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

Published on Feb 1, 2017in American Journal of Psychiatry13.65
· DOI :10.1176/appi.ajp.2016.16020225
Bret R. Rutherford18
Estimated H-index: 18
Melanie M. Wall64
Estimated H-index: 64
+ 6 AuthorsSteven P. Roose52
Estimated H-index: 52
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.Resul...
  • References (13)
  • Citations (32)
Published on Jul 1, 2013in American Journal of Psychiatry13.65
Bret R. Rutherford18
Estimated H-index: 18
Steven P. Roose52
Estimated H-index: 52
Placebo response in clinical trials of antidepressant medications is substantial and has been increasing. High placebo response rates hamper efforts to detect signals of efficacy for new antidepressant medications, contributing to trial failures and delaying the delivery of new treatments to market. Media reports seize upon increasing placebo response and modest advantages for active drugs as reasons to question the value of antidepressant medication, which may further stigmatize treatments for ...
Published on May 1, 2013in Psychological Medicine5.64
Bret R. Rutherford18
Estimated H-index: 18
(Columbia University),
Sue M. Marcus28
Estimated H-index: 28
+ 5 AuthorsSteven P. Roose52
Estimated H-index: 52
(Columbia University)
Background This study is a randomized, prospective, investigation of the relationships between clinical trial design, patient expectancy, and the outcome of treatment with antidepressant medication.
Published on Aug 1, 2010in CNS Neuroscience & Therapeutics3.39
Arif Khan25
Estimated H-index: 25
(Duke University),
Amritha Bhat6
Estimated H-index: 6
+ 2 AuthorsWalter A. Brown35
Estimated H-index: 35
(Brown University)
The increasing rate of failure of antidepressant clinical trials has led to the assertion that antidepressants do not have meaningful clinical benefits. Our hypothesis was that the decrease in antidepressant-placebo differences in antidepressant clinical trials over the past three decades could be explained by changes in research design features rather than a lack of potency of the antidepressants being tested. We collected data from 130 double blind placebo controlled antidepressant clinical tr...
Published on Mar 15, 2010in The Journal of Clinical Psychiatry4.02
Mark Sinyor14
Estimated H-index: 14
Anthony J. Levitt41
Estimated H-index: 41
+ 4 AuthorsKrista L. Lanctôt51
Estimated H-index: 51
Objective: To determine if the inclusion of a placebo arm and/or the number of active comparators in antidepressant trials influences the response rates of the active medication and/or placebo. Data Sources: Searches of MEDLINE, PsycINFO, and pharmaceutical Web sites for published trials or trials conducted but unpublished between January 1996 and October 2007. Study Selection: 2,275 citations were reviewed, 285 studies were retrieved, and 90 were included in the analysis. Trials reporting respo...
Published on Sep 15, 2004in The Journal of Clinical Psychiatry4.02
Heather V. Krell2
Estimated H-index: 2
Andrew F. Leuchter32
Estimated H-index: 32
+ 2 AuthorsMichelle Abrams19
Estimated H-index: 19
Objective: To evaluate the association between treatment expectations and response in a 9-week, single-blind experimental antidepressant treatment study. Method: Twenty-five adult subjects meeting DSM-IV criteria for major depressive disorder with Hamilton Rating Scale for Depression (HAM-D) scores of ≥ 17 completed a treatment trial using the experimental antidepressant reboxetine. Following a 1-week placebo lead-in, subjects received single-blind treatment for 8 weeks with reboxetine 8 to 10 m...
Published on Jun 1, 2004in Journal of Affective Disorders4.08
N. Kennedy2
Estimated H-index: 2
(University of Cambridge),
Eugene S. Paykel66
Estimated H-index: 66
(University of Cambridge)
Abstract Background: Although residual symptoms after remission from depression are common and predict early relapse, little is known about the impact of residual symptoms on longer-term clinical course of depression or social functioning. Methods: Sixty severe recurrent depressives, who remitted from an index episode of depression with residual symptoms or below residual symptomatology, were followed-up at 8–10 years. Subjects underwent detailed longitudinal interviewing on course of depression...
