Is there a way, clinically or through the use of laboratory tests, to determine which patients with major depressive disorder would benefit from L-methylfolate addition?
The short answer is “not any that are proven yet.” The longer answer is “research is in progress and there are some rational if unproven possibilities to guide us.”
First: lab tests for folate.
Since depression can be associated with low folate, it would seem a no brainer to give depressed patients L-methylfolate if their folate were low, but how do you find that out? Turns out it may not be as easy as it appears at first glance. That is, measuring folate in the blood tells you what the level of a mixture of various folates are due to recent ingestion of food containing folates. So, you can actually be folate-depleted in the long term but with a bit of folate in the diet just before the blood test, like a piece of fortified bread which is how bread comes these days, look normal. Better to study RBC folate or CSF folate levels, but not easy to get these from the lab; yet they reflect longer term folate levels. Given these difficulties, some suggest measuring homocysteine levels, which are reciprocally elevated when L-methylfolate levels are low, and it is easier to obtain from labs.
Second: genomic tests related to L-methylfolate synthesis.
What if folates and homocysteine are normal? It turns out that functional deficiencies that do not necessarily show up as changes in metabolites, occur in various inborn errors of metabolism. These are considered research tests yet, but if you are interested, the genes that regulate folate levels are:
methylene tetrahydrofolate reductase (MTHFR); methionine synthase reductase (MTRR); methionine synthase (MTR); and others.
Some early results from the positive trial shows that those patients who responded to 15 mg folate added on to SSRIs were more likely to have a genetic variant of one of these enzymes.
Also, there is genetic interaction called epistasis especially for cognition and studied more in schizophrenia than depression for the enzyme COMT and the enzyme MTHFR, another research finding.
Bottom line: stay tuned. It is likely that genomic tests (some of which you can already get with insurance coverage from Genomind or AssureRX – NEI members get one free test from Genomind) will not tell us what drug will work for sure, but will add to the weight of the evidence when choosing treatments. These are exciting times, but no clear lab test has yet been replicated and ready to apply in clinical practice to tell you who will be more likely to respond to L-methylfolate.
Now for one final interesting finding. Of all the results from the large 15 mg add on study, the one clinical feature that best predicted who was an L-methylfolate responder in that study, was not one of the symptoms of depression. It was BMI>30. Interesting, but not clear why obesity may be linked to L-methylfolate response, and needs to be replicated, but you might keep this in mind if you are prescribing L-methylfolate.
Stephen M. Stahl, MD, PhD
Adjunct Professor, Department of Psychiatry,
University of California, San Diego School of Medicine
Honorary Visiting Senior Fellow, University of Cambridge, UK