Combining Medications to Enhance Depression Outcomes (CO-MED): Acute and Long-Term Outcomes of a Single-Blind Randomized Study
- A. John Rush,
M.D. , - Madhukar H. Trivedi,
M.D. , - Jonathan W. Stewart,
M.D. , - Andrew A. Nierenberg,
M.D. , - Maurizio Fava,
M.D. , - Benji T. Kurian,
M.D. , - Diane Warden,
Ph.D. , - David W. Morris,
Ph.D. , - James F. Luther,
M.A. , - Mustafa M. Husain,
M.D. , - Ian A. Cook,
M.D. , - Richard C. Shelton,
M.D. , - Ira M. Lesser,
M.D. , - Susan G. Kornstein,
M.D. , and - Stephen R. Wisniewski,
Ph.D.
From the Duke–National University of Singapore Graduate Medical School, Singapore; the Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas; the Epidemiology Data Center, Graduate School of Public Health, University of Pittsburgh; the Depression Clinical and Research Program, Massachusetts General Hospital, Boston; New York State Psychiatric Institute and the Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York; the Depression Research and Clinic Program, Semel Institute for Neuroscience and Human Behavior, UCLA; the Department of Psychiatry, Vanderbilt University, Nashville, Tenn.; the Department of Psychiatry, Harbor-UCLA Medical Center and the Los Angeles Biomedical Research Institute, Torrance, Calif.; and the Department of Psychiatry, Virginia Commonwealth University, Richmond.
From the Duke–National University of Singapore Graduate Medical School, Singapore; the Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas; the Epidemiology Data Center, Graduate School of Public Health, University of Pittsburgh; the Depression Clinical and Research Program, Massachusetts General Hospital, Boston; New York State Psychiatric Institute and the Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York; the Depression Research and Clinic Program, Semel Institute for Neuroscience and Human Behavior, UCLA; the Department of Psychiatry, Vanderbilt University, Nashville, Tenn.; the Department of Psychiatry, Harbor-UCLA Medical Center and the Los Angeles Biomedical Research Institute, Torrance, Calif.; and the Department of Psychiatry, Virginia Commonwealth University, Richmond.
From the Duke–National University of Singapore Graduate Medical School, Singapore; the Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas; the Epidemiology Data Center, Graduate School of Public Health, University of Pittsburgh; the Depression Clinical and Research Program, Massachusetts General Hospital, Boston; New York State Psychiatric Institute and the Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York; the Depression Research and Clinic Program, Semel Institute for Neuroscience and Human Behavior, UCLA; the Department of Psychiatry, Vanderbilt University, Nashville, Tenn.; the Department of Psychiatry, Harbor-UCLA Medical Center and the Los Angeles Biomedical Research Institute, Torrance, Calif.; and the Department of Psychiatry, Virginia Commonwealth University, Richmond.
From the Duke–National University of Singapore Graduate Medical School, Singapore; the Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas; the Epidemiology Data Center, Graduate School of Public Health, University of Pittsburgh; the Depression Clinical and Research Program, Massachusetts General Hospital, Boston; New York State Psychiatric Institute and the Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York; the Depression Research and Clinic Program, Semel Institute for Neuroscience and Human Behavior, UCLA; the Department of Psychiatry, Vanderbilt University, Nashville, Tenn.; the Department of Psychiatry, Harbor-UCLA Medical Center and the Los Angeles Biomedical Research Institute, Torrance, Calif.; and the Department of Psychiatry, Virginia Commonwealth University, Richmond.
From the Duke–National University of Singapore Graduate Medical School, Singapore; the Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas; the Epidemiology Data Center, Graduate School of Public Health, University of Pittsburgh; the Depression Clinical and Research Program, Massachusetts General Hospital, Boston; New York State Psychiatric Institute and the Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York; the Depression Research and Clinic Program, Semel Institute for Neuroscience and Human Behavior, UCLA; the Department of Psychiatry, Vanderbilt University, Nashville, Tenn.; the Department of Psychiatry, Harbor-UCLA Medical Center and the Los Angeles Biomedical Research Institute, Torrance, Calif.; and the Department of Psychiatry, Virginia Commonwealth University, Richmond.
