Exploring psychotherapeutic issues and agents in clinical practice
Patients will often share that they have been taking vitamin B supplements to enhance their energy, reduce fatigue, and generally feel better. Is there a connection between the B vitamins and mental health? According to some studies, a connection exists. Firth et al. (2017) conducted a systematic review and meta-analysis of the effects of vitamins and/or supplements on the psychiatric symptoms reported by individuals diagnosed with schizophrenia. Their recent study showed that supplementation with higher doses of vitamins B6, B8, and B12 reduced psychiatric symptoms and shortened the duration of illness. In 2013, Douaund et al. demonstrated that higher doses of B vitamins (e.g., folic acid, B6, B12) reduced gray matter atrophy in the regions of the brain that contribute to cognitive decline and Alzheimer's disease. In much earlier studies, deficiencies in vitamin B12 (i.e., pernicious anemia) were noted to contribute to mental health symptoms ranging from “depression by loss of mental energy to definite psychosis” (McAlpine, 1929).
Vitamin B9, also known as folate or folic acid, a water-soluble B vitamin, is one of the more complex and misunderstood supplements used to treat patients with psychiatric disorders. This vitamin, in the form of folate, occurs naturally in leafy green vegetables, some fruits, legumes, and organ meats. Cooking foods containing folate may inactivate its useful properties; in addition, smoking, alcohol use, diabetes, metabolic diseases, cancer, and medications (e.g., mood stabilizing anticonvulsant agents, L-dopa, and chemotherapy agents) may also affect folate levels (Mental Health America, 2016). Folic acid is the synthetic form of vitamin B9 and is found in fortified foods, such as cereals and baked goods, orange and tomato juices, and over-the-counter supplements. The synthetic supplement, folic acid, is frequently found in combination with other B vitamin complexes and formulations.
According to the Natural Standard (2017), supplementing dietary folate with synthetic folic acid effectively increases the folate levels and reduces homocysteine levels in the blood, a cardiovascular risk factor, and aids in preventing neural tube defects during pregnancy in women of childbearing age.
Conversion of Folate and Folic Acid to L-Methylfolate
To benefit from the cardiovascular and neural tube protective factors of folate and folic acid, it must first be metabolized into its most useful form of L-methylfolate, also known as 5-MTHF. Methylation is the process of converting folate and folic acid to their most useable form, L-methylfolate, which crosses the blood–brain barrier and regulates the production of the trimonoamines: serotonin, norepinephrine, and dopamine. The trimonoamines are the three major neurochemicals involved in the regulation of depression, anxiety, irritability, obsessive and compulsive behaviors, thought processes, and behaviors. The Figure illustrates the multi-step process by which the conversion of folate/folic acid to L-methylfolate occurs. Folic acid is converted by the enzyme dihydrofolate reductase to dihydrofolate, which is then metabolized to 5,10 methylene tetrahydrofolate. To cross the blood–brain barrier in its most active form, 5,10 methylene tetrahydrofolate must be metabolized by the enzyme methylenetetrahydrofolate reductase (MTHFR) to L-methylfolate. Dietary or natural folate, on the other hand, can either be directly metabolized to L-methylfolate or 5,10 methylene tetrahydrofolate, which would then undergo methylation via the enzyme MTHFR to the useable form of L-methylfolate.
Conversion of folate and folic acid into L-methylfolate. Adapted from Crider, Yang, Berry, and Bailey (2012).
