L-Methylfolate Dosing for Depression
For adjunctive treatment of major depressive disorder in patients with inadequate response to SSRIs, L-methylfolate should be dosed at 15 mg daily, as this is the only dose that has demonstrated significant efficacy in controlled trials. 1
Evidence-Based Dosing Recommendations
Standard Dosing
- The effective dose is 15 mg daily as demonstrated in randomized controlled trials of SSRI-resistant depression 1
- The FDA-approved product label indicates usual adult dosing of one to two tablets daily, though this refers to general use rather than depression-specific dosing 2
- A lower dose of 7.5 mg daily showed no significant benefit over placebo in controlled trials 1
Clinical Trial Evidence
- In sequential parallel comparison design trials, only the 15 mg/day dose showed statistically significant superiority over placebo on both primary outcome measures (response rate and symptom reduction) 1
- The number needed to treat for response was approximately 6 with 15 mg/day L-methylfolate as adjunctive therapy 1
- The 7.5 mg dose followed by escalation to 15 mg showed no significant difference from placebo, suggesting the lower dose is inadequate 1
Patient Selection for L-Methylfolate
Best Candidates
- Patients with SSRI-resistant major depressive disorder who have partial or no response to adequate SSRI trials 1
- Patients with biomarkers of inflammation, metabolic disorders, or folate metabolism-related genetic polymorphisms show enhanced responses 3
- Those with suboptimal serum or red blood cell folate levels, as low folate is associated with poorer antidepressant response and treatment resistance 4
Treatment Context
- L-methylfolate is used as adjunctive therapy, not monotherapy—continue the existing SSRI at a stable dose while adding L-methylfolate 1
- Consider after 6-8 weeks of inadequate response to standard antidepressant therapy, consistent with general depression treatment modification guidelines 5, 6
Safety and Tolerability
- L-methylfolate at 15 mg/day is well tolerated with adverse event rates no different from placebo 1
- This represents a significant advantage over other augmentation strategies that may have higher rates of adverse effects such as nausea and vomiting 7
Duration of Treatment
- Once response is achieved with adjunctive L-methylfolate, continue treatment for 4-9 months for first-episode major depressive disorder 5, 6
- Patients with recurrent depression (2 or more episodes) may benefit from years to lifelong therapy 5, 6
Common Pitfall to Avoid
Do not use 7.5 mg daily as the target dose—this lower dose failed to show efficacy in controlled trials and represents underdosing 1. Start directly at 15 mg daily when using L-methylfolate for depression treatment.