Observational studies have found as many as 30% of patients hospitalized for depression are deficient in vitamin B12. A cross-sectional study of 700 community-living, physically disabled women over the age of 65 found that vitamin B12 deficient women were twice as likely to be severely depressed as non-deficient women. A population-based study in 3,884 elderly men and women with depressive disorders found that those with vitamin B12 deficiency were almost 70% more likely to experience depression than those with normal vitamin B12 status. The reasons for the relationship between vitamin B12 deficiency and depression are not clear but may involve S-adenosylmethionine (SAMe).

Vitamin B12 and folate are required for the synthesis of SAMe, a methyl group donor essential for the metabolism of neurotransmitters whose bioavailability has been related to depression. This hypothesis is supported by several studies that have shown supplementation with SAMe improves depressive symptoms. Because few studies have examined the relationship of vitamin B12 status and the development of depression over time, it cannot yet be determined if vitamin B12 deficiency plays a causal role in depression. However, due to the high prevalence of vitamin B12 deficiency in older individuals, it may be beneficial to screen for vitamin B12 deficiency as part of a medical evaluation