MTHFR: The Gene Associated with Folate Deficiency
Many individuals have a genetic variant of the MTHFR gene causing low levels of the MTHFR enzyme necessary to convert folate and/or folic acid to L-methylfolate (Duprey, 2016). Low levels of methyltetrahydrofolate contribute to low levels of the trimonoamines (i.e., serotonin, dopamine, and norepinephrine), which in turn are associated with major depressive disorder; therefore, depression can be associated with a deficiency in folate (Duprey, 2016). In the field of pharmacogenetics, the C677T allele is the most extensively studied, and the “T” allele represents the risk for reduced MTHFR activity. It is estimated that 50% of the population may have the heterozygous C/T genetic variant, whereas 25% may have the homozygous T/T variant; these individuals may have a 50% to 60% reduction in their MTHFR activity (Botto & Yang, 2000). This genetic variant is thought to be up to 20% greater in individuals of Italian, Hispanic, or Asian descent than in those of African descent (Botto & Yang, 2000). Similarly, in a 2013 study by Trimmer, the A1298C allele was associated with elevated levels of homocysteine in the blood, thereby increasing the risks for cardiovascular disease, depression, bipolar disorder, attention-deficit/hyperactivity disorder, schizophrenia, dementia, Alzheimer's disease, fetal neural tube defects, male infertility, migraine headaches, and autism spectrum disorders (Botto & Yang, 2000; Pu, Shen, & Wu, 2013). The estimated incidence of inheriting the “C” allele, which represents the risk for reduced MTHFR activity, is >50% in those of European ancestry, approximately 28% in those of African heritage, and approximately 40% in those of Asian ancestry (Genomind, 2016). With the high incidence of genetic variants, which have been identified as contributing to the risk of multiple psychiatric disorders, it may behoove practitioners to test for these genetic variants to guide treatment decisions when working with patients presenting with psychiatric symptoms and major depressive disorder, in particular.
Choosing the Right B Vitamins to Treat Psychiatric Symptoms
Prior to initiating therapy for suspected folate deficiency, it is recommended that the following blood chemistry tests be obtained: homocysteine levels, unmetabolized folic acid level, complete blood count, serum folate, and red blood cell (RBC) folate levels. These tests are needed to assess for macrocytic anemia and short- and long-term folate status (DiLuglio, 2015). In addition, the genetic variant MTHFR C677T promotes a significant decrease in RBC folate and vitamin B12 levels, which are associated with elevated serum homocysteine levels (Ni et al., 2016), whereas the polymorphism A1298C promotes an increase in serum folate levels associated with lower levels of serum homocysteine (Li, Dai, Zheng, Liu, & Huang, 2015).
Aside from increasing the promotion of dietary intake of folate-containing food sources, individuals struggling with psychiatric symptoms such as depression, psychosis, fatigue, and irritability may benefit from supplementation with the medical food, L-methylfolate. Synthesis of serotonin, norepinephrine, and dopamine is regulated by L-methylfolate, the most psychoactive form of vitamin B9 (folate) (Stahl, 2008). L-methylfolate crosses the blood–brain barrier and is seven times more bioavailable than synthetic folic acid (Williams, Boers, Blom, Aengevaeren, & Vergheugt, 2004).
Patients' symptoms do not exist in isolation and they do not always have one specific identifiable etiology; the same can be said for nutrients, which also do not work in isolation. Vitamins B6, B12, and B9 are all cofactors in the metabolism of homocysteine (DiLuglio, 2015) and are necessary supplements to reduce inflammation caused by elevated homocysteine levels. For those with the MTHFR C677T genetic polymorphism, higher doses of vitamin B2 (riboflavin)—400 mg daily—can also help reduce total plasma homocysteine (Jacques et al., 2002). However, without the ability to fully metabolize folic acid, supplementation with folic acid (vitamin B9) may prove detrimental for those individuals with the C677T genetic polymorphism due to the increased unmetabolized folate circulating in the blood (DiLuglio, 2015). Caution is also recommended when treating patients diagnosed with bipolar disorder, as supplementation with L-methylfolate may induce mania or mixed episodes (Joe [MSC Nutrition] Dietician, 2016).
Although vitamins and supplements are often thought of as “natural” therapies without the side effects of conventional medications, they can have adverse effects and drug–drug interactions. In terms of L-methylfolate, caution is advised when co-administering iron, iron salts, and calcium supplements as well as L-dopa and anticoagulant, anticonvulsant, and tetracycline-related medications. In addition, some nonsteroidal anti-inflammatory drugs may decrease the effectiveness of L-methylfolate (Drugs.com, 2017). No common side effects have been reported with L-methylfolate, although allergic reactions and hypersensitivity have been reported when it was taken as a single agent (Drugs.com, 2017). When taken as an adjunct to other antidepressant agents, the most common side effects included: somnolence, insomnia, dizziness, nausea, fatigue, constipation, and sexual dysfunction (Ginsburg, Oubre, & Daoud, 2011). These adverse effects were no greater than when the antidepressant agent was taken alone (Farrah, 2009).
