Significance of Participants’ Expectations in Managing the Placebo Effect in Antidepressant Research

Ćurković, Marko

doi:10.3389/fpsyt.2019.00713

Cited by 4 publications

(3 citation statements)

References 50 publications

(115 reference statements)

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“…Additionally, we note that a consistent picture regarding the predictive role of the active vs. placebo ratio emerges when we compare the findings from schizophrenia trials to the findings from other psychiatric disorders, especially major depression where the role of the active vs. placebo ratio is well-documented. 36 , 37 This predictor, therefore, can be conceived of as a general methodological factor across various disease conditions, whose effect is mediated by unspecific factors rather than by the symptoms of the disorder. We think that one of the most likely candidates for such an unspecific predictor can be the expectancy effect, which can enhance treatment effects via expectations from either the patient or the physician through the anticipation that the current treatment is efficacious.…”

Section: Discussionmentioning

confidence: 99%

Placebo Response in Trials of Negative Symptoms in Schizophrenia: A Critical Reassessment of the Evidence

Czobor

Kakuszi

Bitter

2022

Schizophrenia Bulletin

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Background Summarizing evidence from clinical trials of patients with schizophrenia with predominant or prominent negative symptoms (NS), a prior meta-analysis reported a large placebo effect in negative symptoms (Cohen’s d = 2.909). Assuming that such an effect was clinically not plausible, we performed a critical re-assessment and an update of the previous results with newly available data from add-on and monotherapy studies. Study Design Random-effect meta/regression analysis of trials that focused on predominant or prominent NS; and adopted a double-blind, randomized, placebo-controlled design. The final pooled meta-analytic database, based on the available add-on and monotherapy studies combined, included 24 publications containing data on a total of 25 studies (21 add-on, 4 monotherapy). Study Results The pooled overall estimate for the placebo effect from the primary analysis for all included studies had a medium effect size, with a Cohen’s d value of 0.6444 (SE = 0.091). The estimates were similar in the add-on and monotherapy studies. Meta-regression indicated that the high placebo response was significantly associated with clinical trial characteristics, including the high ratio of patients assigned to active vs. placebo treatment and short trial duration. Conclusions These results represent a major downward correction for a current effect size estimate of the placebo response in the negative symptoms of schizophrenia. Our findings also pinpoint certain clinical trial characteristics, which may serve as important predictors of the placebo response. The knowledge of these factors can have important implications for drug development and trial design for new drugs for negative symptoms of schizophrenia.

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Section: Discussionmentioning

confidence: 99%

Placebo Response in Trials of Negative Symptoms in Schizophrenia: A Critical Reassessment of the Evidence

Czobor

Kakuszi

Bitter

2022

Schizophrenia Bulletin

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“…The higher control responses in the ESK-NS trials and the expectation related control effect due to the switch to a new antidepressant and/or receipt of a new mechanistic treatment (ESK-NS vs AAPs) previously have been discussed elsewhere. 51 , 52 These design issues conceivably increase the challenge for an active treatment to surpass the higher control effect encountered in a trial design like that used in the ESK-NS pivotal trials. Taken together, the combined effects of these differences on the responses of both active treatment and control arms limit the validity of comparisons across drug types using the extant studies.…”

Section: Discussionmentioning

confidence: 99%

A Meta-Analysis of the Antidepressant Responses in Pivotal Trials on Esketamine Nasal Spray and Atypical Antipsychotics

Wang,

Chen,

et al. 2023

NDT

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Purpose This meta-analysis assessed whether atypical antipsychotics (AAPs) and esketamine nasal spray (ESK-NS), which are mechanistically distinct, differ in antidepressant outcomes. Patients and Methods Data were extracted from 12 trials of ESK-NS or AAPs in depressed patients (4276) with inadequate response or resistance to conventional antidepressants. Montgomery-Åsberg Depression Rating Scale (MADRS) score reductions from baseline and response rates (≥50% reduction) were analyzed. Results At endpoint, the estimated MADRS score reduction of pooled ESK-NS arms was greater than pooled AAP arms (+9.16 points, p < 0.0001). The reduction also was greater in the pooled control arms of the ESK-NS trials than the pooled control arms of the AAP trials (+7.57 points, p < 0.0001). The mean difference in the reductions between pooled ESK-NS and control arms was 1.87 points greater than that between pooled AAP and control arms, but this difference was not significant (95% CI: −4.49, 0.74, p = 0.16). Relative to their respective control arms, the mean difference in response rates was 25% for the pooled ESK-NS and 9% for the pooled AAP arms; the mean response rate was 16% greater in the pooled ESK-NS studies than the pooled AAP studies (p = 0.0004). Comparisons against specific AAPs showed mean differences in the MADRS score reductions at 1 week between the experimental and control arms that were numerically larger in the ESK-NS trials than in the aripiprazole trials (mean difference of 1.71 points, p = 0.06) and the brexpiprazole trials (mean difference of 2.05 points, p = 0.02). Conclusion The ESK-NS arms showed numerically larger MADRS score reductions at week-1 and endpoint, and a significantly larger response rate compared with AAP arms. Prospective studies involving direct comparisons are warranted to compare the relative efficacy between these treatment regimens.

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“…Expectation bias has also been shown to mediate placebo response in antidepressant clinical trials [ 56 ]. Strategies to manage and assess participant expectations may be implemented in trials moving forwards [ 56 , 57 ]; a potential informative way to predict expectation bias could be the use of participant/caregiver questionnaires.…”

Section: Additional Insights From the Balovaptan Clinical Development...mentioning

confidence: 99%

Large multicenter randomized trials in autism: key insights gained from the balovaptan clinical development program

et al. 2022

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Background Autism spectrum disorder (ASD) is a common and heterogeneous neurodevelopmental condition that is characterized by the core symptoms of social communication difficulties and restricted and repetitive behaviors. At present, there is an unmet medical need for therapies to ameliorate these core symptoms in order to improve quality of life of autistic individuals. However, several challenges are currently faced by the ASD community relating to the development of pharmacotherapies, namely in the conduct of clinical trials. Balovaptan is a V1a receptor antagonist that has been investigated to improve social communication difficulties in individuals with ASD. In this viewpoint, we draw upon our recent first-hand experiences of the balovaptan clinical development program to describe current challenges of ASD trials. Discussion points The balovaptan trials were conducted in a wide age range of individuals with ASD with the added complexities associated with international trials. When summarizing all three randomized trials of balovaptan, a placebo response was observed across several outcome measures. Placebo response was predicted by greater baseline symptom severity, online recruitment of participants, and less experienced or non-academic trial sites. We also highlight challenges relating to selection of outcome measures in ASD, the impact of baseline characteristics, and the role of expectation bias in influencing trial results. Conclusion Taken together, the balovaptan clinical development program has advanced our understanding of the key challenges facing ASD treatment research. The insights gained can be used to inform and improve the design of future clinical trials with the collective aim of developing efficacious therapies to support individuals with ASD.

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Significance of Participants’ Expectations in Managing the Placebo Effect in Antidepressant Research

Cited by 4 publications

References 50 publications

Placebo Response in Trials of Negative Symptoms in Schizophrenia: A Critical Reassessment of the Evidence

Placebo Response in Trials of Negative Symptoms in Schizophrenia: A Critical Reassessment of the Evidence

A Meta-Analysis of the Antidepressant Responses in Pivotal Trials on Esketamine Nasal Spray and Atypical Antipsychotics

Large multicenter randomized trials in autism: key insights gained from the balovaptan clinical development program

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