Nutritional support for the methylation cycle is another area in which nutrition plays a critical role. The methylation cycle is essential for mental and physical health. It is critical to the metabolism of catecholamines in the synapse via an enzyme (COMT) as well as the synthesis of ‘depression-relevant' compounds such as melatonin, myelin basic protein, carnitine, CoQ10, etc. Methylation is required to inactivate histamine.
Basic nutrients necessary for normal function of this cycle include B12, glycine, serine, activated B6, selenium, cysteine, methionine and folic acid .
Several studies have shown the utility of folic acid as an adjunct to medication use for depression. In one study (10) the average HAM-D (a standard measure of depression) score decreased from 27 to 7 in those receiving P (fluoxetine) plus F (folic acid), and from 27 to 12 in those on P plus Pl (placebo (p<0.001). Recovery (full) was attained in 73% of the women receiving P +F, but only 47% of those on P + Pl (p<0.06).
A variety of genetic polymorphisms (single nucleotide polymorphisms or SNP's) exist, which can alter function the methylation cycle. One important SNP is the MTHFR SNP, which when present in both copies of a persons genes, indicates the need for a special form of folic acid: L-methyl folate (which crosses the blood brain barrier). This gene acts by reducing the function of the methylation cycle-specifically reducing the conversion of 5,10 methyl-tetrahydrofolate to 5-methyltetrahydrofolate. This reduces the synthesis of methionine (needed for the COMT enzyme, which requires s-adenosylmethionine to function), results in increased homocysteine (a marker of methylation status), and altered (decreased or increased) DNA methylation, leaving certain genes turned on or off, when they should not be. In fact, in a review of 1280 psychiatric cases and 10,429 controls, the odds of having depression was 36% greater if a person had two copies of the MTHFR SNP (8). This means low levels of available folic acid, in this case for genetic reasons, but in other cases due to medications or diet, increases one's risk for depression by 36%.
In some fascinating research in the area of epigenetics (epigenetics describes the part of the genome that is modified by experience as well as methylation, acetylation, ubiquitination, phosphorylation) suggests that genes that are turned on or off by one's environment, one's diet, by stress, or by one's experience are transmitted to subsequent generations. One author suggests that the biological underpinnings of bipolar affective disorder are not primarily genetic, but are epigenetic (10). Another author (11) presents data that suggests that the fact that identical twins are not fully concordant for depression may have to do with reduced methylation of the COMT gene may be associated with bipolar disorder and schizophrenia, as only 26-29% of these patients, when compared with controls showed normal methylation of the COMT gene in the pre-frontal cortex. The environmental exposures at key developmental phases may result in long standing neuro-biological changes leading to pathology. Direct evidence is limited at this point.
One of the critical ingredients for the methylation cycle is B12. B12 plays a vital role in the metabolism of fatty acids essential for the maintenance of myelin in the brain. Absorption of B12 requires the secretion from the cells lining the stomach of a glycoprotein, known as intrinsic factor. The B12-intrinsic factor complex is then absorbed in the ileum (part of the small intestine) in the presence of calcium.
Many physicians think that to assess B12 one must measure B12 levels. However, it is well-established that B12 levels are not a sensitive marker for adequacy of B12 function (17). Some people suggest that measuring methylmalonic acid (MMA) is more sensitive. But at least one study (18) shows that B12 function has a minimal effect on levels of MMA. Assessment of B12 status in practice involves measurement of a number of parameters, including the physical exam (depression, impaired balance, panic, neuropathy) the size of red blood cells (MCV), Hematocrit, homocysteine, and functional immunoassays.
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