L-methylfolate as adjunctive therapy for SSRI-resistant major depression: results
of two randomized, double-blind, parallel-sequential trials.
Author(s): Papakostas GI, Shelton RC, Zajecka JM, Etemad B, Rickels K, Clain A, Baer L,
Dalton ED, Sacco GR, Schoenfeld D, Pencina M, Meisner A, Bottiglieri T, Nelson E,
Mischoulon D, Alpert JE, Barbee JG, Zisook S, Fava M.
Affiliation(s): Center for Treatment-Resistant Depression, Depression Clinical and Research
Program, the Biostatistics Center, and the Clinical Trials Network and Institute,
Massachusetts General Hospital, Boston, MA, USA. gpapakostas@partners.org
Publication date & source: 2012, Am J Psychiatry. , 169(12):1267-74
OBJECTIVE: The authors conducted two multicenter sequential parallel comparison
design trials to investigate the effect of L-methylfolate augmentation in the
treatment of major depressive disorder in patients who had a partial response or
no response to selective serotonin reuptake inhibitors (SSRIs).
METHOD: In the first trial, 148 outpatients with SSRI-resistant major depressive
disorder were enrolled in a 60-day study divided into two 30-day periods.
Patients were randomly assigned, in a 2:3:3 ratio, to receive 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 (7.5 mg/day) for 30 days, or placebo for 60
days. SSRI dosages were kept constant throughout the study. In the second trial,
with 75 patients, the design was identical to the first, except that the
l-methylfolate dosage was 15 mg/day during both 30-day periods.
RESULTS: In the first trial, no significant difference was observed in outcomes
between the treatment groups. In the second trial, adjunctive L-methylfolate at
15 mg/day showed significantly greater efficacy compared with continued SSRI
therapy plus placebo on both primary outcome measures (response rate and degree
of change in depression symptom score) and two secondary outcome measures of
symptom severity. The number needed to treat for response was approximately six
in favor of adjunctive L-methylfolate at 15 mg/day. L-Methylfolate was well
tolerated, with rates of adverse events no different from those reported with
placebo.
CONCLUSIONS: Adjunctive L-methylfolate at 15 mg/day may constitute an effective,
safe, and relatively well tolerated treatment strategy for patients with major
depressive disorder who have a partial response or no response to SSRIs.
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