Supplementary Material for: Systematic Review of Methylenetetrahydrofolate reductase (MTHFR) 677C>T and 1298A>C Variants and Treatment-Resistant Depression: Insights for Precision Psychiatry

Introduction: Treatment-resistant depression (TRD) is a major clinical challenge, affecting approximately one-third of patients with major depressive disorder (MDD). Genetic factors, particularly genetic variants in the MTHFR gene, have been implicated in antidepressant response variability. The MTHFR 677C>T (rs1801133) and 1298A>C (rs1801131) variants are associated with altered folate metabolism, increased homocysteine levels, and potential disruptions in neurotransmitter synthesis, which may contribute to TRD. This systematic review aims to evaluate the association between MTHFR variants and TRD, exploring their potential role in predicting antidepressant response and guiding personalized treatment strategies. Methods: A systematic literature search was conducted following PRISMA guidelines (PROSPERO registration: CRD42024612628). Studies were included if they investigated MTHFR 677C>T and/or 1298 A>C variants in adults with MDD and assessed their association with TRD. Results: Seven studies met the inclusion criteria, and the findings indicate a potential link between MTHFR 677TT and 1298CC genotypes and an increased risk of TRD. However, conflicting evidence exists, as other studies found no significant effect of the MTHFR variants on treatment outcomes. Variability in study designs, definitions of TRD, and confounding factors such as dietary folate intake and comorbidities contribute to inconsistencies in findings. Conclusion: While evidence suggests a role for MTHFR variants in TRD, heterogeneity among studies limits definitive conclusions. Future research should standardize TRD definitions, control for confounding factors, and explore the integration of genetic testing into clinical practice. L-methyl folate supplementation may represent a promising adjunctive strategy for MDD patients carrying MTHFR risk variants.