Published on Jan 1, 2002in Journal of Consulting and Clinical Psychology4.36
Björn Meyer31
Estimated H-index: 31
(LSU: Louisiana State University),
Paul A. Pilkonis54
Estimated H-index: 54
+ 3 AuthorsStuart M. Sotsky22
Estimated H-index: 22
(WashU: Washington University in St. Louis)
Prior analyses from the National Institute of Mental Health Treatment of Depression Collaborative Research Program indicated that patients' expectancies of treatment effectiveness (S. M. Sotsky et al., 1991) and the quality of the therapeutic alliance (J. L. Krupnick et al., 1996) predicted clinical improvement. These data were reanalyzed to examine the hypothesis that the link between treatment expectancies and outcome would be mediated by patients' contribution to the alliance. Among 151 patie...
Published on Aug 1, 1999in Archives of General Psychiatry
Balu Kalayam10
Estimated H-index: 10
George S. Alexopoulos70
Estimated H-index: 70
Background This study investigated the relationship of clinical, neuropsychological, and electrophysiological measures of prefrontal dysfunction with treatment response in elderly patients with major depression. Methods Forty-nine depressed elderly subjects were studied before and after 6 weeks of adequate antidepressant treatment and compared with 22 psychiatrically normal controls. The psychomotor retardation item of the Hamilton Depression Rating Scale, the initiation/perseveration subscore o...
Published on Jan 1, 1998in Prevention & Treatment
Irving Kirsch64
Estimated H-index: 64
Guy Sapirstein4
Estimated H-index: 4
Mean effect sizes for changes in depression were calculated for 2,318 patients who had been randomly assigned to either antidepressant medication or placebo in 19 double-blind clinical trials. As a proportion of the drug response, the placebo response was constant across different types of medication (75%), and the correlation between placebo effect and drug effect was .90. These data indicate that virtually all of the variation in drug effect size was due to the placebo characteristics of the s...
Published on Jan 1, 1996in The Journal of Clinical Psychiatry4.02
Anthony J. Rothschild39
Estimated H-index: 39
Depression in the elderly occurs commonly and is a major public health problem. Unfortunately, despite the availability of safe and effective treatments, late-life depression is often underdiagnosed because the symptoms are unrecognized by the patient and the health care provider. Late-life depression is described in this review, with a focus on symptoms, prevalence, diagnosis, and available treatment modalities.
Cited By32
Published on Nov 13, 2018in Psychological Medicine5.64
Sigal Zilcha-Mano16
Estimated H-index: 16
Patrick J. Brown14
Estimated H-index: 14
+ 2 AuthorsBret R. Rutherford18
Estimated H-index: 18
Published on 2019in Journal of Child Psychology and Psychiatry6.13
Bradley S. Peterson76
Estimated H-index: 76
(Children's Hospital Los Angeles)
Published on May 1, 2019in Journal of Psychiatric Research3.92
Sigal Zilcha-Mano16
Estimated H-index: 16
Zhishun Wang25
Estimated H-index: 25
+ 6 AuthorsBret R. Rutherford1
Estimated H-index: 1
Abstract Background Patient expectancy of therapeutic improvement is a primary mediator of placebo effects in antidepressant clinical trials, but its mechanisms are poorly understood. This study employed a novel antidepressant trial design, with integrated functional magnetic resonance imaging (fMRI), to manipulate patient outcome expectancy and examine its neural mediators. Method Twenty-three depressed outpatients, in a randomized controlled trial were assigned to either Open (high outcome exp...
