Depressed individuals with low serum folate and B12 levels and elevated serum homocysteine levels often fail to respond to conventional antidepressants. Elevated serum homocysteine is a marker for folate, B6, and B12 deficiencies and is a risk factor for Alzheimer disease and other neurodegenerative diseases. The Framingham community-based study confirmed that elevated plasma homocysteine levels (greater than 12 μmol/L) double the risk of developing Alzheimer disease and non–Alzheimer dementias. B-Family Vitamins.

Folate is required for the synthesis of SAMe from homocysteine. Folate deficiency results in increased serum homocysteine levels and increased risk of depressed mood. Folate in the form of l-methylfolinic acid does not require MTHF reductase to become activated, more readily crosses the blood–brain barrier, and is a more effective adjuvant than regular folate. Clinical improvement in depressed patients treated with an SSRI and l-methylfolate (0.5 to 1 mg) was 30 percent greater than that in matched patients treated with an SSRI only. A systematic review of controlled studies (with a total of 247 participants) concluded that folate augmentation (1 to 15 mg per day) enhanced the efficacy of conventional antidepressants. The findings of a small double-blind study (75 participants) suggested that folic acid at 200 to 400 μg per day might enhance the therapeutic benefits of lithium carbonate in acutely manic patients. Preliminary findings suggest that biomarkers associated with inflammation may be useful for identifying nonresponders to SSRIs’ major depressive disorder who are more likely to respond to adjunctive L-methylfolate. Widespread folate deficiency in patients with schizophrenia is probably caused by chronic malnutrition and effects of conventional antipsychotic medications on absorption. Abnormal low brain folate levels in patients with schizophrenia may also result from a heritable deficiency in the enzyme glutamate carboxypeptidase II (GCPII), which is required for folate absorption through the gut. Patients with schizophrenia who take daily folic acid in the form of methylfolate 15 mg together with a conventional antipsychotic may have fewer positive and negative psychotic symptoms and may respond more rapidly than patients taking antipsychotics alone.

Individuals with dementia frequently have normal red blood cell folate levels and fail to improve with supplementation. In a prospective study with 370 participants, deficiency of folate or B12 doubled the risk of developing Alzheimer disease. However, a systematic review of four studies did not find strong evidence supporting the use of folic acid with or without B12 as a treatment of dementia or other forms of severe cognitive impairment. In a double-blind, placebo-controlled study, after four weeks of treatment with 50 mg per day of methylfolate, depressed patients with dementia experienced significant improvements in both mood and memory. Folate supplementation can mask the macrocytic anemia caused by B12 deficiency; thus, patients should be checked for B12 deficiency before starting folate. However, folate supplementation in the form of L-methyl-folinic acid does not mask B12 deficiency and can be recommended without first checking B12 levels.

To find out more about uses of folate and other vitamins in mental health care check out my ebooks on complementary and alternative treatments. 


The Integrative Mental Health Solution, by James Lake MD

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