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

Question

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.

Methods

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.

Conclusions

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

Papakostas GI, Shelton RC, Zajecka JM, et al. (l)-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trials. Am J Psychiatry 2012; 169: 1267– 74.