From the Duke–National University of Singapore Graduate Medical School, Singapore; the Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas; the Epidemiology Data Center, Graduate School of Public Health, University of Pittsburgh; the Depression Clinical and Research Program, Massachusetts General Hospital, Boston; New York State Psychiatric Institute and the Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York; the Depression Research and Clinic Program, Semel Institute for Neuroscience and Human Behavior, UCLA; the Department of Psychiatry, Vanderbilt University, Nashville, Tenn.; the Department of Psychiatry, Harbor-UCLA Medical Center and the Los Angeles Biomedical Research Institute, Torrance, Calif.; and the Department of Psychiatry, Virginia Commonwealth University, Richmond.
From the Duke–National University of Singapore Graduate Medical School, Singapore; the Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas; the Epidemiology Data Center, Graduate School of Public Health, University of Pittsburgh; the Depression Clinical and Research Program, Massachusetts General Hospital, Boston; New York State Psychiatric Institute and the Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York; the Depression Research and Clinic Program, Semel Institute for Neuroscience and Human Behavior, UCLA; the Department of Psychiatry, Vanderbilt University, Nashville, Tenn.; the Department of Psychiatry, Harbor-UCLA Medical Center and the Los Angeles Biomedical Research Institute, Torrance, Calif.; and the Department of Psychiatry, Virginia Commonwealth University, Richmond.
From the Duke–National University of Singapore Graduate Medical School, Singapore; the Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas; the Epidemiology Data Center, Graduate School of Public Health, University of Pittsburgh; the Depression Clinical and Research Program, Massachusetts General Hospital, Boston; New York State Psychiatric Institute and the Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York; the Depression Research and Clinic Program, Semel Institute for Neuroscience and Human Behavior, UCLA; the Department of Psychiatry, Vanderbilt University, Nashville, Tenn.; the Department of Psychiatry, Harbor-UCLA Medical Center and the Los Angeles Biomedical Research Institute, Torrance, Calif.; and the Department of Psychiatry, Virginia Commonwealth University, Richmond.
From the Duke–National University of Singapore Graduate Medical School, Singapore; the Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas; the Epidemiology Data Center, Graduate School of Public Health, University of Pittsburgh; the Depression Clinical and Research Program, Massachusetts General Hospital, Boston; New York State Psychiatric Institute and the Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York; the Depression Research and Clinic Program, Semel Institute for Neuroscience and Human Behavior, UCLA; the Department of Psychiatry, Vanderbilt University, Nashville, Tenn.; the Department of Psychiatry, Harbor-UCLA Medical Center and the Los Angeles Biomedical Research Institute, Torrance, Calif.; and the Department of Psychiatry, Virginia Commonwealth University, Richmond.
From the Duke–National University of Singapore Graduate Medical School, Singapore; the Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas; the Epidemiology Data Center, Graduate School of Public Health, University of Pittsburgh; the Depression Clinical and Research Program, Massachusetts General Hospital, Boston; New York State Psychiatric Institute and the Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York; the Depression Research and Clinic Program, Semel Institute for Neuroscience and Human Behavior, UCLA; the Department of Psychiatry, Vanderbilt University, Nashville, Tenn.; the Department of Psychiatry, Harbor-UCLA Medical Center and the Los Angeles Biomedical Research Institute, Torrance, Calif.; and the Department of Psychiatry, Virginia Commonwealth University, Richmond.
From the Duke–National University of Singapore Graduate Medical School, Singapore; the Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas; the Epidemiology Data Center, Graduate School of Public Health, University of Pittsburgh; the Depression Clinical and Research Program, Massachusetts General Hospital, Boston; New York State Psychiatric Institute and the Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York; the Depression Research and Clinic Program, Semel Institute for Neuroscience and Human Behavior, UCLA; the Department of Psychiatry, Vanderbilt University, Nashville, Tenn.; the Department of Psychiatry, Harbor-UCLA Medical Center and the Los Angeles Biomedical Research Institute, Torrance, Calif.; and the Department of Psychiatry, Virginia Commonwealth University, Richmond.
