<b><i>Systematic Review of Methylenetetrahydrofolate reductase (MTHFR) 677 C&gt;T and 1298 A&gt;C Variants and Treatment-Resistant Depression: Insights for Precision Psychiatry</i></b>

Major depressive disorder (MDD) is a recurrent mental disorder with genetic and environmental interactions. Folate is essential for producing neurotransmitters that regulate mood, cognition, and overall brain health. Methylenetetrahydrofolate reductase (<i>MTHFR</i>) is an enzyme related to folate metabolism and individuals who carry an enzymatic activity reduction through <i>MTHFR </i>genetic variants are associated with an increased risk of MDD and treatment resistance findings. Conversely, some studies did not find these associations. Thus, deepening the understanding of the relationship between carrying the <i>MTHFR</i> 677 C&gt;T and 1298 A&gt;C variants and treatment-resistant depression (TRD) is crucial for identifying personalized therapeutic approaches and improving clinical outcomes in MDD patients. This review provides compelling evidence for the association between <i>MTHFR</i> genetic variants (677C&gt;T and 1298A&gt;C) and TRD. The findings underscore the critical role of these variants in folate and homocysteine metabolism, influencing neurotransmitter synthesis and treatment outcomes. By advancing our understanding of genetic and metabolic contributors to TRD, this research paves the way for more targeted, effective treatments in psychiatry.