title: L-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trials.
abstract: 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).
  
  
  METHODS
  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.
authors.affiliation: 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
authors.forename: George I
authors.initials: GI
authors.lastname: Papakostas
authors.forename: Richard C
authors.initials: RC
authors.lastname: Shelton
authors.forename: John M
authors.initials: JM
authors.lastname: Zajecka
authors.forename: Bijan
authors.initials: B
authors.lastname: Etemad
authors.forename: Karl
authors.initials: K
authors.lastname: Rickels
authors.forename: Alisabet
authors.initials: A
authors.lastname: Clain
authors.forename: Lee
authors.initials: L
authors.lastname: Baer
authors.forename: Elizabeth D
authors.initials: ED
authors.lastname: Dalton
authors.forename: Garret R
authors.initials: GR
authors.lastname: Sacco
authors.forename: David
authors.initials: D
authors.lastname: Schoenfeld
authors.forename: Michael
authors.initials: M
authors.lastname: Pencina
authors.forename: Allison
authors.initials: A
authors.lastname: Meisner
authors.forename: Teodoro
authors.initials: T
authors.lastname: Bottiglieri
authors.forename: Erik
authors.initials: E
authors.lastname: Nelson
authors.forename: David
authors.initials: D
authors.lastname: Mischoulon
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Alpert
authors.forename: James G
authors.initials: JG
authors.lastname: Barbee
authors.forename: Sidney
authors.initials: S
authors.lastname: Zisook
authors.forename: Maurizio
authors.initials: M
authors.lastname: Fava
mesh_terms: D017024:Chemotherapy, Adjuvant; D003865:Major Depressive Disorder / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011569:Psychiatric Status Rating Scales; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D013763:Tetrahydrofolates / Q000008:administration & dosage / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D017367:Selective Serotonin Reuptake Inhibitors; D013763:Tetrahydrofolates; C005984:5-methyltetrahydrofolate