From the Duke–National University of Singapore Graduate Medical School, Singapore; the Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas; the Epidemiology Data Center, Graduate School of Public Health, University of Pittsburgh; the Depression Clinical and Research Program, Massachusetts General Hospital, Boston; New York State Psychiatric Institute and the Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York; the Depression Research and Clinic Program, Semel Institute for Neuroscience and Human Behavior, UCLA; the Department of Psychiatry, Vanderbilt University, Nashville, Tenn.; the Department of Psychiatry, Harbor-UCLA Medical Center and the Los Angeles Biomedical Research Institute, Torrance, Calif.; and the Department of Psychiatry, Virginia Commonwealth University, Richmond.
From the Duke–National University of Singapore Graduate Medical School, Singapore; the Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas; the Epidemiology Data Center, Graduate School of Public Health, University of Pittsburgh; the Depression Clinical and Research Program, Massachusetts General Hospital, Boston; New York State Psychiatric Institute and the Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York; the Depression Research and Clinic Program, Semel Institute for Neuroscience and Human Behavior, UCLA; the Department of Psychiatry, Vanderbilt University, Nashville, Tenn.; the Department of Psychiatry, Harbor-UCLA Medical Center and the Los Angeles Biomedical Research Institute, Torrance, Calif.; and the Department of Psychiatry, Virginia Commonwealth University, Richmond.
From the Duke–National University of Singapore Graduate Medical School, Singapore; the Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas; the Epidemiology Data Center, Graduate School of Public Health, University of Pittsburgh; the Depression Clinical and Research Program, Massachusetts General Hospital, Boston; New York State Psychiatric Institute and the Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York; the Depression Research and Clinic Program, Semel Institute for Neuroscience and Human Behavior, UCLA; the Department of Psychiatry, Vanderbilt University, Nashville, Tenn.; the Department of Psychiatry, Harbor-UCLA Medical Center and the Los Angeles Biomedical Research Institute, Torrance, Calif.; and the Department of Psychiatry, Virginia Commonwealth University, Richmond.
From the Duke–National University of Singapore Graduate Medical School, Singapore; the Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas; the Epidemiology Data Center, Graduate School of Public Health, University of Pittsburgh; the Depression Clinical and Research Program, Massachusetts General Hospital, Boston; New York State Psychiatric Institute and the Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York; the Depression Research and Clinic Program, Semel Institute for Neuroscience and Human Behavior, UCLA; the Department of Psychiatry, Vanderbilt University, Nashville, Tenn.; the Department of Psychiatry, Harbor-UCLA Medical Center and the Los Angeles Biomedical Research Institute, Torrance, Calif.; and the Department of Psychiatry, Virginia Commonwealth University, Richmond.
Abstract
Objective:
Two antidepressant medication combinations were compared with selective serotonin reuptake inhibitor monotherapy to determine whether either combination produced a higher remission rate in first-step acute-phase (12 weeks) and long-term (7 months) treatment.
Method:
The single-blind, prospective, randomized trial enrolled 665 outpatients at six primary and nine psychiatric care sites. Participants had at least moderately severe nonpsychotic chronic and/or recurrent major depressive disorder. Escitalopram (up to 20 mg/day) plus placebo, sustained-release bupropion (up to 400 mg/day) plus escitalopram (up to 20 mg/day), or extended-release venlafaxine (up to 300 mg/day) plus mirtazapine (up to 45 mg/day) was delivered (1:1:1 ratio) by using measurement-based care. The primary outcome was remission, defined as ratings of less than 8 and less than 6 on the last two consecutive applications of the 16-item Quick Inventory of Depressive Symptomatology—Self-Report. Secondary outcomes included side effect burden, adverse events, quality of life, functioning, and attrition.
Results:
Remission and response rates and most secondary outcomes were not different among treatment groups at 12 weeks. The remission rates were 38.8% for escitalopram-placebo, 38.9% for bupropion-escitalopram, and 37.7% for venlafaxine-mirtazapine, and the response rates were 51.6%–52.4%. The mean number of worsening adverse events was higher for venlafaxine-mirtazapine (5.7) than for escitalopram-placebo (4.7). At 7 months, remission rates (41.8%–46.6%), response rates (57.4%–59.4%), and most secondary outcomes were not significantly different.
Conclusions:
Neither medication combination outperformed monotherapy. The combination of extended-release venlafaxine plus mirtazapine may have a greater risk of adverse events.
