L-methylfolate as adjunctive therapy for SSRI-resistant major depression: Results of two randomized, double-blind,,parallel-sequential trials

George I. Papakostas, Richard C. Shelton, John M. Zajecka, Bijan Etemad, Karl Rickels, Alisabet Clain, Lee Baer, Elizabeth D. Dalton, Garret R. Sacco, David Schoenfeld, Michael Pencina, Allison Meisner, Teodoro Bottiglieri, Erik Nelson, David Mischoulon, Jonathan E. Alpert, James G. Barbee, Sidney Zisook, Maurizio Fava

Research output: Contribution to journalArticle

141 Citations (Scopus)

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). 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.

Original languageEnglish (US)
Pages (from-to)1267-1274
Number of pages8
JournalAmerican Journal of Psychiatry
Volume169
Issue number12
DOIs
StatePublished - Dec 1 2012
Externally publishedYes

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Serotonin Uptake Inhibitors
Depression
Major Depressive Disorder
Placebos
Outcome Assessment (Health Care)
Therapeutics
Numbers Needed To Treat
Outpatients

ASJC Scopus subject areas

  • Psychiatry and Mental health

Cite this

L-methylfolate as adjunctive therapy for SSRI-resistant major depression : Results of two randomized, double-blind,,parallel-sequential trials. / Papakostas, George I.; Shelton, Richard C.; Zajecka, John M.; Etemad, Bijan; Rickels, Karl; Clain, Alisabet; Baer, Lee; Dalton, Elizabeth D.; Sacco, Garret R.; Schoenfeld, David; Pencina, Michael; Meisner, Allison; Bottiglieri, Teodoro; Nelson, Erik; Mischoulon, David; Alpert, Jonathan E.; Barbee, James G.; Zisook, Sidney; Fava, Maurizio.

In: American Journal of Psychiatry, Vol. 169, No. 12, 01.12.2012, p. 1267-1274.

Research output: Contribution to journalArticle

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 2012, 'L-methylfolate as adjunctive therapy for SSRI-resistant major depression: Results of two randomized, double-blind,,parallel-sequential trials', American Journal of Psychiatry, vol. 169, no. 12, pp. 1267-1274. https://doi.org/10.1176/appi.ajp.2012.11071114
Papakostas, George I. ; Shelton, Richard C. ; Zajecka, John M. ; Etemad, Bijan ; Rickels, Karl ; Clain, Alisabet ; Baer, Lee ; Dalton, Elizabeth D. ; Sacco, Garret R. ; Schoenfeld, David ; Pencina, Michael ; Meisner, Allison ; Bottiglieri, Teodoro ; Nelson, Erik ; Mischoulon, David ; Alpert, Jonathan E. ; Barbee, James G. ; Zisook, Sidney ; Fava, Maurizio. / L-methylfolate as adjunctive therapy for SSRI-resistant major depression : Results of two randomized, double-blind,,parallel-sequential trials. In: American Journal of Psychiatry. 2012 ; Vol. 169, No. 12. pp. 1267-1274.
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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). 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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AU - Zajecka, John M.

AU - Etemad, Bijan

AU - Rickels, Karl

AU - Clain, Alisabet

AU - Baer, Lee

AU - Dalton, Elizabeth D.

AU - Sacco, Garret R.

AU - Schoenfeld, David

AU - Pencina, Michael

AU - Meisner, Allison

AU - Bottiglieri, Teodoro

AU - Nelson, Erik

AU - Mischoulon, David

AU - Alpert, Jonathan E.

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AU - Fava, Maurizio

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N2 - 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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