A study of 521 subjects over the age of 65 who were not depressed at the beginning, found that low levels of folate and vitamin B12 and high levels of homocysteine were associated with a higher risk of developing depression during a follow-up period of two to three years. There are various ways in which elevated homocysteine may be linked to the underlying biological causes of psychiatric disorders. Homocysteine has been shown to interact with NMDA receptors, cause oxidative stress, induce apoptosis, lead to mitochondrial dysfunction, and cause vascular damage. Elevated levels of homocysteine may also contribute to cognitive impairment, which is often observed in patients with affective disorders and schizophrenia. Supplementation with B vitamins and folic acid has been demonstrated to be effective in reducing homocysteine levels. The addition of L-methylfolate, in doses ranging from 7.5 to 15 mg per day, to antidepressant therapy at the beginning of treatment was found to be more effective than antidepressant therapy alone in alleviating depressive symptoms. Moreover, clinical depression evaluation scores indicated major symptom improvement within 60 days of adding L-methylfolate to antidepressant therapy, and it was better tolerated than SSRI/SNRI monotherapy.