An Overlooked Cause of Depression
By Timothy Rice
While great strides have been made in diagnosing and treating depression, millions of Americans still suffer with this difficult-to-treat disease. It is estimated that 15.7 million American adults experienced depression in the past year.1
Antidepressant use is on the rise with one in 10 Americans using them.2,3 Unfortunately, antidepressants only work as little as 50% of the time and come with an array of side effects.4,5
One reason that so many people continue to bear this burden is that most physicians are unaware of the well-documented link between homocysteine and depression.
A simple blood test that measures homocysteine levels, along with a metabolically active form of folate, better known as 5-MTHF, may offer hope to millions of depression sufferers.
Homocysteine and Depression
Homocysteine is an amino acid that, when elevated, can damage the inner linings of the body’s vessels leading to a range of cardiovascular conditions including stroke. There is also a correlation between high homocysteine levels and depression.6,7
Researchers studied this association in a group of 924 middle-aged men. They found that individuals in the upper tertile for homocysteine levels had more than a two-fold increased risk for being depressed compared to those in the lowest tertile.7
Another study found that people with the highest levels of homocysteine (>12 µmol/L) have significantly lower amounts of SAMe, a nutrient required for the synthesis of mood-enhancing neurotransmitters.8 Not surprisingly, they also had lower levels of mood-enhancing neurotransmitters.
The researchers also found that nearly a third of the depressed participants from the study had red blood cell folate levels below normal, and half of these participants had homocysteine levels higher than levels of the two control groups.8
The connection between low folate levels and imbalances in neurotransmitters shouldn’t be surprising since folate is required for the production of neurotransmitters in the brain.
Improvement with 5-MTHF
Once the connection between high homocysteine levels and the occurrence of depressive symptoms was discovered, researchers began to investigate whether the active form of folate, 5-MTHF, could have a beneficial impact on major depression.9,10
The results of these studies open a new door for the treatment of depression. What the scientists discovered was that taking 5-MTHF in addition to antidepressant drugs dramatically improved response rates and did so in a significantly shorter amount of time.
In one study, only 7% of subjects taking an antidepressant drug experienced major improvement on a standard depression score. That number jumped to 19% in those patients taking 5-MTHF in addition to an antidepressant drug.
The results were even more impressive in those with the most severe depression. Improvements of 40% were experienced while taking 5-MTHF in addition to their antidepressant drug, versus just 16% of those only taking the drug by itself.10
In addition to improving symptom severity, 5-MTHF brought about these improvements significantly faster than antidepressant drugs alone. Specifically, the 5-MTHF group saw improvements in just 177 days, compared to 231 days in the control group. For those with the most severe depression, the results were even more dramatic. The median time to improvement took only 85 days, compared to 150 days in the control group. A key finding was that nearly twice as many people in the antidepressant-only group stopped therapy due to adverse events (34%) versus the 5-MTHF group (17.9%), providing evidence of the nutrient’s superior safety profile.10
These results are very encouraging, especially considering the fact that major depression is notoriously difficult to treat, with only about 30% of patients treated with a single antidepressant achieving resolution of their symptoms, a figure that rises to just 50% to 55% when a second drug is added.11,12
This correlation makes supplementing with the metabolically active form of folate, 5-MTHF, a good idea for anyone suffering from depression.
Cognitive Decline, Alzheimer’s Disease, and Aging
Depression by itself is bad enough. But now, scientists are finding that depression can lead to Alzheimer’s disease and cognitive decline.13,14
Research has confirmed the link between elevated homocysteine, cognitive decline, and Alzheimer’s disease.15-17
A study published in the New England Journal of Medicine following elderly participants with dementia found that more than 75% of participants were eventually diagnosed with Alzheimer’s disease over an eight-year follow-up period.18 The researchers reviewed participants’ homocysteine levels and found that for those with homocysteine levels greater than 14 µmol/L, the risk of Alzheimer’s nearly doubled. They concluded that increased plasma levels of homocysteine are a strong, independent risk factor for the development of dementia and Alzheimer’s disease.
Homocysteine alone is not the sole cause of age- related cognitive decline or memory impairment related to Alzheimer’s disease, but there is a significant amount of evidence pointing to its role as a contributing factor.
Get Tested and Safely Lower Homocysteine
Those striving for longevity and seeking to safeguard their health can readily and safely prevent and modulate elevated homocysteine levels. Certain factors such as a diet poor in folate or other important B vitamins may be partially to blame. Sometimes other more complex issues need to be addressed as well to optimally maintain homocysteine levels. It is also important to avoid leading a sedentary lifestyle and consuming excessive amounts of foods rich in the amino acid methionine, such as red meats and dairy products. Decreasing or eliminating consumption of alcohol and smoking is also important.
Homocysteine levels should be part of a yearly battery of blood tests to ensure a healthy, long life. Life Extension® advises that the optimal range for homocysteine levels is <7-8 µmol/L, a much more aggressive cut-off than the currently accepted <15 µmol/L.
Individuals with elevated homocysteine levels should begin supplementation with 5-MTHF and retest levels after 3 months.
The buildup of homocysteine poses a major threat to one’s health, raising the risk for cardiovascular and neurodegenerative diseases. New findings are confirming the connection between levels of homocysteine and psychiatric conditions like depression.
