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Published Online: 1 December 2012

l-Methylfolate as Adjunctive Therapy for SSRI-Resistant Major Depression: Results of Two Randomized, Double-Blind, Parallel-Sequential Trials

George I. Papakostas, M.D., Richard C. Shelton, M.D., John M. Zajecka, M.D., Bijan Etemad, M.D., Karl Rickels, M.D., Alisabet Clain, M.S., Lee Baer, Ph.D., Elizabeth D. Dalton, B.A., Garret R. Sacco, B.A., David Schoenfeld, Ph.D., Michael Pencina, Ph.D., Allison Meisner, M.A., Teodoro Bottiglieri, Ph.D., Erik Nelson, M.D., David Mischoulon, M.D., Ph.D., Jonathan E. Alpert, M.D., Ph.D., James G. Barbee, M.D., Sidney Zisook, M.D., and Maurizio Fava, M.D.Authors Info & Affiliations
Publication: American Journal of Psychiatry
Volume 169, Number 12
https://doi.org/10.1176/appi.ajp.2012.11071114
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Abstract

Patients with major depression who have an insufficient response to selective serotonin reuptake inhibitors (SSRIs) may benefit from the addition of 15 mg/day of l-methylfolate, the only form of folate that crosses the blood-brain barrier. Adding 7.5 mg/day was no more effective than adding placebo, but 15.0 mg/day plus ongoing SSRI treatment produced a 32% response rate, compared to 15% for augmentation with placebo. Side effects in the two groups were comparable in type and frequency.

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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Information & Authors

Information

Published In

Go to American Journal of Psychiatry
Go to American Journal of Psychiatry
American Journal of Psychiatry
Volume 169 • Number 12 • December 2012
Pages: 1267 - 1274
PubMed: 23212058

History

Received: 25 July 2011
Revision received: 12 March 2012
Revision received: 2 July 2012
Accepted: 16 July 2012
Published online: 1 December 2012
Published in print: December 2012

