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Higher dose l-methylfolate may be an effective adjunctive therapy for adults with major depression who have inadequate response to SSRIs

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Question: In adults with major depression who have had a partial or non-response to selective serotonin reuptake inhibitors (SSRIs), is the addition of l-methylfolate effective?

Patients: 148 adults (trial 1) and 75 adults (trial 2) with Diagnostic Statistical Manual of Mental Disorders - IV (DSM-IV) major depressive disorder who had not responded to at least 8 weeks adequate treatment with an SSRI (≥20 mg/day of fluoxetine, citalopram or paroxetine; ≥10 mg/day escitalopram; or ≥50 mg/day of sertraline). Exclusion criteria: pregnancy, breastfeeding or being of child-bearing age and not using contraception; ≥25% improvement in depressive symptom severity in the 2 weeks between screening and baseline; substance use disorder within the previous 6 months; unstable medical or psychiatric illness; hypothyroidism; past failure of sufficient symptom improvement after more than two antidepressant trials; those taking supplements containing >400 µg folate or >6 µg vitamin B12.

Setting: Multicentre clinical sites in the US (both trials).

Intervention: In trial 1 participants were randomised in a 2 : 3:3 ratio to one of the three treatment groups: l-methylfolate for 60 days (7.5 mg/day for 30 days followed by 15 mg/day for 30 days); placebo for …

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  • Sources of funding: Both trials were funded by Pamlab.


  • Correspondence to Seren H Roberts, Institute of Medical and Social Care Research, Bangor University, Cambrian House, Archimedes Centre, Wrexham Technology Park, Wrexham, LL13 7YP, UK;

  • Competing interests SHR and RT are principal investigators on a large NIHR HTA funded trial of folic acid augmentation of antidepressants (FolATED).

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