Mechanisms of the placebo effect in pain and psychiatric disorders

Holmes, R Davis; Tiwari, Arun; Kennedy, James L.

doi:10.1038/tpj.2016.15

Cited by 36 publications

(27 citation statements)

References 129 publications

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“…Although the small number of subjects does not allow us to estimate the frequency of placebo responders in the population, our finding of one in five agrees with estimates from the pain literature suggesting that about 30% of patients respond to placebo with a measurable effect [18,19]. …”

Section: Discussionsupporting

confidence: 82%

The Effect of Aerosol Saline on Laboratory-Induced Dyspnea

O’Donnell

Lansing

Schwartzstein

et al. 2016

Lung

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Purpose In the ‘placebo arm’ of a recent study we found that aerosol saline (sham treatment) produced substantial relief of laboratory-induced dyspnea (Breathing Discomfort – BD) in nearly half the subjects. The sham intervention included a physiological change, and instructions to subjects could have produced expectation of dyspnea relief. In the present study we attempted to discover whether the response to sham aerosol was driven by behavioral or physiological aspects of the intervention. Methods Dyspnea (air hunger) was evoked by constraining tidal volume during graded hypercapnia. We measured Petco2 vs BD relationship before and after aerosol saline. To minimize subjects’ expectations of dyspnea relief, participants in were clearly instructed that we would only deliver saline aerosol. In Protocol 1, we delivered aerosol saline with a ventilator (mimicking our prior study); in Protocol 2, we delivered aerosol without a ventilator. Results Administration of aerosol saline had little effect on BD in this group of subjects with one exception: one subject experienced appreciable reduction in BD in Protocol 1. This treatment effect was less in Protocol 2. The two most likely explanations are a) that procedures surrounding ventilator administration of aerosol produced a psychological placebo treatment effect even though the subject knew a drug was not given, b) there were behavioral changes in breathing undetected by our measurements of respiratory flow and volume that altered the subjects comfort. Conclusion When the expectation of treatment effect is minimized, a significant reduction in dyspnea in response to saline placebo is uncommon but not impossible.

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Section: Discussionsupporting

confidence: 82%

The Effect of Aerosol Saline on Laboratory-Induced Dyspnea

O’Donnell

Lansing

Schwartzstein

et al. 2016

Lung

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“…Among individual factors, low pretreatment symptom severity has been associated with higher likelihood of placebo response [16,17]. However, other factors such as gender and age, while significant in venlafaxine versus placebo studies [18], did not replicate in a meta-analysis by Holmes et al [19]. The neurobiological basis of the placebo response is characterized by an increase in the metabolic activity of the frontal and striatal cortical regions [20] and increased endogenous opioid release in the subgenual anterior cingulate cortex, nucleus accumbens, midline thalamus, and amygdala [21,22].…”

Section: Introductionmentioning

confidence: 84%

“…The individual items are summed to measure depression severity [none (< 6), mild (6-13), moderate (14)(15)(16)(17)(18), severe (19)(20)(21)(22)(23), and very severe (> 23)] [27]. In the EMBARC trial, the HAMD 17 was administered at each study visit (baseline and weeks 1, 2, 3, 4, 6, and 8 of stage 1).…”

Section: Outcomementioning

confidence: 99%

A Novel Strategy to Identify Placebo Responders: Prediction Index of Clinical and Biological Markers in the EMBARC Trial

Trivedi

South

Rush³

et al. 2018

Psychother Psychosom

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Background: One in three clinical trial patients with major depressive disorder report symptomatic improvement with placebo. Strategies to mitigate the effect of placebo responses have focused on modifying study design with variable success. Identifying and excluding or controlling for individuals with a high likelihood of responding to placebo may improve clinical trial efficiency and avoid unnecessary medication trials. Methods: Participants included those assigned to the placebo arm (n = 141) of the Establishing Moderators and Biosignatures for Antidepressant Response in Clinical Care (EMBARC) trial. The elastic net was used to evaluate 283 baseline clinical, behavioral, imaging, and electrophysiological variables to identify the most robust yet parsimonious features that predicted depression severity at the end of the double-blind 8-week trial. Variables retained in at least 50% of the 100 imputed data sets were used in a Bayesian multiple linear regression model to simultaneously predict the probabilities of response and remission. Results: Lower baseline depression severity, younger age, absence of melancholic features or history of physical abuse, less anxious arousal, less anhedonia, less neuroticism, and higher average theta current density in the rostral anterior cingulate predicted a higher likelihood of improvement with placebo. The Bayesian model predicted remission and response with an actionable degree of accuracy (both AUC > 0.73). An interactive calculator was developed predicting the likelihood of placebo response at the individual level. Conclusion: Easy-to-measure clinical, behavioral, and electrophysiological assessments can be used to identify placebo responders with a high degree of accuracy. Development of this calculator based on these findings can be used to identify potential placebo responders.

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“…Furthermore, few studies include or adjust for placebo response, which has been shown to account for 67.6% of the efficacy observed in antidepressant treatment (Rief et al 2009). Placebo response is a major concern for drug trials, as well as for biomarker investigations, and likely has a significant genetic component (Walsh et al 2002;Tiwari et al 2013;Holmes et al 2016). Importantly, objective criteria are not available to support the diagnosis of MDD based on clinical criteria only, resulting in the risk of clinician-dependent variability in terms of both diagnosis type and severity.…”

Section: Introductionmentioning

confidence: 99%

Consensus paper of the WFSBP Task Force on Genetics: Genetics, epigenetics and gene expression markers of major depressive disorder and antidepressant response

Fabbri

Hosák

Mößner

et al. 2016

The World Journal of Biological Psychiatry

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Major depressive disorder (MDD) is a heritable disease with a heavy personal and socio-economic burden. Antidepressants of different classes are prescribed to treat MDD, but reliable and reproducible markers of efficacy are not available for clinical use. Further complicating treatment, the diagnosis of MDD is not guided by objective criteria, resulting in the risk of under-or overtreatment. A number of markers of MDD and antidepressant response have been investigated at the genetic, epigenetic, gene expression and protein levels. Polymorphisms in genes involved in anti-depressant metabolism (cytochrome P450 isoenzymes), antidepressant transport (ABCB1), glucocorticoid signalling (FKBP5) and serotonin neurotransmission (SLC6A4 and HTR2A) were among those included in the first pharmacogenetic assays that have been tested for clinical applicability. The results of these investigations were encouraging when examining patient-outcome improvement. Furthermore, a nine-serum biomarker panel (including BDNF, cortisol and soluble TNF-a receptor type II) showed good sensitivity and specificity in differentiating between MDD and healthy controls. These first diagnostic and response-predictive tests for MDD provided a source of optimism for future clinical applications. However, such findings should be considered very carefully because their benefit/cost ratio and clinical indications were not clearly demonstrated. Future tests may include combinations of different types of biomarkers and be specific for MDD subtypes or pathological dimensions.

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Mechanisms of the placebo effect in pain and psychiatric disorders

Cited by 36 publications

References 129 publications

The Effect of Aerosol Saline on Laboratory-Induced Dyspnea

The Effect of Aerosol Saline on Laboratory-Induced Dyspnea

A Novel Strategy to Identify Placebo Responders: Prediction Index of Clinical and Biological Markers in the EMBARC Trial

Consensus paper of the WFSBP Task Force on Genetics: Genetics, epigenetics and gene expression markers of major depressive disorder and antidepressant response

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