Those interested in guarding themselves from the devastating consequences of elevated homocysteine levels should begin proper supplementation with the bioactive form of folate, 5-MTHF, a convenient and low-cost nutrient that can provide the body with the best ammunition for controlling homocysteine. Daily doses of 1,000 mcg to 5,000 mcg (1-5 mg) of bioactive folate are typically used in research studies to achieve clinically beneficial reductions in plasma homocysteine concentrations.
For optimal homocysteine reduction, adequate amounts of other B-vitamins such as B2, B6, and B12 are also required. These powerful and inexpensive nutritional strategies are readily available to help individuals prevent the wide array of chronic disorders and complications that can be traced to excessive levels of homocysteine.
If you have any questions on the scientific content of this article, please call a Life Extension® Wellness Specialist at 1-866-864-3027.
- Available at: http://www.nimh.nih.gov/health/statistics/prevalence/major-depression-among-adults.shtml. Accessed November 23, 2015.
- Available at: http://well.blogs.nytimes.com/2013/08/12/a-glut-of-antidepressants/?_r=1. Accessed November 11, 2015.
- Lindsley CW. The top prescription drugs of 2011 in the United States: antipsychotics and antidepressants once again lead CNS therapeutics. ACS Chem Neurosci. 2012;3(8):630-1.
- Berney P. Dose-response relationship of recent antidepressants in the short-term treatment of depression. Dialogues in Clinical Neuroscience. 2005;7(3):249-62.
- Available at: http://www.webmd.com/depression/features/coping-with-side-effects-of-depression-treatment. Accessed May 5, 2016.
- Folstein M, Liu T, Peter I, et al. The homocysteine hypothesis of depression. Am J Psychiatry. 2007;164(6):861-7.
- Tolmunen T, Hintikka J, Voutilainen S, et al. Association between depressive symptoms and serum concentrations of homocysteine in men: a population study. Am J Clin Nutr. 2004;80(6):1574-8.
- Bottiglieri T, Laundy M, Crellin R, et al. Homocysteine, folate, methylation, and monoamine metabolism in depression. J Neurol Neurosurg Psychiatry. 2000;69(2):228-32.
- Papakostas GI, Cassiello CF, Iovieno N. Folates and S-adenosylmethionine for major depressive disorder. Can J Psychiatry. 2012;57(7):406-13.
- Ginsberg LD, Oubre AY, Daoud YA. 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.
- Farah A. The role of L-methylfolate in depressive disorders. CNS Spectr. 2009;14(1 Suppl 2):2-7.
- Wade RL, Kindermann SL, Hou Q, et al. Comparative assessment of adherence measures and resource use in SSRI/SNRI-treated patients with depression using second-generation antipsychotics or L-methylfolate as adjunctive therapy. J Manag Care Pharm. 2014;20(1):76-85.
- Diniz BS, Butters MA, Albert SM, et al. Late-life depression and risk of vascular dementia and Alzheimer’s disease: systematic review and meta-analysis of community-based cohort studies. Psychiatry. 2013;202(5):329-35.
- Butters MA, Young JB, Lopez O, et al. Pathways linking late-life depression to persistent cognitive impairment and dementia.Dialogues Clin Neurosci. 2008;10(3):345-57.
- 5-methyltetrahydrofolate. Monograph. Altern Med Rev. 2006;11(4):330-7.
- Weir DG, Scott JM. Brain function in the elderly: role of vitamin B12 and folate. Br Med Bull. 1999;55(3):669-82.
- Bottiglieri T, Parnetti L, Arning E, et al. Plasma total homocysteine levels and the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene: a study in an Italian population with dementia. Mech Ageing Dev. 2001;122(16):2013-23.
- Seshadri S, Beiser A, Selhub J, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. N Engl J Med. 2002;346(7):476-83.
- Venn BJ, Green TJ, Moser R, et al. Comparison of the effect of low-dose supplementation with L-5-methyltetrahydrofolate or folic acid on plasma homocysteine: a randomized placebo-controlled study. Am J Clin Nutr. 2003;77(3):658-62.
- Willems FF, Boers GH, Blom HJ, et al. Pharmacokinetic study on the utilisation of 5-methyltetrahydrofolate and folic acid in patients with coronary artery disease. Br J Pharmacol. 2004;141(5):825-30.
- Prinz-Langenohl R, Bramswig S, Tobolski O, et al. [6S]-5-methyltetrahydrofolate increases plasma folate more effectively than folic acid in women with the homozygous or wild-type 677C-->T polymorphism of methylenetetrahydrofolate reductase. Br J Pharmacol. 2009;158(8):2014-21.
- Huang J, Zhang L, He M, et al. Comprehensive evaluation of postpartum depression and correlations between postpartum depression and serum levels of homocysteine in Chinese women. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2015;40(3):311-6.
- Knudson-Martin C, Silverstein R. Suffering in silence: a qualitative meta-data-analysis of postpartum depression. J Marital Fam Ther. 2009;35(2):145-58.
- Aishwarya S, Rajendiren S, Kattimani S, et al. Homocysteine and serotonin: association with postpartum depression. Asian J Psychiatr. 2013;6(6):473-7.
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- Horikawa C, Otsuka R, Kato Y, et al. Cross-sectional association between serum concentrations of n-3 long-chain PUFA and depressive symptoms: results in Japanese community dwellers. Br J Nutr. 2016;115(4):672-80.
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