the patient homozygous for MTHFR C677T, minimization of the FA dosage resulted in the normalization of CSF 5MTHF and an increased CSF-to-serum 5MTHF ratio.

Conclusions: Our data suggest that excess supplementation of FA impaired 5MTHF transport across the blood-CSF barrier. In the treatment of CFD, supplementation of folinic acid or 5MTHF (in cases of impaired 5MTHF synthesis) is preferred over the use of FA. The reference values of CSF 5MTHF concentration based on 600 pediatric cases were also provided.

  

B12 - Forms and why it matters

To prevent the folate trap, adequate B12 is critical.

                          

Methylcobalamin        Active, supports methylation directly

Hydroxycobalamin      Longer-lasting, converted to methyl- or adeno-B12

Adenosylcobalamin     Active in mitochondria

Cyanocobalamin         Synthetic, less ideal, may not work in autism

 

Methylcobalamin or hydroxycobalamin are best for autism and CFD.

 

Can it be oral?

Yes, but high doses needed (1–5 mg daily)

Subcutaneous injections may be better absorbed in some

 

What About Betaine / TMG?

Betaine (trimethylglycine) provides methyl groups to convert homocysteine to methionine via the BHMT pathway (mostly in the liver, not brain).

Useful if:

·         Homocysteine is high

·         B12 metabolism is impaired

·         Need extra methylation support

 But, it does not bypass the folate trap in the brain — you still need functional methionine synthase and B12.

 

When Do You Need More SAMe?

SAMe (S-adenosylmethionine) is the body’s master methyl donor, essential for: 

·         Neurotransmitter synthesis

·         Myelination

·         Detox pathways

 

You may need extra SAMe if:

·         You have low methionine/SAMe

·         There is fatigue, depression, or tics

·         Homocysteine is high despite folate + B12

Oral SAMe is poorly absorbed unless enteric-coated.

Do not assume “more folate = better” without addressing B12

 

Conclusion

Whether a person with autism stands to benefit from tuning up their folate metabolism will depend on their unique situation. Many people need no intervention at all.

For others it is highly beneficial to customise an intervention plan. It would include some, or all, of the following. 

·   Reduce expose to synthetic folic acid used to fortify flour, pasta, bread, rice, breakfast cereals etc.

·   Supplement with 5-MTHF or calcium folinate / Leucovorin

·   Supplement vitamin B12, in the form of methylcobalamin or hydroxycobalamin

·    Supplement Betaine/TMG

·    Supplement SAM

     ·  Consider supplementing PQQ if positive for FRAA 

 

The only substance that is prescription-only is calcium folinate / Leucovorin. It looks like 5-MTHF is actually the better choice for most people and it is much more accessible.

We have seen that the potency of generic calcium folinate / Leucovorin is highly variable, possibly due to different excipients that are added. How reliable the OTC 5-MTHF supplements are is an open question.

If you find this subject confusing, use ChatGPT to help you. You can even upload a screenshot of your MTHFR/MTR/MTRR mutations and then get tailored advice. It is free !!  (for now)

 

If you are someone who likes lab tests, the options include: 

• Folate receptor antibodies (FRAA) – to check for blocking autoantibodies www.fratnow.com
• Serum and CSF 5-MTHF – to detect cerebral folate deficiency
• Homocysteine – elevated if methylation is impaired
• MMA (methylmalonic acid) – elevated in B12 deficiency
• Vitamin B12 – ideally with active B12
• Genetic testing – particularly MTHFR, MTR, and MTRR variants to assess methylation capacity

High MMA = likely B12 deficiency, even if serum B12 is "normal".

This is especially important in people with neurological symptoms or MTHFR-related metabolism issues.

 

Measuring serum (blood) 5-MTHF provides insight into how much active folate is circulating in the body. This helps detect:

• Folate trap from B12 deficiency (high folate, low methylation)
• Impaired folate metabolism in MTHFR or MTR/MTRR variants
• Folate absorption or transport problems, especially if CSF 5-MTHF is also tested
  It’s particularly useful when deciding whether folinic acid, 5-MTHF, or B12 supplementation is effective or needed.