Authors

Affiliations

George I. Papakostas, M.D.
From the Center for Treatment-Resistant Depression, Depression Clinical and Research Program, the Biostatistics Center, and the Clinical Trials Network and Institute, Massachusetts General Hospital, Boston; Harvard Medical School, Boston; the Harvard Clinical Research Institute, Boston; the Department of Biostatistics, Boston University, Boston; the Department of Psychiatry, Vanderbilt University School of Medicine, Nashville; Rush University Medical Center, Chicago; the Department of Psychiatry, University of Pennsylvania, Philadelphia; Baylor Research Institute, Institute of Metabolic Disease, Dallas; the Department of Psychiatry, University of Cincinnati Academic Health Center, Cincinnati; the Louisiana State University Health Sciences Center, New Orleans; the Department of Psychiatry, University of California San Diego; and San Diego VA Healthcare Service.
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Richard C. Shelton, M.D.
From the Center for Treatment-Resistant Depression, Depression Clinical and Research Program, the Biostatistics Center, and the Clinical Trials Network and Institute, Massachusetts General Hospital, Boston; Harvard Medical School, Boston; the Harvard Clinical Research Institute, Boston; the Department of Biostatistics, Boston University, Boston; the Department of Psychiatry, Vanderbilt University School of Medicine, Nashville; Rush University Medical Center, Chicago; the Department of Psychiatry, University of Pennsylvania, Philadelphia; Baylor Research Institute, Institute of Metabolic Disease, Dallas; the Department of Psychiatry, University of Cincinnati Academic Health Center, Cincinnati; the Louisiana State University Health Sciences Center, New Orleans; the Department of Psychiatry, University of California San Diego; and San Diego VA Healthcare Service.
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John M. Zajecka, M.D.
From the Center for Treatment-Resistant Depression, Depression Clinical and Research Program, the Biostatistics Center, and the Clinical Trials Network and Institute, Massachusetts General Hospital, Boston; Harvard Medical School, Boston; the Harvard Clinical Research Institute, Boston; the Department of Biostatistics, Boston University, Boston; the Department of Psychiatry, Vanderbilt University School of Medicine, Nashville; Rush University Medical Center, Chicago; the Department of Psychiatry, University of Pennsylvania, Philadelphia; Baylor Research Institute, Institute of Metabolic Disease, Dallas; the Department of Psychiatry, University of Cincinnati Academic Health Center, Cincinnati; the Louisiana State University Health Sciences Center, New Orleans; the Department of Psychiatry, University of California San Diego; and San Diego VA Healthcare Service.
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Bijan Etemad, M.D.
From the Center for Treatment-Resistant Depression, Depression Clinical and Research Program, the Biostatistics Center, and the Clinical Trials Network and Institute, Massachusetts General Hospital, Boston; Harvard Medical School, Boston; the Harvard Clinical Research Institute, Boston; the Department of Biostatistics, Boston University, Boston; the Department of Psychiatry, Vanderbilt University School of Medicine, Nashville; Rush University Medical Center, Chicago; the Department of Psychiatry, University of Pennsylvania, Philadelphia; Baylor Research Institute, Institute of Metabolic Disease, Dallas; the Department of Psychiatry, University of Cincinnati Academic Health Center, Cincinnati; the Louisiana State University Health Sciences Center, New Orleans; the Department of Psychiatry, University of California San Diego; and San Diego VA Healthcare Service.
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Karl Rickels, M.D.
From the Center for Treatment-Resistant Depression, Depression Clinical and Research Program, the Biostatistics Center, and the Clinical Trials Network and Institute, Massachusetts General Hospital, Boston; Harvard Medical School, Boston; the Harvard Clinical Research Institute, Boston; the Department of Biostatistics, Boston University, Boston; the Department of Psychiatry, Vanderbilt University School of Medicine, Nashville; Rush University Medical Center, Chicago; the Department of Psychiatry, University of Pennsylvania, Philadelphia; Baylor Research Institute, Institute of Metabolic Disease, Dallas; the Department of Psychiatry, University of Cincinnati Academic Health Center, Cincinnati; the Louisiana State University Health Sciences Center, New Orleans; the Department of Psychiatry, University of California San Diego; and San Diego VA Healthcare Service.
