Folate: A Secret Weapon Against Depression?

There is a growing body of research exploring potential biomarkers for depression. A biomarker, or “biological marker,” is some measurable indicator that all is not well in the body; for example, elevated body temperature is a biomarker for a possible infection. These indicators can be extremely helpful in diagnosis and treatment as they provide objective, more concrete evidence for disease than subjective evaluation might.

“A biomarker is ‘a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.’

— Biomarkers Definition Working Group

Unfortunately, exact specifics on how biological information can be used to improve diagnosis and treatment of depression remains elusive. The challenge lies largely in navigating the innumerable variables that accompany the disorder- more of which are being uncovered by research. Findings of a host of inflammatory, metabolic, and neurotrophic indicators crowd the landscape with data, yet it is too early to determine which indicators may be most useful. Today’s most comprehensive approaches focus on whether (and which) biomarkers can predict response to treatment.

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Folate and Depression

One promising frontier uses folate levels to predict a person’s risk for depression and the likelihood that they will have a positive response to antidepressant medications. Folate is the naturally occurring form of vitamin B9 found in foods such as asparagus, eggs, and leafy greens. Folic acid is the synthetic form of folate found in most supplements. Both folate and folic acid facilitate the formation of red blood cells, protein metabolism, and cell growth in the body. In addition to anemia and other physical complications, recent studies reveal that folate deficiency is a major risk for the development of depression.

Folate is implicated in depression in a couple of ways. First, it regulates the levels of tetrahydrobiopterin, or BH4, in the body. BH4 is an important cofactor in the formation of dopamine and serotonin, meaning that it must be present in order for them to be made. Disruptions in the levels of these two important neurotransmitters can lead to mood disorders including depression.

Folate deficiency → lower levels of BH4 → lower levels of serotonin & dopamine

Folate is also involved in the breakdown of homocysteine, a metabolic byproduct. Higher levels of homocysteine have been linked to many disorders including heart disease, Alzheimer's and depression. Folate therapy is thought to be particularly useful in treatment-resistant depression, providing a treatment option for individuals who do not approach remission after multiple antidepressant trials. It has been shown that lower levels of folate correlate with a poor response to antidepressants while higher levels improve response rates.

Evidence is growing to support folate as a viable adjunct to antidepressant medication, but further research is necessary to understand (1) the long term effects of elevated folate levels in the body, and (2) the innate antidepressant value of folate versus its complementary impact on the body’s regulation of mood, sleep, appetite, and overall functioning.

There is considerable research linking folate and depression. One 2013 PMC study followed participants over a two-year period and found a statistically significant improvement in depression symptoms among the 554 participants whose antidepressant regimen included L-Methylfolate. 90% of participants were completely compliant and took the supplement as directed everyday. 502 participants took the L-Methylfolate as adjuvant therapy alongside the following primary depression medications:

Impact of Depression on Quality of Life

Patient response to “How difficult have these problems made it for you to do your work, take care of things at home, or get along with other people?” Note that “… these problems …” refers to the symptoms assessed on the 9-item Patient Health Questionnaire, which immediately preceded this question on the surveys.

Impact of Depression on Quality of Life  Patient response to “How difficult have these problems made it for you to do your work, take care of things at home, or get along with other people?” Note that “… these problems …” refers to the symptoms assessed on the 9-item Patient Health Questionnaire, which immediately preceded this question on the surveys.  Source: (Shelton, 2013)

Impact of Depression on Quality of Life

Patient response to “How difficult have these problems made it for you to do your work, take care of things at home, or get along with other people?” Note that “… these problems …” refers to the symptoms assessed on the 9-item Patient Health Questionnaire, which immediately preceded this question on the surveys.

Source: (Shelton, 2013)

Source: Shelton RC, Sloan Manning J, Barrentine LW, Tipa EV. Assessing Effects of l-Methylfolate in Depression Management: Results of a Real-World Patient Experience Trial. Prim Care Companion CNS Disord. 2013;15(4):PCC.13m01520. doi:10.4088/PCC.13m01520

  • SSRI (citalopram, escitalopram, paroxetine, fluoxetine, sertraline); n= 234

  • SNRI (venlafaxine, desvenlafaxine, duloxetine); n= 168

  • Bupropion; n= 124 

  • Trazodone; n= 53

  • Other; n= 215

376 participants had a 50% reduction in depression scores. This study tracked patients overall quality of life score by asking how treatment affected their ability to function in their daily life. Authors report that this “real world” reporting of treatment benefits can be of value alongside clinically controlled trials in establishing recommendations and informing future research.

Final Recommendations

Most people can get all the folate they require through a balanced diet alone. Whole foods like spinach, broccoli, beets, and lentils are excellent sources. Folate deficiency is often linked to poor absorption (which could be related to a genetic mutation of the MTHFR gene), and in these cases, a supplement containing the active form of folate, L-Methylfolate (or 5-MTHF), can be used. Supplements with L-Methylfolate are preferable to those containing folic acid as an increased level of folic acid in the body may lead to other health problems.

If you are currently struggling with depression and unsure if you are getting enough folate, consider meeting with an integrative practitioner. Dr. Beata Lewis of Mind Body 7 specializes in nutrient and vitamin testing and can evaluate your folate levels to determine whether or not they may be contributing to your experience of depression.

Citrus fruits  like oranges, lemons, grapefruits, and limes are puckeringly good sources of folate.

Citrus fruits like oranges, lemons, grapefruits, and limes are puckeringly good sources of folate.