CSF 5-MTHF (cerebrospinal fluid via lumbar puncture) gives a direct measure of active folate availability inside the brain. This is important because:

• Some children with autism or FRAA (folate receptor autoantibodies) have low CSF 5-MTHF even with normal blood folate. Some have FRAA and normal CSF 5-MTHF
• High serum folic acid can block transport of 5-MTHF into the brain, lowering CSF levels.
• It can help diagnose Cerebral Folate Deficiency (CFD), especially if symptoms improve with folinic acid.

Low CSF 5-MTHF with normal serum levels suggests a transport problem, not a folate intake issue.

PQQ as a Folate Transport Enhancer

A supplement called Pyrroloquinoline quinone (PQQ) may help bypass folate receptor autoantibody (FRAA) blockage by upregulating alternative folate transporters (RFC and PCFT) in the brain. This could improve delivery of both calcium folinate (leucovorin) and 5-MTHF into the brain when folate receptor alpha (FRα) is blocked.

Human data is lacking; all evidence from animal/cell studies. Some people report adverse effects (e.g. fatigue, overactivation)

For individuals with FRAA, PQQ might enhance the effectiveness of folinic acid or 5-MTHF by improving alternative transport into the brain.

Interview Series with Leading Autism Researchers

Seth Bittker, a regular reader of this blog and our occasional guest blogger, is creating an excellent interview series with leading autism researchers.

These interviews will be of interest to all readers of this blog.  There is something for everyone, whether you are the type that reads the literature in detail, or is more interested in the lay summary.

There are three interviews, all with podcasts, and more will be added later.

1)    Dr. Richard Frye on folate receptor alpha antibodies and folinic supplementation in autism. 

2)    Dr. Robert Hendrenon his recent double blind placebo controlled trial of methyl-B12 in autism.  

3)    Dr. Derrick Lonsdale on thiamine deficiency and supplementation of thiamine derivatives in autism.   

Good work Seth!  I am sure he will be interested in your suggestions for future interview candidates. 

By the way, in the third interview, Dr Lonsdale refers to his preferred thiamine supplement called TTFD, this has been used for decades in Japan.   It is also called Fursultiamine and the Japanese brand name is Alinamin, which is made by Takeda, a major Japanese company.  The Japanese website (in English) is here.

Takeda have various combinations with other B vitamins and some are sold on Amazon/eBay.  Some with very high amounts of B12.  

In interview number two above, Dr Hendrenon clearly does believe in the merits of extra B12 in autism.  His trial did inject the vitamin, rather than take it orally. 

It is best to only supplement at high doses the B vitamins that really help in your specific case; there are known  negative reactions to some B vitamins, so best to go through them one by one.

There is also a version of TTFD sold as Allithiamine by a small US company, Ecological Formulas, which Seth is investigating.

So as long as swallowing pills is possible, you have the opportunity to replicate Dr Lonsdale's trial and see if you have a responder or not. 


Side Effects of high dose B vitamins

According to the University of Maryland taking any one of the B vitamins for a long period of time can result in an imbalance of other important B vitamins, they suggest taking a B-complex vitamin which includes all B vitamins.

This might explain why some people who initially respond well to high doses of biotin, vitamin B7, later experience a negative response. 

Many people do not respond well to high doses of multiple B vitamins as prescribed by some DAN-type doctors.

Dr Frye, from interview number one, is also a big believer in B vitamin supplementation.

Clearly B vitamin supplementation needs to be much better thought out, to keep any good effects, without developing any bad effects. 

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.

Evaluation of Mirtazapine and Folic Acid for Schizophrenia:(RECOVERY2)

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.

Source: https://commons.wikimedia.org/wiki/File:MTHFR_metabolism.svg

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.

Association of MTHFR Gene Variants with Autism

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.

Effects of add-on mirtazapine on neurocognition in schizophrenia

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.

A Review of the Pharmacological and Clinical Profile of Mirtazapine

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.

Mirtazapine Treatment of Anxiety in Children and Adolescents With Pervasive Developmental Disorders

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.