For many years researchers and clinicians have felt that there is a relationship between sub-optimal function of the methylation pathway and mental health.
Overmethylation and Undermethylation
These terms were introduced used many years ago to explain to patients that there are differences in their biochemistry, therefore their treatment program should be different.
These descriptors were applied by the Pfeiffer/Walsh Clinic in Chicago to describe a clear difference they observed in the patients attending the clinic. They are not however accurate scientific terms.
With modern equipment and technology, research is in process aimed to illuminate the actual science.
The core difference to be remembered is that individuals have different biochemistry and if prescribed the incorrect nutrient, it may exacerbate symptoms and complicate recovery.
Urine Pyrrole concentrations reflect oxidative stress and are likely independent of methylation issues.
Here is a very simple explanation to enable basic understanding of the biochemistry.
SAMe Responder (Undermethylation)
In the first half of the methylation cycle, the amino acid Methionine is converted to homocysteine through the intermediaries SAMe [s-adenosylmethionine], and SAH [s-andenosyl homocysteine].
It is the SAMe that donates the methyl group to multiple biochemical reactions and the SAH that is a potent inhibitor of methylation.
When this side of the cycle is functioning poorly, we now refer to this as SAMe Responders for scientific correlation with the appropriate biochemistry (historically referred to as Undermethylators) .
The usual reason for poor functioning here is likely that the enzyme responsible for the initial conversion, Methionine Adenosyltransferase (MAT), carries a minor genetic defect, Single Nuclear Polymorphism (SNP), and thus cannot function at full measure.
This step is Magnesium-dependent and the conversion should be aided by magnesium supplementation.
From observational data it seems likely these patients have certain personality traits that are very different to those without this defect. They are referred to as “SAMe Responders” and with training with experienced practitioners, and a degree of experience, clinicians can pick SAMe Responders with a carefully taken clinical history.
Biochemical confirmation is difficult. One of the multitudes of biochemical reactions involving methylation is the metabolism of histamine which has to be “methylated” to be broken down. A slightly elevated histamine would be in keeping with “SAMe Responders”. Histamine is an indicative test, not fully accurate. There are now more detailed ways to measure methylation status. Other tests for methylation need to be done carefully due to the reactivity of the amino acids. It is also more expensive and not covered by a medical rebate. Patients already on antidepressant/antihistamine medications will not get a reliable methylation test as medications influence the result. All testing is an indicator, not a diagnosis.
For the reasons stated above ‘SAMe Responders” would be likely to show clinical improvement by supplementation with Magnesium, SAMe and in some cases methionine.
It is also hypothesised that this group are relatively low in serotonin and thus more likely to respond favourably to the Selective Serotonin Reuptake Inhibitor (SSRI) type medication. Therefore, caution should be used as Serotonin-norepinephrine reuptake inhibitors (SNRI) medication may create an exacerbation of symptoms.
There is a theory that after treatment commences for SAMe Responders, there may be changes which trigger oxidative stress, which may trigger a short term high urinary pyrrole measurement. This is yet to be researched but can be observed by 6 monthly Urinary tests until the urine is clear of pyrrole.
It has been observed in the literature that a number of people with depression respond well to S-adenosyl methionine. The Pfeiffer/Walsh clinic found these people that respond well to SAMe tended to be those with high histamine.
Folate Responder (Overmethylation)
In the second half of the methylation cycle, Homocysteine is converted back to methionine by being remethylated. This methyl donation can be accomplished by 2 ways. The first involving methylfolate in conjunction with B12 and the second using trimethylglycine [TMG or Betaine].
In many patients it is this half of the methylation cycle that is functioning sub-optimally due to minor defects in the enzymes involved [Methionine Synthetase (MS), Catechol-O-methyltransferase (COMT), or Methylene-TetraHydroFolate Reductase (MTHFR)]. It must be emphasised that most enzymes still function fine even given these defects [SNPs].
So, whilst methyl groups are being produced the process is inefficient and the term “Folate Responder” is used for these patients for scientific correlation with the appropriate biochemistry (previously referred to as “Overmethylators”).
Again, with observational data these patients have different personality traits. A trained and astute clinician can suspect this issue with a carefully taken clinical history.
Biochemically this group would be expected to have a slightly depressed histamine and likely elevated homocysteine.
We would expect these patients to respond favourably to supplementation with various forms of folate, B12, B3 and TMG.
We hypothesised these patients are likely to be low in noradrenalin and would be more likely to respond favourable to the SNRI type medication. Therefore, caution should be used as SSRI may cause exacerbation of symptoms.
Refer to the references in the reference section of this site for further reading.