Effect of L-Methylfolate on Inflammatory Markers: A Randomized Clinical Trial of Patients With Major Depression

Objective: Elevated levels of high sensitivity C-reactive protein (hsCRP) and obesity (body mass index [BMI] ≥30 kg/m2) may be associated with an increased risk of depression and poor antidepressant response. Previous studies have suggested an association between inflammation and response to treatment. The effect of L-methylfolate 15 mg as an adjunct to selective serotonin reuptake inhibitors (SSRIs) on response and correlations with baseline levels of inflammatory biomarkers was examined. 
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 post hoc analysis, mean change from baseline to endpoint for HDRS was examined for correlations with baseline BMI, hsCRP, and other inflammatory markers.
Results: Pooled differences in mean change on HDRS-17 and HDRS-28 were significantly greater (p=0.05 and p=0.02, respectively) with L-methylfolate than placebo. Mean improvement in symptoms on HDRS-28 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), and among those with elevated baseline hsCRP ≥median (2.25 mg/L) (-7.7 ± 7.4 vs. -3.7 ± 7.5; 95% CI: -7.227, 0.002, p=0.050).
Conclusions: A robust response was observed with adjunctive L-methylfolate when examined by the presence of baseline inflammation and elevated BMI. The presence of these markers in individuals with depression may enhance the antidepressant effect of adjunctive L-methylfolate. Confirmatory research is needed.