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Alisabet Clain, M.S.
From the Center for Treatment-Resistant Depression, Depression Clinical and Research Program, the Biostatistics Center, and the Clinical Trials Network and Institute, Massachusetts General Hospital, Boston; Harvard Medical School, Boston; the Harvard Clinical Research Institute, Boston; the Department of Biostatistics, Boston University, Boston; the Department of Psychiatry, Vanderbilt University School of Medicine, Nashville; Rush University Medical Center, Chicago; the Department of Psychiatry, University of Pennsylvania, Philadelphia; Baylor Research Institute, Institute of Metabolic Disease, Dallas; the Department of Psychiatry, University of Cincinnati Academic Health Center, Cincinnati; the Louisiana State University Health Sciences Center, New Orleans; the Department of Psychiatry, University of California San Diego; and San Diego VA Healthcare Service.
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Lee Baer, Ph.D.
From the Center for Treatment-Resistant Depression, Depression Clinical and Research Program, the Biostatistics Center, and the Clinical Trials Network and Institute, Massachusetts General Hospital, Boston; Harvard Medical School, Boston; the Harvard Clinical Research Institute, Boston; the Department of Biostatistics, Boston University, Boston; the Department of Psychiatry, Vanderbilt University School of Medicine, Nashville; Rush University Medical Center, Chicago; the Department of Psychiatry, University of Pennsylvania, Philadelphia; Baylor Research Institute, Institute of Metabolic Disease, Dallas; the Department of Psychiatry, University of Cincinnati Academic Health Center, Cincinnati; the Louisiana State University Health Sciences Center, New Orleans; the Department of Psychiatry, University of California San Diego; and San Diego VA Healthcare Service.
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Elizabeth D. Dalton, B.A.
From the Center for Treatment-Resistant Depression, Depression Clinical and Research Program, the Biostatistics Center, and the Clinical Trials Network and Institute, Massachusetts General Hospital, Boston; Harvard Medical School, Boston; the Harvard Clinical Research Institute, Boston; the Department of Biostatistics, Boston University, Boston; the Department of Psychiatry, Vanderbilt University School of Medicine, Nashville; Rush University Medical Center, Chicago; the Department of Psychiatry, University of Pennsylvania, Philadelphia; Baylor Research Institute, Institute of Metabolic Disease, Dallas; the Department of Psychiatry, University of Cincinnati Academic Health Center, Cincinnati; the Louisiana State University Health Sciences Center, New Orleans; the Department of Psychiatry, University of California San Diego; and San Diego VA Healthcare Service.
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Garret R. Sacco, B.A.
From the Center for Treatment-Resistant Depression, Depression Clinical and Research Program, the Biostatistics Center, and the Clinical Trials Network and Institute, Massachusetts General Hospital, Boston; Harvard Medical School, Boston; the Harvard Clinical Research Institute, Boston; the Department of Biostatistics, Boston University, Boston; the Department of Psychiatry, Vanderbilt University School of Medicine, Nashville; Rush University Medical Center, Chicago; the Department of Psychiatry, University of Pennsylvania, Philadelphia; Baylor Research Institute, Institute of Metabolic Disease, Dallas; the Department of Psychiatry, University of Cincinnati Academic Health Center, Cincinnati; the Louisiana State University Health Sciences Center, New Orleans; the Department of Psychiatry, University of California San Diego; and San Diego VA Healthcare Service.
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David Schoenfeld, Ph.D.
From the Center for Treatment-Resistant Depression, Depression Clinical and Research Program, the Biostatistics Center, and the Clinical Trials Network and Institute, Massachusetts General Hospital, Boston; Harvard Medical School, Boston; the Harvard Clinical Research Institute, Boston; the Department of Biostatistics, Boston University, Boston; the Department of Psychiatry, Vanderbilt University School of Medicine, Nashville; Rush University Medical Center, Chicago; the Department of Psychiatry, University of Pennsylvania, Philadelphia; Baylor Research Institute, Institute of Metabolic Disease, Dallas; the Department of Psychiatry, University of Cincinnati Academic Health Center, Cincinnati; the Louisiana State University Health Sciences Center, New Orleans; the Department of Psychiatry, University of California San Diego; and San Diego VA Healthcare Service.
