Note: Many thanks to Catherine Passariello, Ph.D., for being a co-author. Follow her as she speaks about genetic testing and psychopharmacology at www.interviewlibrary.info – a podcast interview.
Fifty percent or more of depressed people fail to respond to their first trial of an antidepressant, and the percentage only decreases as numbers of antidepressant trials increase.
Failure can occur even with a correct diagnosis and good medications. But now a genetic mutation may help explain why this is so.
This can all be a bit technical, so read it slowly. Maybe even read it twice. It is not thorny or impossible to understand.
It is now accepted that inadequate folic acid intake or a deficiency in its conversion is associated with high homocysteine levels and an inadequate monoamine production. This effectively is a lessening of norepinephrine, dopamine, and serotonin levels Knowing this information makes for a significant paradigm shift in understanding biological depression. It moves the traditional focus away from primarily blocking the re-update of neurohormonal entities to now actually increasing hormone production. This is done by reducing homocysteine levels. And this, in turn, is partially done by an enzyme which converts folic acid into its active form.
That enzyme is the MTHFR – the initials stand for MethyleneTetraHydroFolateReductase. It converts folic acid, which is vitamin B9, into l-methylfolate. Unconverted (the fancy term is ‘not reduced’) folic acid is not active, but l-methylfolate is quite active. This active form induces a cascade of biochemical actions affecting many of our body systems. We now know that many people have a ‘sluggish’ enzyme insofar as being able to make that folic acid conversion.
The question exists about taking extra regular B9 to override the compromised MTHFR. No, it does not, but taking more B9 may help if there is a primary B9 deficiency.
MTHFR was discovered in 2003 as part of the Human Genome Project. The MTHFR gene produces the MTHFR enzyme, which changes dietary folic acid (also known as 5,10- MethyleneTetraHydroFolate, into 5-MTHF; this is also called l-methylfolate. The problem lies in that there is a single point variation (C677T) of the MTHFR gene that directly effects how well the enzyme works: the gene can either have the C or the T variant. We all inherit two copies of every gene, one from our biological mother and one from our biological father, each copy is called an allele. Two C copies (C/C) makes for a normally functioning enzyme, two T copies (T/T) for a severely reduced functioning enzyme, and a mixed combination (T/C) is for a less diminished function enzyme. So, if a T/T or T/C form exists, the enzyme owner could suffer. The T/T or T/C forms are still compatible with life; they can, however, result in a host of biological limitations. About 40% of people have the C/C, 40% have the C/T, and this leaves 20% with a T/T variation.
Getting past the hurdle of a less than optimal MTHFR improves a host of biochemical events, often including a reduction of depression. Indeed, the relation of depression to elevated homocysteine has been referred to as the Homocysteine Theory of Depression.
This is the biochemical cascade: the 5-MTHF is necessary to convert homocysteine (an amino acid) into methionine (another amino acid). Methionine later changes into SAMe (s-adenosylmethionine) which supports the immune system, helps with anti-inflammation, and makes and breakdowns neurotransmitters. It also helps to grow and maintain cells. Your doctor will say that SAMe is a methyl donor, and that the SAMe donated methyl group goes directly into the production of norepinephrine, dopamine, serotonin and melatonin.
Without SAMe, which comes from methionine, which in turn comes from the breakdown of homocysteine because of the l-methylfolate, the neurotransmitters will be produced in short supply.
Here is a quick summary of the downstream effects of a poorly functioning MTHFR enzyme:
- When homocysteine is not sufficiently broken down into methionine, there is a build-up of homocysteine in the system, a condition termed as hyperhomocysteinenemia. This is associated with cardiac and vascular problems, inflammation, some cancers, IBS, possible pregnancy issues, migraines, and even some dementias.
- Low SAMe leads to a decrease in its products which is associated with depression. Taking extra SAMe offers mixed results as an antidepressant.
Too much homocysteine is toxic. It can interfere with the synthesis and repair of DNA and worsen inflammatory responses. An oxidized homocysteine can also stimulate the NMDA (N-methyl-D-aspartate) receptor which will let calcium enter a cell. This then releases a substance known as proteases, and the process can result in cell death and hasten dementia. Homocysteine can also damage cells that line arteries and contribute to the atherosclerotic processes.
Life-style can also increase homocysteine levels, such as smoking, obesity, some medications, insufficient exercise, and psychosocial stresses. Excessive alcohol use and poor diet may cause a multiple B vitamin depletions. Exercise distributes the homocysteine more evenly throughout the body. Some lipid lowering medications, as well as lithium, methotrexate, birth control pills, L-dopa, and some anticonvulsants also increase homocysteine levels.
All this is fascinating. For a long time, the strategy to address this gamut of problems was simply to add folic acid. But too often this did not work well enough. The reason was the sluggish MTHFR enzyme. With a sluggish enzyme, the ingested folic acid never became ‘active.’
Fortunately, l-methylfolate formulations now exist that can bypass the sluggish enzyme. It would seem that getting around the sluggish MTHFR would therefore solve so many problems. The effect of these l-methylfolate formulations can sometimes be positively dramatic.
But, and medicine is replete with the ‘buts’, the real-time practice of medicine is not always so uncomplicated as is the draw to this charismatic concept. Each case needs a rigorous consideration because other processes can cause these same medical problems.
Many folks remember when the antidepressant Prozac had the reputation that it could fix so many things. In time, however, Prozac’s ranking was re-measured in step with its reality – it was good but not magic. The same is happening for the MTHFR. Too many people speak of it as the present-day Prozac. It’s not. But it is a great new tool.