L-methylfolate Augmentation to Antidepressants for Adolescents with Treatment-Resistant Depression: A Case Series

Despite antidepressant treatment, some patients continue to experience significant symptoms of depression. Literature has demonstrated modest benefit of folate supplementation in treatment-resistant depression among adults, though evidence is lacking in the pediatric population. This case series describes 10 adolescents (mean age 14.4 ± 2.8 years) with treatment-resistant depression prescribed adjunctive l-methylfolate (LM). The patient population was predominantly female (80%), Caucasian (90%), with an average of three comorbid psychiatric diagnoses, and failures of three psychotropic medications before starting LM. The majority of patients (80%) had a single mutation among the two methylene tetrahydrofolate reductase (MTHFR) gene variants evaluated (50% A1298 AC; 30% C677 CT), indicating reduced MTHFR activity. Eighty percent of patients demonstrated improvement in depression, anxiety, and irritability. Overall, LM was well tolerated. These cases suggest that LM as an adjunct to antidepressant treatment may be a safe and effective strategy for managing treatment-resistant depression in pediatric patients.