The Biological Relationship Between Depression, Vitamins B9, B12, and D and Genetic Variants: A Systematic Review

Abstract

Background and Aims: Depression is a main leading cause of disability worldwide; studies have described it as a multifactorial disease that involves biological, psychological, and environmental factors. This systematic review explores the role of vitamins B9, B12, and D in depression, particularly emphasizing on their biological effects, genetic variant interactions, and potential treatment implications. Methods: A systematic literature review was conducted in Web of Science (WOS) and PubMed up to June 15th, 2025. This review included 24 studies from randomized controlled trials (RCTs), observational studies, and case reports, and identified studies examiningexamineand examine the associations between genetic variants involved in vitamins B9, B12, and D metabolism; their biological processes; and outcomes in depression. Following the PRISMA criteria, researchers analyzed and extracted data independently, this resulted in the inclusion of 24of 24 eligible papers (14 of vitamins B9, B12 and 10 of vitamin D) . Results: Studies varied widely in design and methodology. Deficiencies in vitamins B9 (folate) and B12 (cobalamin) are associated with decreased neurotransmitter biosynthesis, higher homocysteine levels, and increased depressive symptoms. Vitamin D deficiency has been also associated with mood regulation through its effects on neurotransmission. Genetic variants, particularly in the MTHFR gene, have been associated with significant influence on individual susceptibility to depression, in some populations, highlighting the interaction between genetics and micronutrient bioavailability, and the need of further studies with diverse populations, larger study samples and the inclusion of more genetic variants. Conclusions: This systematic review emphasizes the role of vitamins B9, B12, and D, and, and genetic variants associated with development of depression. Regardless of the encouraging findings that supplementation with vitamins B9, B12, and D could support depressive symptomatology, additional research is needed to propose therapeutic guidelines. Personalized strategies taking into accountconsidering dietary, genetic and environmental factors could enhance treatment results for individuals with depression.