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Abstract

Objective:

Causes of placebo effects in antidepressant trials have been inferred from observational studies and meta-analyses, but their mechanisms have not been directly established. The goal of this study was to examine in a prospective, randomized controlled trial whether patient expectancy mediates placebo effects in antidepressant studies.

Method:

Adult outpatients with major depressive disorder were randomly assigned to open or placebo-controlled citalopram treatment. Following measurement of pre- and postrandomization expectancy, participants were treated with citalopram or placebo for 8 weeks. Independent samples t tests determined whether patient expectancy differed between the open and placebo-controlled groups, and mixed-effects models assessed group effects on Hamilton Depression Rating Scale (HAM-D) scores over time while controlling for treatment assignment. Finally, mediation analyses tested whether between-group differences in patient expectancy mediated the group effect on HAM-D scores.

Results:

Postrandomization expectancy scores were significantly higher in the open group (mean=12.1 [SD=2.1]) compared with the placebo-controlled group (mean=11.0 [SD=2.0]). Mixed-effects modeling revealed a significant week-by-group interaction, indicating that HAM-D scores for citalopram-treated participants declined at a faster rate in the open group compared with the placebo-controlled group. Patient expectations postrandomization partially mediated group effects on week 8 HAM-D.

Conclusions:

Patient expectancy is a significant mediator of placebo effects in antidepressant trials. Expectancy-related interventions should be investigated as a means of controlling placebo responses in antidepressant clinical trials and improving patient outcome in clinical treatment.

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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
Pages: 135 - 142
PubMed: 27609242

History

Received: 22 February 2016
Revision received: 3 May 2016
Accepted: 6 June 2016
Published online: 9 September 2016
Published in print: February 01, 2017

Keywords

  1. Antidepressants
  2. Mood Disorders-Unipolar

Authors

Details

Bret R. Rutherford, M.D.
From Columbia University College of Physicians and Surgeons, New York State Psychiatric Institute, New York; the Department of Psychology and Neuroscience and the Institute of Cognitive Science, University of Colorado at Boulder, Boulder, Colo.; the Institute for the Developing Mind, Children’s Hospital Los Angeles; the Keck School of Medicine at the University of Southern California, Los Angeles; Harvard Medical School, Boston; and Beth Israel Deaconess Medical Center, Boston.
Melanie M. Wall, Ph.D.
From Columbia University College of Physicians and Surgeons, New York State Psychiatric Institute, New York; the Department of Psychology and Neuroscience and the Institute of Cognitive Science, University of Colorado at Boulder, Boulder, Colo.; the Institute for the Developing Mind, Children’s Hospital Los Angeles; the Keck School of Medicine at the University of Southern California, Los Angeles; Harvard Medical School, Boston; and Beth Israel Deaconess Medical Center, Boston.
Patrick J. Brown, Ph.D.
From Columbia University College of Physicians and Surgeons, New York State Psychiatric Institute, New York; the Department of Psychology and Neuroscience and the Institute of Cognitive Science, University of Colorado at Boulder, Boulder, Colo.; the Institute for the Developing Mind, Children’s Hospital Los Angeles; the Keck School of Medicine at the University of Southern California, Los Angeles; Harvard Medical School, Boston; and Beth Israel Deaconess Medical Center, Boston.
Tse-Hwei Choo, B.A.
From Columbia University College of Physicians and Surgeons, New York State Psychiatric Institute, New York; the Department of Psychology and Neuroscience and the Institute of Cognitive Science, University of Colorado at Boulder, Boulder, Colo.; the Institute for the Developing Mind, Children’s Hospital Los Angeles; the Keck School of Medicine at the University of Southern California, Los Angeles; Harvard Medical School, Boston; and Beth Israel Deaconess Medical Center, Boston.
Tor D. Wager, Ph.D.
From Columbia University College of Physicians and Surgeons, New York State Psychiatric Institute, New York; the Department of Psychology and Neuroscience and the Institute of Cognitive Science, University of Colorado at Boulder, Boulder, Colo.; the Institute for the Developing Mind, Children’s Hospital Los Angeles; the Keck School of Medicine at the University of Southern California, Los Angeles; Harvard Medical School, Boston; and Beth Israel Deaconess Medical Center, Boston.
Bradley S. Peterson, M.D.
From Columbia University College of Physicians and Surgeons, New York State Psychiatric Institute, New York; the Department of Psychology and Neuroscience and the Institute of Cognitive Science, University of Colorado at Boulder, Boulder, Colo.; the Institute for the Developing Mind, Children’s Hospital Los Angeles; the Keck School of Medicine at the University of Southern California, Los Angeles; Harvard Medical School, Boston; and Beth Israel Deaconess Medical Center, Boston.
Sarah Chung, B.A.
From Columbia University College of Physicians and Surgeons, New York State Psychiatric Institute, New York; the Department of Psychology and Neuroscience and the Institute of Cognitive Science, University of Colorado at Boulder, Boulder, Colo.; the Institute for the Developing Mind, Children’s Hospital Los Angeles; the Keck School of Medicine at the University of Southern California, Los Angeles; Harvard Medical School, Boston; and Beth Israel Deaconess Medical Center, Boston.
Irving Kirsch, Ph.D.
From Columbia University College of Physicians and Surgeons, New York State Psychiatric Institute, New York; the Department of Psychology and Neuroscience and the Institute of Cognitive Science, University of Colorado at Boulder, Boulder, Colo.; the Institute for the Developing Mind, Children’s Hospital Los Angeles; the Keck School of Medicine at the University of Southern California, Los Angeles; Harvard Medical School, Boston; and Beth Israel Deaconess Medical Center, Boston.
Steven P. Roose, M.D.
From Columbia University College of Physicians and Surgeons, New York State Psychiatric Institute, New York; the Department of Psychology and Neuroscience and the Institute of Cognitive Science, University of Colorado at Boulder, Boulder, Colo.; the Institute for the Developing Mind, Children’s Hospital Los Angeles; the Keck School of Medicine at the University of Southern California, Los Angeles; Harvard Medical School, Boston; and Beth Israel Deaconess Medical Center, Boston.

Notes

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

Competing Interests

Dr. Rutherford has received consulting fees from Pfizer. Dr. Wager has received consulting fees from Janssen and Ryan & Conlon, LLC. All other authors report no financial relationships with commercial interests.

Funding Information

National Institute of Mental Health10.13039/100000025: K23 MH085236
Supported by NIMH grant K23 MH085236 (to Dr. Rutherford).

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