Evid Based Mental Health 16:75 doi:10.1136/eb-2013-101269
  • Therapeutics

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


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 30 days followed by l-methylfolate for 30 days (7.5 mg/day); or placebo for 60 days. Trial 2 had the same study design as trial 1, except that the dosing of l-methylfolate was 15 mg during both 30 day periods. Current SSRI treatment was continued throughout the trials.

Outcomes: Primary outcome (both trials): difference in Hamilton Depression Scale (HAM-D) response rates, defined as a reduction of ≥50% in HAM-D score during treatment or a final score of ≤7; and degree of improvement in HAM-D score. Secondary outcomes: changes in scores on the Clinical Global Impression Scale (CGI) severity and improvement scales and quick inventory of depressive symptomology-self-rated (QIDS-SR); HAM-D remission rate and QIDS-SR response and remission rates. Assessments were carried out every 10 days, and analyses conducted for each of the two, 30-day phases of treatment.

Patient follow-up: Study completion 80% in trial 1 and 81.3% in trial 2.


Design: Two randomised controlled trials.

Allocation: Unclear.

Blinding: Both trials were double blinded.

Follow-up period: 60 days intervention period in both trials.

Main results

In the first trial 7.5 mg/day adjunctive l-methylfolate did not improve HAM-D response or degree of improvement compared with placebo in either phase of the trial. Participants who increased to 15 mg/day for the second phase of the trial did demonstrate improved response compared with placebo, though this fell short of clinical significance (24% vs 9%; p=0.1). In the second trial 15 mg l-methylfolate improved HAM-D response rates compared with placebo (32.3% vs 14.6%; p=0.04) and also gave greater improvement in HAM-D (−5.58 vs −3.04; p=0.05). In the second trial 15 mg l-methylfolate also improved the secondary outcomes of score change on CGI severity scale (−0.92 vs −0.34; p=0.01) and QIDS-SR (−4.7 vs −2.62; p=0.04) compared with placebo.


In people with major depression who have had partial or non-response to SSRIs alone, augmentation with the 15 mg dose of l-methylfolate may be effective.

Abstracted from

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


  1. Richard Tranter2
  1. 1Institute of Medical and Social Care Research, Bangor University, Wrexham, UK;
  2. 2Kawai Clinic, Nelson Hospital, Nelson Marlborough DHB, Nelson, New Zealand

Folate is a B vitamin with an essential role in the biosynthesis of neurotransmitters, and implicated in the pathogenesis and treatment of depression. Low folate is associated with depression and a poorer response to antidepressants. Although evidence suggests sufficient folate protects against depressive symptoms, there is limited evidence to support folate alone as an effective treatment. Thus, the focus has been on folate as an adjunct to antidepressant treatments. With up to 50% of patients failing to respond adequately to antidepressants, folate is a potentially appealing means to enhance antidepressant efficacy.

Papakostas and colleagues add to the growing body of evidence in favour of adjuvant folate and antidepressant therapy, particularly for treatment-resistant depression, although one relatively robust study showed no benefit of folic acid and other B vitamins in depression.1 Like previous studies, there are methodological limitations to this study, including a relatively small sample size, short treatment period and short duration of follow-up. Use of high doses of folate is also noteworthy given concerns that exposure to high doses accelerates tumour growth in people with a history of colorectal cancer.2 A strength of this study is the use of l-methylfolate instead of synthetic folic acid.

On balance, one must be cautious in recommending adjunctive antidepressant treatment with folate as they have yet to be fully established: (a) any long-term risks and benefits of exposure to high doses, (b) a dose-response relationship, or (c) the optimal duration of treatment required. The evidence base needs large, pragmatic clinical trials to replicate promising results from small-sized and medium-sized studies. These must also measure the important individual differences in folate metabolism to determine if there are clinical subgroups who respond to folate augmentation and how to identify them. There is still much research to be carried out before we can safely recommend widespread adjuvant prescribing for depression.


  • 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).