By: Jacqueline Meaney, PharmD [PGY-1 Resident at Gainesville VAMC in Florida]
Major depressive disorder (MDD) is a psychiatric disorder that is characterized by feelings of worthlessness, helplessness, and an inability to experience pleasure in activities that were enjoyable in the past.1 Major depressive disorder is one of the most prevalent mental disorders among adults in the United States, with a lifetime prevalence of 16.2%. Of the people affected by major depressive disorder, 38% experience severe depression, and 12.9% experience very severe depression.1-3 MDD has a significant impact on all aspects of a patient’s life, including sleeping habits, eating habits, personal relationships, ability to concentrate, and general well-being.4 In addition, MDD has been associated with increased morbidity and has been shown to complicate recovery from myocardial infarctions and other serious illnesses. MDD has a high rate of recurrence and can lead to suicide if left untreated.5,6
Current treatment guidelines for MDD recommend starting with antidepressants as monotherapy, typically with a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI), depending on patient parameters.7-9 However, studies have shown that some patients require supplementation with l-methylfolate in order to benefit from either SSRIs or SNRIs.10,11 In addition, other studies have shown that patients treated with l-methylfolate in addition to an SSRI or SNRI had a more significant reduction in measures of depression than did patients receiving monotherapy with an SSRI or SNRI.5,11
L-methylfolate (levomefolic acid) is the active form of folic acid (vitamin B9). Folic acid is converted to l-methylfolate by the enzyme methylenetetrahydrofolate reductase (MTHFR), which is encoded by the MTHFR gene. Polymorphisms in the MTHFR gene lead to a reduced ability to convert dietary folic acid to l-methylfolate, which is needed by the body in order to regulate homocysteine levels.12 Specifically, l-methylfolate allows for the conversion of homocysteine to methionine. Elevated concentrations of homocysteine in the blood is known as hyperhomocysteinemia, and has been associated with increased risk for depression.13 People with MTHFR polymorphisms may not be able to benefit from regular folic acid supplementation and may require supplementation with l-methylfolate due to their inability to convert sufficient amounts folic acid to l-methylfolate in the body.14 Folate status has been associated with the efficacy of selective serotonin reuptake inhibitors (SSRIs) in treating major depressive disorder, and studies have shown that patients often require supplementation with l-methylfolate in order to see any benefit from SSRIs10 and SNRIs.5
At gene position 677, the presence of a cytosine leads to the transcription and production of an alanine, resulting in the normal form of MTHFR. The presence of the 677T allele leads to the substitution of alanine for valine, which results in a thermolabile form of MTHFR that has reduced levels of activity.15, 16 People with the 677CC genotype have the normal genotype, and people with the 677TT genotype are homozygous for the thermolabile mutant form of MTHFR. People with the 677TT genotype tend to have mild MTHFR deficiency, which predisposes them to hyperhomocysteinemia due to a lack of l-methylfolate to be used to convert homocysteine to methionine.17 Multiple studies have linked the 677TT genotype to high levels of homocysteine in the blood. High levels of homocysteine may increase the risk of depression if it is left untreated.14, 15, 18-21
The prevalence of the 677TT genotype is estimated at 10% of Caucasians and Asians. These people have 70% lower activity of MTHFR, resulting in reduced amounts of folic acid being converted to l-methylfolate.12 For this reason, individuals with the 677TT genotype are more likely to be affected by low folate intake.17 It is estimated that 40% of the population has the 677CT heterozygous genotype for MTHFR, and may also have a reduced ability to convert folic acid to its active form. Therefore, people with the 677TT and 677CT genotypes may benefit from supplementation with l-methylfolate (marketed as levomefolate calcium under the brand name Deplin®), because they may not be able to fully benefit from supplementation of folic acid.18
A second MTHFR polymorphism can be found at position 1298 on the MTHFR gene, where the presence of an adenine results in the normal allele, and the presence of a cytosine results in the mutant allele. People with the 1298AA genotype have the normal genotype and people with 1298CC are homozygous for the mutant allele. MTHFR enzymes encoded by 1298A have been shown to have the same functionality as the MTHFR enzymes encoded by 1298C. However, it is suggested that the presence of the 1298CC genotype can magnify the effects of the 677CT (heterozygous) genotype.15, 18, 22-24
Overall, multiple studies have shown that MTHFR genotype abnormalities can be associated with MDD prognosis. This information could be used to help clinicians identify patients at risk of a poor prognosis, who may require early interventions.15 In addition, multiple studies have proven that l-methylfolate may be effective for the adjunctive treatment of MDD when combined with an SSRI or SNRI. These studies report little to no adverse effects from l-methylfolate, with the greatest barrier to patient adherence being an inability to afford the medication.2, 3 It is important to be aware of the link between genetics and depression, because some cases of depression may be caused by a treatable deficiency.
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- Ginsberg LD, et al. L-methylfolate Plus SSRI or SNRI from Treatment Initiation Compared to SSRI or SNRI Monotherapy in a Major Depressive Episode. Innov Clin Neurosci. 2011;8(1): 19-28.
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- Sun XY, Zhang ZJ, Shi YY, et al. Influence of methylenetetrahydrofolatereductase gene polymorphisms on antidepressant response. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2013; 30(1):26-30.
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- Delport D, Schoeman R, van der Merwe N, et al. Significance of dietary folate intake, homocysteine levels and MTHFR677 C&T genotyping in South African patients diagnosed with depression: test development for clinical application. Metab Brain Dis. 2014; Feb 18.
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- Alpert JE, Mischoulon D, Nierenberg AA, et al. Nutrition and depression: Focus on folate. Nutrition. 2003; 16(7–8):544–546.
- Bjelland I, Tell GS, Vollset SE, et al. Folate, vitamin B12, homocysteine, and the MTHFR 677CT polymorphism in anxiety and depression: The Hordaland Homocysteine Study. Arch Gen Psychiatry. 2003; 60(6):618–626.
- Papakostas GI, Cassiello CF, Iovieno N. Folates and s-adenosylmethionine for major depressive disorder. Can J Psychiatry. 2012; 57(7):406–413.
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[pubmed_related keyword1=”genetics” keyword2=”depression” keyword3=”disorder”]