A Model of Placebo Response in Antidepressant Clinical Trials

Rutherford, Bret R.; Roose, Steven P.

doi:10.1176/appi.ajp.2012.12040474

Cited by 224 publications

(226 citation statements)

References 61 publications

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“…31 The magnitude of the expectancy effect was apparent in a withdrawal study in which patients were injected with analgesia either in plain view or without the patient's knowledge in a cohort of healthy patients with experimentally induced pain and a second cohort of post-operative patients. In this evaluation, hidden injection resulted in significantly less pain relief in both experiments.…”

Section: Expectancy and The Pre-cebo Effectmentioning

confidence: 99%

Placebo Effect in Clinical Trial Design for Irritable Bowel Syndrome

Shah¹,

Pimentel²

2014

J Neurogastroenterol Motil

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Ongoing efforts to improve clinical trial design in irritable bowel syndrome have been hindered by high placebo response rates and ineffective outcome measures. We assessed established strategies to minimize placebo effect as well as the various approaches to placebo effect which can affect trial design. These include genetic markers such as catechol-O-methyltransferase, opioidergic and dopaminergic neurobiologic theory, pre-cebo effect centered on expectancy theory, and side effect unblinding grounded on conditioning theory. We reviewed endpoints used in the study of IBS over the past decade including adequate relief and subjective global relief, emphasizing their weaknesses in fully evaluating the IBS condition, specifically their motility effects based on functional net value and relative benefit-harm based on dropouts due to adverse events. The focus of this review is to highlight ongoing efforts to improve clinical trial design which can lead to better outcomes in a real-world setting.

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Section: Expectancy and The Pre-cebo Effectmentioning

confidence: 99%

Placebo Effect in Clinical Trial Design for Irritable Bowel Syndrome

Shah¹,

Pimentel²

2014

J Neurogastroenterol Motil

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“…The factors that affect placebo response in adults with depressive disorders (Sneed et al 2008;Papakostas and Fava 2009;Iovieno and Papakostas 2012;Rutherford et al 2012;Rutherford and Roose 2013) and anxiety disorders (Khan et al 2005;Stein et al 2006;Feltner et al 2009;Rutherford et al 2015) have been extensively evaluated; however, relatively limited information is available regarding the characterization of placebo response in pediatric patients with anxiety (Cohen et al 2010). In anxious adults, Stein et al (2006) have observed that placebo response for generalized anxiety disorder (GAD) was greater in studies conducted in Europe and in fixed-dose studies and was affected by lower baseline symptom severity, but was unaffected by gender and age.…”

Section: Introductionmentioning

confidence: 99%

Placebo Response in Pediatric Anxiety Disorders: Implications for Clinical Trial Design and Interpretation

Dobson

2016

Journal of Child and Adolescent Psychopharmacology

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Objectives: The characterization and prediction of placebo response in clinical trials of youth with anxiety disorders have received little attention, despite the critical effects of placebo response rate on the success or failure of clinical trials. With this in mind, we sought to examine the factors that predict or influence placebo response in randomized controlled trials of youth with anxiety disorders. Methods: Prospective, randomized, parallel-group controlled trials of psychopharmacologic interventions in pediatric patients with anxiety disorders were identified using a search of PubMed/Medline (1966. Weighted least squares regression models and z-tests were utilized to examine the impact of continuous and categorical variables, respectively, on placebo response. These variables included demographic (e.g., age, percent white, percent female), clinical (e.g., baseline symptom severity), and trial characteristics (sample size, duration, funding). Finally, the relationship between the class of comparator medication and placebo response rate was examined using a multiple comparison for proportions test.Results: The analyses of data from 14 trials involving 2230 patients and 9 medications reveal that higher placebo response rates were associated with a greater number of study sites ( p = 0.013) and fewer patients per site ( p < 0.008), while placebo dropout rates increased with more recent publication ( p = 0.01) and were positively associated with the number of study visits ( p < 0.02). Lower placebo response rates were associated with federally funded studies (z = -4.61, p < 0.001), studies conducted in the United States (z = 1.81, p < 0.035), and with an increased likelihood of detecting a significant effect on the primary outcome (z = 4.58, p < 0.0001). Additionally, studies, in which the majority of patients (>60%) had a diagnosis of social anxiety disorder, exhibited lower placebo response rates ( p < 0.001). Finally, for trials, effect size has decreased over time ( p = 0.004). Conclusions: Important trial-specific factors affect placebo response and placebo dropout in youth with anxiety disorders and have pragmatic implications for the conduct and design of clinical trials and raise the possibility that limiting the number of sites while maximizing the number of patients per site could enhance the ability to detect medication-placebo differences.

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“…However, more prosaic reasons for nonresponse are evident. Antidepressant response rates have declined by a couple of points every decade that they have been in use, such that the underlying dynamic is less likely to be pharmacological than related to the pattern of use [22]. The category of depression has widened over the past decades, and has incorporated less unwell patients with increasingly diverse sources of unhappiness.…”

Section: Introductionmentioning

confidence: 99%

The Integrative Management of Treatment-Resistant Depression: A Comprehensive Review and Perspectives

Carvalho

Berk

Hyphantis

et al. 2014

Psychother Psychosom

102

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Background: Major depressive disorder is a prevalent and disabling illness. Notwithstanding numerous advances in the pharmacological treatment of depression, approximately 70% of patients do not remit after first-line antidepressant treatment. Methods: The MEDLINE/PubMed, EMBASE and ClinicalTrials.gov electronic databases were searched from inception to October 1, 2013, for randomized controlled trials (RCT), relevant open-label trials, meta-analyses and ongoing trials of pharmacological and psychotherapeutic approaches to treatment-resistant depression (TRD). Results: Switching to a different antidepressant is a useful option following nonresponse to a first-line agent. Although widely used in clinical practice, there is limited evidence to support antidepressant combination for TRD. Notwithstanding evidence for lithium or T₃ augmentation to be successful in TRD, most studies were carried out when participants were treated with tricyclic antidepressants (TCA). Of the available strategies to augment the response to new-generation antidepressants, the use of some atypical antipsychotics is best supported by evidence. Several novel therapeutic options are currently discussed. Evidence suggests that cognitive therapy (CT) is an effective strategy for TRD. Conclusions: The success of switching to a different antidepressant following a first-line agent is supported by evidence, but there is limited evidence for effective combination strategies. Lithium and T₃ augmentation of TCA have the strongest evidence base for successful treatment of TRD. The use of augmentation of newer-generation antidepressants with atypical antipsychotics is supported by a growing evidence base. Current evidence supports CT as an effective strategy for TRD. There is a need for additional large-scale RCT of TRD. The development of new antidepressants targeting novel pathways opens a promising perspective for the management of TRD.

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A Model of Placebo Response in Antidepressant Clinical Trials

Cited by 224 publications

References 61 publications

Placebo Effect in Clinical Trial Design for Irritable Bowel Syndrome

Placebo Effect in Clinical Trial Design for Irritable Bowel Syndrome

Placebo Response in Pediatric Anxiety Disorders: Implications for Clinical Trial Design and Interpretation

The Integrative Management of Treatment-Resistant Depression: A Comprehensive Review and Perspectives

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