Published on 2019in Advances in Therapy3.26
Koen Demyttenaere70
Estimated H-index: 70
(Katholieke Universiteit Leuven),
Ellen Frank96
Estimated H-index: 96
(University of Pittsburgh)
+ 1 AuthorsElif Cindik-Herbrüggen
A symposium held at the 31st European College of Neuropsychopharmacology congress in October 2018 in Barcelona, Spain discussed patients’ expectations of treatment of their depression and how these can be integrated into patient management. Since treatment non-compliance is a major problem in patients suffering from depression, it is important to identify patients’ expectations to improve treatment compliance and in turn efficacy. Currently, there is no established protocol for choosing the righ...
Published on Apr 1, 2019in Biological Psychiatry11.50
Bret R. Rutherford18
Estimated H-index: 18
(Columbia University),
Mark Slifstein53
Estimated H-index: 53
(SBU: Stony Brook University)
+ 8 AuthorsEmily Valente
Abstract Background A high-risk subgroup of older patients with depression has slowed processing and gait speeds. This study examined whether carbidopa/levodopa (L-DOPA) monotherapy increased dopamine availability, increased processing/gait speed, and relieved depressive symptoms. Methods Adult outpatients with depression >59 years old underwent baseline [ 11 C]raclopride positron emission tomography followed by open L-DOPA for 3 weeks (1 week each of 150 mg, 300 mg, and 450 mg). Generalized est...
Published on Aug 1, 2018in Psychoneuroendocrinology4.01
Jens Gaab26
Estimated H-index: 26
(University of Basel)
Abstract Placebos are usually employed deceptively in clinical trials in order to control for non-specific effects. However, since placebos themselves have been found to cause clinically relevant changes and in some cases are indistinguishable from the verum they are tested against, this theoretically inert, but practically effective intervention has become a scientific discipline in its own right. In this review, it is argued that placebos are generic and genuine biopsychosocial interventions a...
Published on Jun 13, 2019in Frontiers in Psychiatry3.16
Irving Kirsch64
Estimated H-index: 64
(Harvard University)
The aim of this review is to evaluate the placebo effect in the treatment of anxiety and depression. Antidepressants are supposed to work by fixing a chemical imbalance, specifically, a lack of serotonin or norepinephrine in the brain. However, analyses of the published and the unpublished clinical trial data are consistent in showing that most (if not all) of the benefits of antidepressants in the treatment of depression and anxiety are due to the placebo response, and the difference in improve...
Published on May 1, 2019in Journal of Affective Disorders4.08
Thulasi Thiruchselvam1
Estimated H-index: 1
(U of T: University of Toronto),
David J. A. Dozois38
Estimated H-index: 38
(UWO: University of Western Ontario)
+ 3 AuthorsLena C. Quilty28
Estimated H-index: 28
(U of T: University of Toronto)
Abstract Background Patient outcome expectancy - the belief that treatment will lead to an improvement in symptoms – is linked to favourable therapeutic outcomes in major depressive disorder (MDD). The present study extends this literature by investigating the temporal dynamics of expectancy, and by exploring whether expectancy during treatment is linked to differential outcomes across treatment modalities, for both optimistic versus pessimistic expectancy. Methods A total of 104 patients with M...
Published on Mar 12, 2019in Human Psychopharmacology-clinical and Experimental2.27
Laura M. Juliano18
Estimated H-index: 18
(AU: American University),
Peter G. Kardel (AU: American University)+ 2 AuthorsKathryn C. Edwards (AU: American University)
Published on Feb 20, 2019in Challenges
Susan L. Prescott57
Estimated H-index: 57
Alan C. Logan19
Estimated H-index: 19
The emerging concept of planetary health—defined as the interdependent vitality of all natural and anthropogenic ecosystems (social, political, and otherwise)—emphasizes that the health of human civilization is intricately connected to the health of natural systems within the Earth’s biosphere. In the clinical setting, narrative medicine underscores the importance of absorbing, reflecting upon, and responding to the narratives—the stories—conveyed by patients. Education and interventions using t...
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