Researchers believe that depression, particularly in the elderly, may be related to elevated homocysteine levels. A deficiency in B vitamins may be the cause.
While elevated homocysteine levels are linked to heart disease and stroke, it may also contribute to depression, particularly in older people.
Negative effects of homocysteine
Homocysteine is a harmful amino acid that naturally occurs in all humans. It is involved in cellular metabolism and the manufacture of proteins.
Homocysteine irritates the lining of the blood vessels causing them to become scarred, hardened, and narrowed. This inflammation makes the heart work harder which can lead to heart disease. High levels of homocysteine also cause increased blood clotting. Blood clots decrease or block the flow of blood through blood vessels, resulting in strokes and heart attacks.
Homocysteine levels naturally vary according to age, gender, diet, hereditary factors, and general health. Approximately 5-10% of the population have levels that are too high.
In the 2000s, studies suggested that high levels of homocysteine were associated with poorer mental functioning, which lead to ongoing investigations into the role of homocysteine in Alzheimer’s disease. Additional studies suggested that high levels of homocysteine can lead to osteoporosis and an increased risk of broken bones in the elderly.
Depression and homocysteine
Our bodies naturally use vitamin B12 and folic acid to convert homocysteine into a compound called SAMe – a source of methyl-groups. Without sufficient B-vitamins, blood homocysteine levels rise. Elevated homocysteine levels are linked to an increased risk of cardiovascular, neurological and psychiatric diseases, including stroke and dementia.
Researchers believe that high homocysteine levels contribute to cerebral vascular disease and neurotransmitter deficiency, both which can lead to depression. A study conducted in 2005 found that total homocysteine levels were higher in elderly patients with late-onset major depression (Chen CS et al 2005).
Cause of elevated homocysteine
Plasma homocysteine levels are strongly influenced by diet, genetic factors, a deficiency in folic acid, B6 and B12 vitamins, aging and smoking. Large amounts of coffee can elevate homocysteine as well as some medications.
High homocysteine levels in the blood (hyperhomocysteinemia) has been suggested as being a risk factor for cardiovascular disease, blood clotting abnormalities, atherosclerosis, myocardial infarction (heart attack), and ischemic stroke. Taking vitamin B12 supplements in combination with other B vitamins (mainly folic acid) has been shown to be effective for lowering homocysteine levels. It is not clear whether lowering homocysteine levels results in reduced cardiovascular morbidity and mortality. More evidence is needed to fully explain the association of total homocysteine levels with vascular risk and the potential use of vitamin supplementation.
People using the following drugs should discuss increasing their intake of folic acid, vitamin B6, and vitamin B12 with their doctor:
- Lipid-lowering drugs such as fenofibrate (Tricor) and bezafibrate (Bezalip);
- Metformin (Glucophage), a drug to modify insulin resistance;
- Anti-epileptic drugs such as phenobarbital, phenytoin (Dilantin), primidone (Mysoline) and carbamazepine (Tegretol);
- Levadopa (Sinemet) for treatment of Parkinson’s disease;
- Methotrexate (Rheumatrex, Trexall) for treatment of cancer, psoriasis, rheumatoid arthritis, and systemic lupus erythematosus;
- Androgen treatment; and
- Nitrous oxide (“laughing gas”), a mild anesthetic.
Sam-e and other supplements may lower homocysteine
Many nutrients and supplements influence the body’s use of the brain’s neurotransmitters. Similar to prescription drugs used to treat depression, these natural therapies increase the production of neurotransmitters or reduce their rate of breakdown. Unlike prescription drugs, however, natural therapies can also minimize the effects of oxidative stress and inflammation that contributes to depression.
According to an article by Life Extension on natural treatments for depression, the following supplements may decrease homocysteine levels and improve or eliminate depressive symptoms:
- Folic acid
- Vitamin B12 (cobalamin) (sublingual (under the tongue), transdermal (skin) or injection form only)
- Vitamin B6 (pyridoxine)
- Trimethylglycine and zinc
- SAMe (“Does SAMe increase or decrease homocysteine?”)
- Creatine & choline-producing nutrients (inhibits the release of homocysteine)
While high plasma homocysteine levels increase the risk of heart disease and stroke, it can also lead to depression, particularly in elderly patients who are often deficient in folic acid and vitamins B6 and B12. People struggling with depression that has not responded to other therapies may want to have their homocysteine levels tested and begin supplementing with B vitamins.
Chen CS, Tsai JC et al, “Homocysteine levels, MTHFR C677T genotype, and MRI Hyperintensities in late-onset major depressive disorder,” American Journal of Geriatric Psychiatry, 2005 Oct;13(10):869–75.
Folstein M, Liu T, Peter I, Buell J, Arsenault L, Scott T, Qiu WW, “The homocysteine hypothesis of depression,” The American Journal of Psychiatry, June 2007.
“Depression,” Life Extension online, Accessed November 18th, 2009, http://www.lef.org/protocols/emotional_health/depression_01.htm.
Parkavi Chellappa; Radhakrishnan Ramaraj, “Depression, Homocysteine Concentration, and Cardiovascular Events,” Journal of American Medical Association. 2009;301(15):1541-b-1542.
Henning Tiemeier, H. Ruud van Tuijl, Albert Hofman, John Meijer, Amanda J. Kiliaan, and Monique M.B. Breteler, “Vitamin B12, Folate, and Homocysteine in Depression: The Rotterdam Study,” American Journal of Psychiatry, Dec 2002; 159: 2099 – 2101.
Simon Gilbody Tracy Lightfoot Trevor Sheldon J, “Is low folate a risk factor for depression? A meta-analysis and exploration of heterogeneity,” Epidemiology Community Health2007;61:631-637
“Cardiovascular disease/hyperhomocysteinemia.” Mayoclinic.com. Updated October 1. 2011. Accessed January 9th, 2012.
McCully, Kilmer S. The Homocysteine Revolution. 2nd ed. New York: McGraw Hill 1999.American Heart Association. 7272 Greenville Ave., Dallas, TX 75231. (800)242-8721.
Homocysteine.net, May 10, 2004. [cited March 23, 2005]. http://www.homocysteine.net.
“Serum Folate, Vitamin B12, and homocysteine in Major Depressive Disorder, Part 2: Predictors of Relapse During the Continuation Phase of Pharmacotherapy,” Journal of Clinical Psychiatry 65, No. 8 (August 2004).