Many manufacturers of nutritional supplements offer products touted to be “equivalent” to methylfolate and L-methylfolate; however, L-methylfolate is considered a medical food and is only available by prescription. The U.S. Food and Drug Administration (2012) defines a medical food as a specially formulated food product that must be used under medical supervision; all components of the medical food must have generally recognized as safe status. A medical food is intended to provide specific dietary management of a disease or condition for which distinct nutritional requirements have been established by medical evaluation.
L-methylfolate 15 mg daily is the recommended treatment for individuals with the MTHFR genetic variant and as an adjunctive therapy to those who have not fully responded to selective serotonin reuptake inhibitor anti-depressant therapy (Papakostas et al., 2012). Although L-methylfolate is not yet indicated as a stand-alone treatment for depression or other psychiatric disorders, it may be helpful as a complementary and integrative therapy to other psychotropic medications or vitamins and supplements. The Table offers suggestions on what type of patients might benefit from L-methylfolate supplementation.
Individuals Who May Benefit from L-Methylfolate
When considering patients' overall treatments, providers must be aware of the potential role that vitamins, supplements, and medical foods, such as L-methylfolate, play in treating psychiatric symptoms across the lifespan.
- Botto, L.D. & Yang, Q. (2000). 5, 10 methylene-tetrahydrofolate reductase gene variants and congenital anomalies: A HuGE review. American Journal of Epidemiology, 151, 862–877. doi:10.1093/oxfordjournals.aje.a010290 [CrossRef]
- Crider, K.S., Yang, T.P., Berry, R.J. & Bailey, L.B. (2012). Folate and DNA methylation: A review of molecular mechanisms and the evidence of folate's role. Advances in Nutrition, 3, 21–38. doi:10.3945/an.111.000992 [CrossRef]
- DiLuglio, B.E. (2015). What is MTHFR? Retrieved from https://previmedica.com/understanding-mthfr-genetic-mutation/#more-15
- Douaund, G., Refsum, H., de Jager, C.A., Jacoby, R., Nichols, R.E., Smith, S.M. & Smith, A.D. (2013). Preventing Alzheimer's disease-related gray matter atrophy by B-vitamin treatment. Proceedings of the National Academy of Sciences, 110, 9523–9528. doi:10.1073/pnas.1301816110 [CrossRef]
- Drugs.com. (2017). L-methylfolate. Retrieved from https://www.drugs.com/cdi/l-methylfolate.html
- Duprey, R.P. (2016). MTHFR gene polymorphism positive treatment-resistant depression: Prevalence and treatment recommendations. Neuropsychiatry, 6, 43–46. doi:10.4172/Neuropsychiatry.1000117 [CrossRef]
- Farrah, A. (2009). The role of L-methylfolate in depressive disorders. CNS Spectrums, 14 (Suppl. 2), 2–7. doi:10.1017/S1092852900003473 [CrossRef]
- Firth, J., Stubbs, B., Sarris, J., Rosenbaum, S., Teasdale, S., Berk, M. & Yung, A.R. (2017). The effects of vitamin and mineral supplementation on symptoms of schizophrenia: A systematic review and meta-analysis. Psychological Medicine. Advance online publication. doi:10.1017/S0033291717000022 [CrossRef]
- Genomind. (2016). Allele frequencies. Retrieved from https://portal.genomind.com/Assets/Spotlights/Genecept%20Assay%20Genotype%20Table_Allele%20Frequency%20Distribution%20sell%20sheet.pdf
- Ginsberg, L.D., Oubre, A.Y. & Daoud, Y.A. (2011). L-methylfolate plus SSRI or SNRI from treatment initiation compared to SSRI or SNRI monotherapy in a major depressive episode. Innovations in Clinical Neuroscience, 8, 19–28.
- Jacques, P.F., Kalmbach, R., Bagley, P.J., Russo, G.T., Rogers, G., Wilson, P.W. & Selhub, J. (2002). The relationship between riboflavin and plasma total homocysteine in the Framingham Offspring Cohort is influenced by folate status and the C677T transition in the methylenetetrahydrofolate reductase gene. Journal of Nutrition, 132, 283–288.
