High levels of homocysteine are associated with cerebrovascular disease, monoamine neurotransmitters, and depression of mood. A plausible hypothesis for these associations is that high homocysteine levels cause cerebral vascular disease and neurotransmitter deficiency, which cause depression of mood.
The homocysteine depression hypothesis, if true, would mandate inclusions of imaging studies for cerebrovascular disease and measures of homocysteine, folate, and B12 and B6 vitamins in the clinical evaluation of older depressed patients. Longitudinal studies and clinical trials should be designed to challenge the hypothesis.
Introduction
If depression of mood is in some cases a symptom of disease, knowledge of etiology would lead to prevention and knowledge of pathogenesis would lead to a cure. Although there probably are multiple genetic and environmental causes of depression, we review the evidence here to support one hypothesis or model of depression as a disease. The hypothesis is that genetic and environmental factors elevate homocysteine levels, which cause vascular disease of the brain, and/or transmitter alterations, which cause depression.
Background
We provide background information, recently reviewed by Coppen and Bolander-Gouaille (1), and then review studies supporting the hypothesis. Homocysteine is a sulfurated amino acid derived from ingested methionine found in cheeses, eggs, fish, meat, and poultry. It is directly toxic to neurons and blood vessels and can induce DNA strand breakage, oxidative stress, and apoptosis (2, 3). The methionine-homocysteine metabolic pathway intermediaries are S-adenosylmethionine and S-adenosylhomocysteine. The pathway produces methyl groups required for the synthesis of catecholamines and DNA. This is accomplished by remethylating homocysteine—using B12 and folate as cofactors—back to methionine. Homocysteine is cleared by transulfuration to cysteine and glutathione, an important antioxidant. Transulfuration requires vitamins B6 and B12.
The components of the homocysteine-methionine cycle, as well as cysteine and glutathione and the enzymes of the pathway, are affected by genetic variation, diet, kidney and gastrointestinal diseases, and prescribed and over-the-counter drugs. Since homocysteine is a sensitive indicator of B vitamin deficiency, an elevated homocysteine level is a marker for a pathogenic process as well as a cause of pathology.
Marshal Folstein, M.D., Timothy Liu, M.D., Inga Peter, Ph.D., Jennifer Buel, B.S., Lisa Arsenault, B.S., Tammy Scott, Ph.D. and Wendy W. Qiu, M.D., Ph.D.
