Interrelationship of Micronutrients and Mental Health Remains Unclear

January 26, 2009

Are serum concentrations of folate and vitamin B12 related to the onset of dementia? Can depression be prevented with folate, vitamin B12, and B6 supplementation? Two recent studies shed light on these questions.

Are serum concentrations of folate and vitamin B12 related to the onset of dementia? Can depression be prevented with folate, vitamin B12, and B6 supplementation? Two recent studies shed light on these questions.

Kim and colleagues1 prospectively assessed changes in folate, B12, and homocysteine serum concentrations in patients without dementia from baseline to the emergence of incident dementia in a 2.4-year study. Pyridoxine (vitamin B6), an important co-factor in the metabolism of homocysteine along with folate and B12, was not examined in this study.

Folate, B12, and homocysteine are necessary for production of mono­amine neurotransmitters as well as phospholipids and nucleotides. Low folate levels are associated with elevated total plasma homocysteine, which has been linked to neurotoxic effects. Kim and associates posited that deficiencies in folate and B12 and/or hyperhomocysteinemia might be involved in the pathogenesis of dementia. Although these associations have been suggested in cross-sectional population studies and in the cross-sectional findings in Kim’s study, the investigators point out that “cross-sectional studies are limited in the extent to which causal relationships can be inferred.”

The researchers also note that prospective studies have been mixed in supporting these associations but hoped their study might add to the relatively sparse data on longitudinal changes before onset of dementia. Approximately 1200 persons over 65 years of age without signs of dementia were recruited for the study; 518 met criteria and participated. Incident cases of dementia subsequently occurred in 45 persons as measured with the Mini-Mental State Examination (MMSE), the Instrumental Activities of Daily Living Scale, and the Clinical Dementia Rating Scale.

The onset of dementia was associated with lower baseline folate levels, but no association was found with baseline B12 or homocysteine concentrations. During the 2.4-year study, there was some increased occurrence of dementia in those with a relative decline in folate and B12 concentrations or a relative increase in homocysteine; but the association of the latter was weakened with analysis of the effect of folate and B12 changes, and all associations were reduced with adjustment for weight change over this period.

Although changes in micronutrient levels may relate to neurodegener­-ative processes, these investigators acknowledge that their measurements were not adequate to confirm these nor to distinguish changes that may mark rather than are causal to incident cases or to discern changes independent of fluctuations in body weight. Despite the need for better data, however, they remain concerned about the implications of micronutrient levels in elderly persons.

“Attention needs to be paid to the nutritional status of people with dementia from the time of diagnosis onward,” the investigators declared. They add “there may be good arguments for focusing interventions for the prevention of dementia on nutritionally deficient frail populations.”

Nutritional intervention in depression
Impressed with the roles of the B vitamins and folate in neurological functioning, and with cross-sectional study data that show lower vitamin B serum concentrations in some populations with depression, Ford and coworkers2 investigated whether supplementation might help prevent onset of depression in elderly persons at risk for vitamin deficiencies.

Their 2-year, placebo-controlled, randomized trial recruited 299 men 75 years or older without significant depression or cognitive impairment. Participants had Beck Depression Inventory (BDI) scores of less than 18 and MMSE scores higher than 24. The participants who were randomized to active treatment received B12, 400 mg; folic acid, 2 mg; and B6, 25 mg daily.

Using the BDI measure of depressive symptoms as the primary outcome, the investigators found that 84.3% of the men who received vitamins and 79.1% of those who received placebo remained free of clinically significant depression. The study was underpowered, however, to establish the difference as statistically significant. There was also no statistically significant difference between the groups in changes in BDI scores, incidence of clinically significant depressive symptoms, or remission of depression.

Despite not having evidence to support this treatment intervention, Ford and colleagues consider it “theoretically attractive.” They note the possibility that significant differences may emerge in a larger study population or in a different cohort than the elderly men who do not have baseline major depression.

“It remains to be determined wheth­er vitamin supplementation would be an effective adjunctive antidepressant treatment for people with severe depression,” the investigators indicate, and whether women would benefit more than men from this theoretical approach.



1. Kim JM, Stewart R, Kim SW, et al. Changes in folate, vitamin B12 and homocysteine associated with incident dementia. J Neurol Neurosurg Psychiatry. 2008;79:864-868.
2. Ford AH, Flicker L, Thomas J, et al. Vitamins B12, B6, and folic acid for onset of depressive symptoms in older men: results from a 2-year placebo-controlled randomized trial. J Clin Psychiatry. 2008;69:1203-1209.