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Michael Pencina, Ph.D.
From the Center for Treatment-Resistant Depression, Depression Clinical and Research Program, the Biostatistics Center, and the Clinical Trials Network and Institute, Massachusetts General Hospital, Boston; Harvard Medical School, Boston; the Harvard Clinical Research Institute, Boston; the Department of Biostatistics, Boston University, Boston; the Department of Psychiatry, Vanderbilt University School of Medicine, Nashville; Rush University Medical Center, Chicago; the Department of Psychiatry, University of Pennsylvania, Philadelphia; Baylor Research Institute, Institute of Metabolic Disease, Dallas; the Department of Psychiatry, University of Cincinnati Academic Health Center, Cincinnati; the Louisiana State University Health Sciences Center, New Orleans; the Department of Psychiatry, University of California San Diego; and San Diego VA Healthcare Service.
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Allison Meisner, M.A.
From the Center for Treatment-Resistant Depression, Depression Clinical and Research Program, the Biostatistics Center, and the Clinical Trials Network and Institute, Massachusetts General Hospital, Boston; Harvard Medical School, Boston; the Harvard Clinical Research Institute, Boston; the Department of Biostatistics, Boston University, Boston; the Department of Psychiatry, Vanderbilt University School of Medicine, Nashville; Rush University Medical Center, Chicago; the Department of Psychiatry, University of Pennsylvania, Philadelphia; Baylor Research Institute, Institute of Metabolic Disease, Dallas; the Department of Psychiatry, University of Cincinnati Academic Health Center, Cincinnati; the Louisiana State University Health Sciences Center, New Orleans; the Department of Psychiatry, University of California San Diego; and San Diego VA Healthcare Service.
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Teodoro Bottiglieri, Ph.D.
From the Center for Treatment-Resistant Depression, Depression Clinical and Research Program, the Biostatistics Center, and the Clinical Trials Network and Institute, Massachusetts General Hospital, Boston; Harvard Medical School, Boston; the Harvard Clinical Research Institute, Boston; the Department of Biostatistics, Boston University, Boston; the Department of Psychiatry, Vanderbilt University School of Medicine, Nashville; Rush University Medical Center, Chicago; the Department of Psychiatry, University of Pennsylvania, Philadelphia; Baylor Research Institute, Institute of Metabolic Disease, Dallas; the Department of Psychiatry, University of Cincinnati Academic Health Center, Cincinnati; the Louisiana State University Health Sciences Center, New Orleans; the Department of Psychiatry, University of California San Diego; and San Diego VA Healthcare Service.
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Erik Nelson, M.D.
From the Center for Treatment-Resistant Depression, Depression Clinical and Research Program, the Biostatistics Center, and the Clinical Trials Network and Institute, Massachusetts General Hospital, Boston; Harvard Medical School, Boston; the Harvard Clinical Research Institute, Boston; the Department of Biostatistics, Boston University, Boston; the Department of Psychiatry, Vanderbilt University School of Medicine, Nashville; Rush University Medical Center, Chicago; the Department of Psychiatry, University of Pennsylvania, Philadelphia; Baylor Research Institute, Institute of Metabolic Disease, Dallas; the Department of Psychiatry, University of Cincinnati Academic Health Center, Cincinnati; the Louisiana State University Health Sciences Center, New Orleans; the Department of Psychiatry, University of California San Diego; and San Diego VA Healthcare Service.
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David Mischoulon, M.D., Ph.D.
