02. The Potential Use of Folate and Its Derivatives in Treating Psychiatric Disorders: A Systematic Review

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FOMO—the fear of missing out. You might have a sort of FOMO by extension, a fear that your patients might be missing out on something they need that you’re not prescribing, such as L-methylfolate. Take a hypothetical Rhonda Baker, for example. Could she be homozygous for low efficacy alleles of the methyltetrahydrofolate reductase (MTFR) gene, in which case perhaps her depression won’t respond fully to an antidepressant or her bipolar depression won’t fully respond to lamotrigine? Worse yet, could lamotrigine actually be interfering with folate availability such that you’re inadvertently making her mood disorder worse while trying to help? Should you think about recommending L-methylfolate for her and maybe for all of your patients with mood disorders or at least screening everyone for low efficacy MTFR alleles?

Hi! Jim Phelps here for the Psychopharmacology Institute. Let’s slow down and review some basics and then come back to those clinical questions. What is L-methylfolate? What’s the evidence that adding it can help depression treatment? And what’s the story with lamotrigine and folate? If you’ve been mystified or left still slightly uncertain about folate’s metabolic pathways, this article we’re reviewing here by Nelson Lam and colleagues reminds us that many foods contain tetrahydrofolate. Think of that as the main form of folate metabolically, tetrahydrofolate. To get there from supplements or from food fortification requires 2 enzymatic steps, but those are not genetically limited. So, either way, you can get easily plenty of tetrahydrofolate on board either through diet or through supplements. But then the crucial step comes. Tetrahydrofolate must be methylated to serve as a methyl donor in the synthesis of dopamine, norepinephrine, and serotonin as well as DNA synthesis and epigenetic control processes. The enzyme for that methylation step? That’s MTFR—methyltetrahydrofolate reductase.

As you know, some versions of that MTFR enzyme are not very good at the job. Evolutionarily, if you are wondering why these inefficient enzymes are still around, they’ve been associated with increased fetal survival and may confer some resistance to colon cancer. But if Ms. Baker is homozygous for those inefficient enzymes, she’s one of the roughly 15% of the general population that makes low amounts of methyltetrahydrofolate, which places her at increased statistical risk of severe depression.

But there are many further details about folate in the article by Dr. Lam and colleagues. I’m just going to cut to the clinical issues. How often should you prescribe L-methylfolate? Which version? Who needs genetic testing to determine their MTFR alleles? To address these questions requires going beyond Lam et al.’s article. So, after a brief literature review, which is included in the references for this Quick Take, here are my conclusions.

First, there are over-the-counter forms of L-methylfolate that cost as little as $10 a month for 15 mg a day. During my search, I did not discover any indications that prescription versions are better than over-the-counter generics other than perhaps the greater assurance that the pills contain what they purport to contain and, maybe more importantly, that your patient will actually acquire them without getting lost in the vitamin aisle. Second, you don’t need to test everyone for their MTFR alleles. If you plan to give L-methylfolate only to those with inefficient alleles, then test only those patients who have not responded to an antidepressant because L-methylfolate has been studied only as an adjunct, not as monotherapy. Testing might be particularly appropriate in Hispanic patients, for whom the incidence of homozygosity for those inefficient alleles is over 25%. In North American Caucasians, it’s 10%–15%.

Lastly, you may have heard concerns about folate in patients taking lamotrigine. The study on which those concerns are based found that people taking lamotrigine alone did statistically better than those taking lamotrigine and folic acid. So, if you’re starting lamotrigine, don’t add folic acid for now until we know more. It might be that you could add L-methylfolate, but that hasn’t been studied. And since the mechanism of this apparent negative interaction isn’t known, we can’t know whether using a form of folate that’s farther down the metabolic pathway solves the problem. Finally, if your patient is already taking folic acid supplements, and lamotrigine hasn’t worked very well, you might consider trying it again after stopping the supplement for a few months.

To conclude, your patients are not missing out if you’re not prescribing L-methylfolate. For those who are still taking an antidepressant to which they have not responded, consider genetic testing for the MTFR genotype and then an over-the-counter L-methylfolate for the 10%–25% who are homozygous for inefficient alleles.

