Women often seek antidepressant alternatives for major depressive disorder (MDD) in anticipation of or during pregnancy. In this preliminary study, EnBrace HR, a prenatal supplement containing methylfolate, was investigated for depressive relapse prevention and for acute treatment of MDD in women planning pregnancy or during pregnancy ⁽¹⁾. At enrollment, Group 1 participants were well (not depressed) and planned to discontinue antidepressants for pregnancy. Group 2 participants were depressed. Primary outcome variables by group included MDD relapse and depressive symptoms, verified with the Mini-International Neuropsychiatric Interview and the Montgomery-Åsberg Depression Rating Scale (MADRS), respectively. Biomarkers of inflammation and the folate cycle were collected. The results showed that Group 1 participants experienced lower rates of depressive relapse than expected from a historical comparison group and no significant changes in MADRS scores. Group 2 participants experienced significant improvements in MADRS scores with 5 improving >50% and 1 improving 33.3%. One adverse event occurred, a hospitalization for depression. The authors conclude that EnBrace HR is a well-tolerated intervention with potential efficacy for prevention and treatment of perinatal depression.