Datasets from the following study: Methylenetetrahydrofolate reductase Variants, Expression, and Their Associations with Depression Severity, Adverse Childhood Experiences, and Treatment Resistance in Major Depressive Disorder

ABSTRACT Background: Variants of the methylenetetrahydrofolate reductase (MTHFR) gene have been associated with depression severity and treatment resistance, potentially through impaired one-carbon metabolism. However, the clinical relevance of predicted MTHFR enzymatic activity for symptom burden, functional impairment, suicidality, and adverse childhood experiences (ACEs) in major depressive disorder (MDD) remains insufficiently characterized. Methods: This cross-sectional observational study included 78 adult outpatients with DSM-5–diagnosed MDD who had available pharmacogenetic testing for MTHFR 677C>T and 1298A>C variants. Predicted MTHFR enzymatic activity was estimated based on combined genotypes and participants were classified into preserved (>50%; n = 49) or reduced (≤50%; n = 29) enzymatic activity groups. Depressive severity was assessed using the 17-item Hamilton Depression Rating Scale (HDRS17). Functional impairment, medication adherence, treatment characteristics, lifetime course variables, suicidality, and ACEs were evaluated using standardized instruments. Groups were compared using appropriate statistical tests. Results: Patients with reduced predicted MTHFR enzymatic activity (≤50%) exhibited a more severe clinical profile, including higher depressive symptom severity (HDRS-17: 12.1 ± 6.8 vs 9.1 ± 5.0; p = 0.04), a greater frequency of recurrent depressive episodes (≥3 episodes: 86.2% vs 63.3%; p = 0.04), more suicide attempts (24.1% vs 6.1%; p = 0.03), and higher use of antipsychotic augmentation (27.6% vs 8.2%; p = 0.04). Functional impairment across work/school, social, and family domains was significantly worse in the low-activity group (all p ≤ 0.04). Rates of high ACE exposure (ACE ≥ 4) did not differ between groups (24.5% vs 27.6%; p = 0.76). Genotype and allele analyses showed an enrichment of the 677T and 1298C alleles among individuals with reduced enzymatic activity (both p < 0.01). Higher ACE scores were associated with greater depressive severity across subgroups, particularly among patients with reduced MTHFR activity and treatment-resistant depression. Conclusions: Reduced predicted MTHFR enzymatic activity is associated with greater depressive severity, functional impairment, suicidality, and treatment complexity in MDD, independent of medication adherence and overall ACE burden. Functional stratification based on predicted MTHFR activity may help identify clinically vulnerable subgroups and refine prognostic assessment in major depressive disorder.