For more on all this, Dr. Lam’s review, which is linked here at the Psychopharmacology Institute, has one of the best single picture illustrations of folate metabolism that I’ve ever seen. If you’ve struggled with remembering the pathways as I have, look at the article at Figure 1. Even the fine print is worth your time.

Abstract

Objectives: To examine the strengths and limitations of existing data to provide guidance for the use of folate supplements as treatment, with or without other psychotropic medications, in various psychiatric disorders. To identify area for further research in terms of the biosynthesis of mechanism of folate and genetic variants in metabolic pathway in human.

Methods: A systematic review of published literature following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, to assess whether folate supplements are beneficial in certain psychiatric disorders (depression, bipolar disorder, schizophrenia, autism spectrum disorder, and attention deficit hyperactivity disorder). Methodology of this review is registered with Prospero (Registration number CRD 42021266605).

Data sources: Eligible studies were identified using a systematic search of four electronic databases: Embase, Pubmed, PsycINFO, and Cochrane. The search strategy covered the time period from 1974 to August 16th, 2021. Therefore, this review examines randomized control trials or open-label trials completed during this period.

Results: We identified 23 studies of folate supplements in various psychiatric disorders for critical review. Of these, 9 studies investigated the efficacy of folate supplements in major depressive disorders, 5 studies in schizophrenia, 6 studies in autism spectrum disorder, 2 studies in bipolar affective disorder and 1 study in attention deficit hyperactive disorder. The most consistent finding association of oral levomefolic acid or 5-methylfolate with improvement in clinical outcomes in mental health conditions as mentioned above, especially in major depressive disorder (including postpartum and post-menopausal depression), schizophrenia, autism spectrum disorder, attention deficit hyperactivity disorder and bipolar affective disorder. Folate supplements were well tolerated.

Limitation: Our results are not representative of all types of studies such as case reports or case series studies, nor are they representative of the studies conducted in languages that are not in English or not translated in English.

Conclusion: Increasing evidence from clinical trials consistently demonstrate folate supplements, especially levomefolic acid or 5-methylfolate, may improve clinical outcomes for certain psychiatric diseases, especially as an adjunct pharmacotherapy with minimal side effects.

Reference

Lam, N., Long, X. X., Li, X., Saad, M., Lim, F., Doery, J. C., Griffin, R. C., & Galletly, C. (2022). The potential use of folate and its derivatives in treating psychiatric disorders: A systematic review. Biomedicine & Pharmacotherapy, 146, 112541.

Related References

• Wan, L., Li, Y., Zhang, Z., Sun, Z., He, Y., & Li, R. (2018). Methylenetetrahydrofolate reductase and psychiatric diseases. Translational Psychiatry, 8(1), 1-12.
• Rosenberg, N., Murata, M., Ikeda, Y., Opare-Sem, O., Zivelin, A., Geffen, E., & Seligsohn, U. (2002). The frequent 5,10-methylenetetrahydrofolate reductase C677T polymorphism is associated with a common haplotype in whites, Japanese, and Africans. American Journal of Human Genetics, 70(3), 758–762. 
• Maruf, A. A., Poweleit, E. A., Brown, L. C., Strawn, J. R., & Bousman, C. A. (2022). Systematic review and meta-analysis of L-methylfolate augmentation in depressive disorders. Pharmacopsychiatry, 55(3), 139–147. 
• Hickey, S. E., Curry, C. J., & Toriello, H. V. (2013). ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing. Genetics in Medicine, 15(2), 153-156.
• Geddes, J. R., Gardiner, A., Rendell, J., Voysey, M., Tunbridge, E., Hinds, C., Yu, L. M., Hainsworth, J., Attenburrow, M. J., Simon, J., Goodwin, G. M., Harrison, P. J., & CEQUEL Investigators and Collaborators (2016). Comparative evaluation of quetiapine plus lamotrigine combination versus quetiapine monotherapy (and folic acid versus placebo) in bipolar depression (CEQUEL): a 2× 2 factorial randomised trial. The Lancet Psychiatry, 3(1), 31-39.
• Mischoulon, D., Zajecka, J., Freeman, M. P., & Fava, M. (2016). Does folic acid interfere with lamotrigine?. The Lancet Psychiatry, 3(8), 704-705.