- Joe (MSC Nutrition), Dietician. (2016). L-methylfolate (5-MTHF): Your must-read beginner's guide. Retrieved from https://www.dietvsdisease.org/?s=l+methylfolate
- Li, W.-X., Dia, S.-X., Zheng, J.-J., Liu, J.Q. & Huang, J.F. (2015). Homocysteine metabolism gene polymorphisms (MTHFR C677T, MTHFR A1298C, MTR A2756G and MTRR A66G) jointly elevate the risk of folate deficiency. Nutrients, 7, 6670–6687. doi:10.3390/nu7085303 [CrossRef]
- McAlpine, D. (1929). A review of the nervous and mental aspects of pernicious anemia. Lancet, 2, 643–647. doi:10.1016/S0140-6736(01)04242-8 [CrossRef]
- Mental Health America. (2016).Complementary and alternative medicine for mental health. Retrieved from http://www.mentalhealthamerica.net/sites/default/files/MHA_CAM.pdf
- Natural Standard. (2017). Folic acid; Patient monograph. Retrieved from http://www.mayoclinic.org/drugs-supplements/folate/background/hrb-20059475
- Ni, J., Zhang, L., Zhou, T., Xu, W.J., Xue, J.L., Cao, N. & Wang, X. (2016). Association between the MTHFR C677Y polymorphism, blood folate and vitamin B12 deficiency and elevated serum total homocysteine in healthy individuals in Yunnan Province, China. Journal of the Chinese Medical Association, 80, 147–153. doi:10.1016/j.jcma.2016.07.005 [CrossRef]
- Papakostas, G.I., Shelton, R.C., Zajecka, J.M., Etemad, B., Rickels, K., Clain, A. & Fava, M. (2012). L-methylfolate as adjunctive therapy for SSRI-resistant major depression: Results of two randomized, double blind, parallel-sequential trials. American Journal of Psychiatry, 169, 1267–1274. doi:10.1176/appi.ajp.2012.11071114 [CrossRef]
- Pu, D., Shen, Y. & Wu, J. (2013). Association between MTHFR gene polymorphisms and the risk of autism spectrum disorders: A meta-analysis. Autism Research, 6, 384–392. doi:10.1002/aur.1300 [CrossRef]
- Stahl, S.M. (2008). L-Methylfolate: A vitamin for your monoamines. Journal of Clinical Psychiatry, 69, 1352–1353. doi:10.4088/JCP.v69n0901 [CrossRef]
- Trimmer, E.E. (2013). Methylenetetrahydrofolate reductase: Biochemical characterization and medical significance. Current Pharmaceutical Design, 19, 2574–2593. doi:10.2174/1381612811319140008 [CrossRef]
- U.S. Food and Drug Administration. (2012). Section 5(b) of the Orphan Drug Amendments (21 USC 360ee (b)(3)). In 2012 FDA rare disease patient advocacy day: Regulation of medical foods. Retrieved from https://www.fda.gov/downloads/forindustry/developingproductsforrarediseasesconditions/oopdnewsarchive/ucm292733.pdf
- Williams, F.F., Boers, G.H., Blom, H.J., Aengevaeren, W.R. & Vergheugt, F.W. (2004). Pharmacokinetic study on the utilisation of 5-methyltetrahydrofolate and folic acid in patients with coronary artery disease. British Journal of Pharmacology, 141, 825–830. doi:10.1038/sj.bjp.0705446 [CrossRef]
Individuals Who May Benefit from L-Methylfolate
| Documented sub-therapeutic folate levels|
| Poor response to antidepressant therapies|
| Various medical conditions and psychiatric disorders, including:|
| Eating disorders|
| Alcohol use disorders|
| Depressive and bipolar disorders|
| Gastrointestinal disorders|
| Coronary artery disease|
| Acute myocardial infarction|
| Elevated homocysteine levels|
| Low levels of MTHFR|
|Individuals taking medications, such as:|
| Mood-stabilizing anticonvulsant agents|
| Chemotherapy agents|
| Antidepressant agents|
| “Statins” used to lower cholesterol|
| Oral contraceptives|
| Warfarin and other blood thinning agents|
|Individuals of Hispanic or Mediterranean descent|
|Individuals with a preference for a “natural” product|