Background: Major depressive disorder (MDD) includes a metabolic component that is associated with poor antidepressant response, and correction may improve core symptoms. This analysis assessed the effect of L-methylfolate 15 mg as an adjunct to SSRIs on the Maier subscale of the HDRS and correlations with inflammatory biomarkers. Methods: 75 inadequate responders to SSRIs were enrolled in a 60-day, multi-center, double-blind, placebo-controlled trial. Patients received L-methylfolate 15 mg/day for 60 days, placebo for 30 days followed by L-methylfolate 15 mg/day for 30 days, or placebo for 60 days. In a sub-analysis, mean change from baseline to endpoint was evaluated for the Maier subscale (HDRS items 1, 2, 7-10, and 13) for L-methylfolate and placebo. In addition, correlations between BMI and hs-CRP were examined. Results: 74 patients were enrolled. For pooled data, mean change on the Maier subscale was -3.3 ± 3.7 for L-methylfolate vs. -1.5 ± 3.2 for placebo (95% CI: -2.936, -0.296, p=0.016). Mean improvement in symptoms was significantly greater with L-methylfolate vs. placebo (-7.4 ± 7.9 vs. -2.4 ± 5.3) among patients with a BMI ≥30 kg/m2 (95% CI: -7.449, -1.871, p=0.001). Mean symptom improvement was significantly greater with L-methylfolate than placebo (-7.7 ± 7.4 vs. -3.7 ± 7.5) in patients with elevated baseline hsCRP >median (2.25 mg/L) (95% CI: -7.227, 0.002, p=0.050). Conclusions: A robust response in core symptoms on the Maier subscale was observed with L-methylfolate as an adjunct to SSRIs. Addressing metabolic imbalances (BMI or inflammation) may enhance the treatment effect.
George Papakostas, MD; John Zajecka, MD; Richard Shelton, MD; Maurizio Fava, MD