From the Center for Treatment-Resistant Depression, Depression Clinical and Research Program, the Biostatistics Center, and the Clinical Trials Network and Institute, Massachusetts General Hospital, Boston; Harvard Medical School, Boston; the Harvard Clinical Research Institute, Boston; the Department of Biostatistics, Boston University, Boston; the Department of Psychiatry, Vanderbilt University School of Medicine, Nashville; Rush University Medical Center, Chicago; the Department of Psychiatry, University of Pennsylvania, Philadelphia; Baylor Research Institute, Institute of Metabolic Disease, Dallas; the Department of Psychiatry, University of Cincinnati Academic Health Center, Cincinnati; the Louisiana State University Health Sciences Center, New Orleans; the Department of Psychiatry, University of California San Diego; and San Diego VA Healthcare Service.
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Jonathan E. Alpert, M.D., Ph.D.
From the Center for Treatment-Resistant Depression, Depression Clinical and Research Program, the Biostatistics Center, and the Clinical Trials Network and Institute, Massachusetts General Hospital, Boston; Harvard Medical School, Boston; the Harvard Clinical Research Institute, Boston; the Department of Biostatistics, Boston University, Boston; the Department of Psychiatry, Vanderbilt University School of Medicine, Nashville; Rush University Medical Center, Chicago; the Department of Psychiatry, University of Pennsylvania, Philadelphia; Baylor Research Institute, Institute of Metabolic Disease, Dallas; the Department of Psychiatry, University of Cincinnati Academic Health Center, Cincinnati; the Louisiana State University Health Sciences Center, New Orleans; the Department of Psychiatry, University of California San Diego; and San Diego VA Healthcare Service.
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James G. Barbee, M.D.
From the Center for Treatment-Resistant Depression, Depression Clinical and Research Program, the Biostatistics Center, and the Clinical Trials Network and Institute, Massachusetts General Hospital, Boston; Harvard Medical School, Boston; the Harvard Clinical Research Institute, Boston; the Department of Biostatistics, Boston University, Boston; the Department of Psychiatry, Vanderbilt University School of Medicine, Nashville; Rush University Medical Center, Chicago; the Department of Psychiatry, University of Pennsylvania, Philadelphia; Baylor Research Institute, Institute of Metabolic Disease, Dallas; the Department of Psychiatry, University of Cincinnati Academic Health Center, Cincinnati; the Louisiana State University Health Sciences Center, New Orleans; the Department of Psychiatry, University of California San Diego; and San Diego VA Healthcare Service.
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Sidney Zisook, M.D.
From the Center for Treatment-Resistant Depression, Depression Clinical and Research Program, the Biostatistics Center, and the Clinical Trials Network and Institute, Massachusetts General Hospital, Boston; Harvard Medical School, Boston; the Harvard Clinical Research Institute, Boston; the Department of Biostatistics, Boston University, Boston; the Department of Psychiatry, Vanderbilt University School of Medicine, Nashville; Rush University Medical Center, Chicago; the Department of Psychiatry, University of Pennsylvania, Philadelphia; Baylor Research Institute, Institute of Metabolic Disease, Dallas; the Department of Psychiatry, University of Cincinnati Academic Health Center, Cincinnati; the Louisiana State University Health Sciences Center, New Orleans; the Department of Psychiatry, University of California San Diego; and San Diego VA Healthcare Service.
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Maurizio Fava, M.D.
From the Center for Treatment-Resistant Depression, Depression Clinical and Research Program, the Biostatistics Center, and the Clinical Trials Network and Institute, Massachusetts General Hospital, Boston; Harvard Medical School, Boston; the Harvard Clinical Research Institute, Boston; the Department of Biostatistics, Boston University, Boston; the Department of Psychiatry, Vanderbilt University School of Medicine, Nashville; Rush University Medical Center, Chicago; the Department of Psychiatry, University of Pennsylvania, Philadelphia; Baylor Research Institute, Institute of Metabolic Disease, Dallas; the Department of Psychiatry, University of Cincinnati Academic Health Center, Cincinnati; the Louisiana State University Health Sciences Center, New Orleans; the Department of Psychiatry, University of California San Diego; and San Diego VA Healthcare Service.
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Notes

