Patient Expectancy as a Mediator of Placebo Effects in Antidepressant Clinical Trials.
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.


METHODS
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.
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.
Bret R
BR
Rutherford
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
MM
Wall
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
PJ
Brown
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
TH
Choo
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
TD
Wager
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
BS
Peterson
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
S
Chung
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
I
Kirsch
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
SP
Roose
D000328:Adult; D000928:Antidepressive Agents / Q000627:therapeutic use*; D015283:Citalopram / Q000627:therapeutic use*; D003865:Major Depressive Disorder / Q000175:diagnosis / Q000188:drug therapy* / Q000523:psychology; D006801:Humans; D008875:Middle Aged; D015990:Placebo Effect; D011446:Prospective Studies; D011569:Psychiatric Status Rating Scales / Q000706:statistics & numerical data; D011594:Psychometrics; D012718:Set, Psychology; D016896:Treatment Outcome
D000928:Antidepressive Agents; D015283:Citalopram
Antidepressants; Mood Disorders-Unipolar