Rakesh Jain, MD, on L-Methylfolate as an Adjunctive Treatment for Depression

Psych Congress Steering Committee member Rakesh Jain, MD, MPH, discusses a paper he co-authored on the use of L-methylfolate as an adjunctive treatment for depression.

Rakesh Jain, MD, MPH, is a psychiatrist and a clinical professor of psychiatry at Texas Tech University School of Medicine at Permian Basin.

Read the paper here: Good, Better, Best: Clinical Scenarios for the Use of L-methylfolate in Patients With MDD


Hello, Psych Congress family members. This is Rakesh Jain sending you this brief podcast. I am a psychiatrist. I am a clinical professor of psychiatry at Texas Tech University School of Medicine at Permian Basin, and I'm a proud member of the Steering Committee at Psych Congress.

I wanted to report to you the publication of a recent review paper that I coauthored. The title of this new paper, published in late 2019 in the journal CNS Spectrums, has the enigmatic title "Good, Better, Best: Clinical Scenarios for the Use of L‑Methylfolate in Patients With Major Depressive Disorder."

My coauthors were Drs. Sloan Manning and Andrew Cutler. Allow me to briefly tell you about this paper and also invite you to seek a copy of this article online and read it for yourself.

As you know, depression is among the most prevalent mental disorders worldwide, and a substantial proportion of patients do not respond adequately to our standard antidepressants.

Our understanding of the pathophysiology of depression is no longer limited to the chemical imbalance of neurotransmitters, but also involves the interplay of proinflammatory modulators in the CNS as well as folate metabolism.

Additional factors such as stress and metabolic disorders may also contribute to the challenges our patients face. Multiple inflammatory metabolic and genetic markers have been identified and could provide critical information to help us clinicians individualize treatments for patients to achieve optimal outcomes.

Recent advancements in research have clarified the underlying causes of depression, and they have led to possible new avenues for adjunctive treatment. Among those, of course, is L‑methylfolate, a medical food that is thought to enhance synthesis of multiple monoamines such as serotonin, norepinephrine, and dopamine.

It suppresses inflammation and promotes neural health. Clinical studies that assess supplemental use of L‑methylfolate in patients with usual care in resistant depression found that it resulted in improved outcomes. We authors are reporting the results of multiple such studies in our paper.

Patients with SSRI-resistant depression, and particularly those patients with biomarkers of inflammation or metabolic disorder, particularly if they had 2 or more of these factors, were the best responders. I'll tell you more about that in just a minute.

Considering this, the goals of this review paper that I've been talking about were one, to highlight recent advances in the pathophysiology of major depressive disorder as it pertains to folate and associated biomarkers, and number two, to establish the profile of patients with depression who could benefit most from supplemental use of L‑methylfolate.

Of course, what I just said begs the question, "Where should I use it? Where should I avoid it?" Me and my coauthors divided this issue into 4 subgroups.

Group number one: where should we actually avoid using L‑methylfolate? We found there were 2 kinds of patients we ought not to consider using it, such as patients who have hypersensitivity to L‑methylfolate, or in patients who already have high folate levels.

Good candidates might include those who are seeking general health benefit. There are many patients who prefer nutritional products with a limited side effect profile who have a holistic frame of mind. Then this might be appropriate. Also, patients who have had a partial response to SSRIs or to SNRIs.

Even better candidates—which is the third group—might be patients who have known evidence of a treatment failure, particularly with an SSRI, and those patients who have certain genetic challenges, mutations such as the MTR, AGGG allele presence, low SAM‑E levels, high BMI.

This is very important. As you know, very many of our patients have BMIs of 30 or greater, or have elevated levels of C‑reactive protein, or interleukin‑8, which is an inflammatory cytokine. All these patients may have a particular benefit with augmentation with L‑methylfolate.

Based on data, we three authors thought that the best candidates might be those ‑‑ in addition to the ones we have mentioned ‑‑ patients with documented low folate levels, or they have impaired MTHFR enzyme activity as demonstrated by gene testing. That is becoming increasingly more common.

Another group might be patients with SSRI failure and 2 markers of inflammation such as obesity or folic gene polymorphisms, or a BMI of 30 or greater. That is an important group.

And finally, as I said, patients who have an elevated BMI, and in addition to that have elevated levels of C‑reactive protein, leptin, TNF-alpha, or other inflammatory cytokines might very well end up being ideal candidates for augmentation of L‑methylfolate.

In the last few minutes, I've covered a lot of ground with you. I'm hoping that I whetted your appetite to read the full article, which I would like to encourage you to access it from your medical library, or just from the Internet.

Thank you very much for giving me a few minutes of your time, listening to this podcast, and I wish you and your patients the very best of success in treatment.

This is Rakesh Jain, member of Psych Congress Steering Committee, saying goodbye to you.