Address correspondence to Dr. Papakostas ([email protected]).

Funding Information

Dr. Papakostas has received research support from, served as a consultant or speaker for, or received honoraria for CME activities for Abbott, AstraZeneca, Brainsway, Bristol-Myers Squibb, Cephalon, Dey Pharma, Eli Lilly, Forest, GlaxoSmithKline, Lundbeck, NIMH, Otsuka, Pamlab, Ridge Diagnostics, Roche, Takeda, Theracos, and Sunovion. Dr. Shelton has received research support or served as a consultant for Bristol-Myers Squibb, Eli Lilly, Cyberonics, Elan, Euthymics Bioscience, Forest, Janssen Pharmaceutica, Medtronic, Novartis, Otsuka, Pamlab, Pfizer, Repligen, Ridge Diagnostics, Takeda Pharmaceuticals, and St. Jude Medical. Dr. Zajecka has received research support from or served as a consultant, adviser, or speaker for Abbott, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Cyberonics, Eli Lilly, Forest, GlaxoSmithKline, Hoffman-LaRoche, McNeil, Novartis, Otsuka, Pamlab, Pfizer, Shire, and Takeda. Dr. Schoenfeld is a patent holder for the sequential parallel design used in this study; the patent is owned by his employer, Massachusetts General Hospital. Dr. Pencina has served as a consultant for Pamlab and RCT Logic. Ms. Meisner has served as a consultant for Massachusetts General Hospital and Pamlab, has received a grant from the National Heart, Lung and Blood Institute, and has received funds from grants at the Harvard School of Public Health. Dr. Bottiglieri has received research support from and has served as a consultant for Pamlab, has served as the chairman of the advisory board for Methylation Sciences, and holds stock options in Methylation Sciences. Dr. Nelson has received research support from AstraZeneca, Eli Lilly, GlaxoSmithKline, and Pamlab. Dr. Mischoulon has received research support or honoraria for consulting, speaking, and writing from the Bowman Family Foundation, Bristol-Myers Squibb, Cederroth, FisherWallace, Ganeden, Lichtwer Pharma, Nordic Naturals, and Pamlab and has received royalties from Back Bay Scientific and Lippincott Williams & Wilkins. Dr. Alpert has received research support from or served as an adviser, consultant, or speaker for Abbott, Alkermes, APA, Lichtwer Pharma, Lorex, Aspect Medical Systems, AstraZeneca, Bristol-Myers Squibb, Cephalon, Cyberonics, Eli Lilly, Forest, GlaxoSmithkline, J & J Pharmaceuticals, MGH Psychiatry Academy/Reed Medical Education, MGH Psychiatry Academy/Primedia, Novartis, Organon, Pamlab, Pfizer, Pharmavite, Roche, Sanofi/Synthelabo, Solvay, Wyeth-Ayerst, and Xian-Janssen and has received editorial fees from Belvoir Publishing. Dr. Barbee has received research support from or served as a speaker for AstraZeneca, Bristol-Myers Squibb, Dey Pharmaceuticals, Eli Lilly, Forest, Merck, Pfizer, and Sheppard Pratt Health System and has done forensic consulting work for various attorneys. Dr. Zisook has received research support from Pamlab. Dr. Fava has received research support from Abbott, Alkermes, Aspect Medical Systems, AstraZeneca, BioResearch, BrainCells, Bristol-Myers Squibb, Cephalon, BioPharma, Clinical Trials Solutions, Clintara, Covidien, Eli Lilly, EnVivo Pharmaceuticals, Euthymics Bioscience, Forest, Ganeden Biotech, GlaxoSmithKline, Icon Clinical Research, i3 Innovus, Johnson & Johnson Pharmaceutical Research and Development, Lichtwer Pharma, Lorex Pharmaceuticals, NARSAD, National Center for Complementary and Alternative Medicine, National Institute on Drug Abuse, NIMH, Novartis, Organon, Pamlab, Pfizer, Pharmavite, Photothera, Roche, RCT Logic, Sanofi-Aventis, Shire, Solvay, Synthelabo, and Wyeth-Ayerst; he has served as an adviser or consultant (unpaid except as otherwise noted) for Abbott Laboratories, Affectis Pharmaceuticals, Alkermes, Amarin Pharma, Aspect Medical Systems, AstraZeneca, Auspex Pharmaceuticals, Bayer, Best Practice Project Management, BioMarin Pharmaceuticals, Biovail, BrainCells, Bristol-Myers Squibb, CeNeRx BioPharma, Cephalon, Clinical Trials Solutions, CNS Response, Compellis Pharmaceuticals, Cypress Pharmaceutical, DiagnoSearch Life Sciences, Dinippon Sumitomo Pharma, Dov Pharmaceuticals, Edgemont Pharmaceuticals, Eisai, Eli Lilly, ePharmaSolutions, EPIX Pharmaceuticals, Euthymics Bioscience, Fabre-Kramer, Forest, GenOmind, GlaxoSmithKline, Grunenthal, i3 Innovus, Janssen Pharmaceutica, Jazz Pharmaceuticals, Johnson & Johnson Pharmaceutical Research and Development (remunerated), Knoll Pharmaceuticals, Labopharm, Lorex Pharmaceuticals, Lundbeck, MedAvante, Merck, MSI Methylation Sciences, Naurex, Neuronetics, Novartis, Nutrition 21, Orexigen Therapeutics, Organon, Otsuka, Pamlab, Pfizer, PharmaStar, Pharmavite, PharmoRx Therapeutics, Precision Human Biolaboratory, Prexa Pharmaceuticals, Puretech Ventures, PsychoGenics, Psylin Neurosciences, Rexahn Pharmaceuticals, Ridge Diagnostics, Roche, RCT Logic, Sanofi-Aventis, Sepracor, Servier Laboratories, Schering-Plough, Solvay, Somaxon, Somerset Pharmaceuticals, Sunovion, Synthelabo, Takeda, Tetragenex, TransForm Pharmaceuticals, Transcept Pharmaceuticals, and Vanda Pharmaceuticals; he has provided speaking/publishing (unpaid except as otherwise noted) for Adamed, Advanced Meeting Partners, APA, American Society of Clinical Psychopharmacology, AstraZeneca, Belvoir Media Group (remunerated), Boehringer Ingelheim, Bristol-Myers Squibb, Cephalon, CME Institute/Physicians Postgraduate Press (remunerated), Eli Lilly, Forest, GlaxoSmithKline, Imedex, MGH Psychiatry Academy/Primedia, MGH Psychiatry Academy/Reed Elsevier (remunerated), Novartis, Organon, Pfizer, PharmaStar, United BioSource, and Wyeth-Ayerst; he has equity holdings in Compellis; he is a patent holder for the sequential parallel design used in this study (the patent is owned by Massachusetts General Hospital) and has a patent application for a combination of ketamine and scopolamine in major depression; and he receives royalties from Lippincott Williams & Wilkins. The other authors report no financial relationships with commercial interests.Both trials were funded by Pamlab.

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