Early score fluctuation and placebo response in a study of major depressive disorder

Targum, Steven D.; Cameron, Beth R.; Ferreira, Ludvina; Macdonald, I. D.

doi:10.1016/j.jpsychires.2019.11.014

Cited by 11 publications

(12 citation statements)

References 37 publications

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“…3 This phenomenon is a challenge for researchers; however, attention has begun to focus on trying to understand and quantify the magnitude of the placebo response. 1,2 In RCTs of non-treatment-resistant depression (non-TRD) in patients with MDD, [4][5][6][7][8][9][10][11][12][13][14] the placebo effect has been found to have a large magnitude and to be associated with several factors, although with some inconsistent findings. These factors have included later publication years, number of trial arms, multicenter setting, dosing schedule, increased length of the trial, sham device placement, the magnitude of active response, early score fluctuations, and inflation of baseline severity.…”

Section: Introductionmentioning

confidence: 99%

Magnitude of the Placebo Response Across Treatment Modalities Used for Treatment-Resistant Depression in Adults

et al. 2021

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IMPORTANCEThe placebo effect in depression clinical trials is a substantial factor associated with failure to establish efficacy of novel and repurposed treatments. However, the magnitude of the placebo effect and whether it differs across treatment modalities in treatment-resistant depression (TRD) is unclear.OBJECTIVE To examine the magnitude of the placebo effect in patients with TRD across different treatment modalities and its possible moderators. DATA SOURCESSearches were conducted on MEDLINE, Web of Science, and PsychInfo from inception to June 21, 2021. STUDY SELECTION Randomized clinical trials (RCTs) were included if they recruited patients with TRD and randomized them to a placebo or sham arm and a pharmacotherapy, brain stimulation, or psychotherapy arm. DATA EXTRACTION AND SYNTHESIS Independent reviewers used standard forms for data extraction and quality assessment. Random-effects analyses and standard pairwise meta-analyses were performed. MAIN OUTCOMES AND MEASURES The primary outcome was the Hedges g value for the reported depression scales. Secondary outcomes included moderators assessed via meta-regression and response and remission rates. Heterogeneity was assessed with the I 2 test, and publication bias was evaluated using the Egger test and a funnel plot. Cochrane Risk of Bias Tool was used to estimate risks. RESULTS Fifty RCTs were included involving various types of placebo or sham interventions with a total of 3228 participants (mean [SD] age, 45.8 [6.0] years; 1769 [54.8%] female). The pooledplacebo effect size for all modalities was large (g = 1.05; 95% CI, 0.91-1.1); the placebo effect size in RCTs of specific treatment modalities did not significantly differ. Similarly, response and remission rates associated with placebo were comparable across modalities. Heterogeneity was large. Three variables were associated with a larger placebo effect size: open-label prospective treatment before double-blind placebo randomization (β = 0.35; 95% CI, 0.11 to 0.59; P = .004), later year of publication (β = 0.03; 95% CI, 0.003 to 0.05; P = .03), and industry-sponsored trials (β = 0.34; 95% CI, 0.09 to 0.58; P = .007). The number of failed interventions was associated with the probability a smaller placebo effect size (β = −0.12; 95% CI, −0.23 to −0.01, P = .03). The Egger test result was not significant for small studies' effects. (continued) Key Points Question What is the placebo effect magnitude in different treatment modalities used for management of patients with treatment-resistant depression? Findings In this systematic review and meta-analysis of 3228 patients with treatment-resistant depression in 50 randomized clinical trials, the placebo effect size was large and consistent across treatment modalities. Response and remission rates associated with placebo effect were comparable across modalities.Meaning The findings of this study suggest a placebo effect size benchmark may be used to interpret the findings of past and future clinical trials.

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Section: Introductionmentioning

confidence: 99%

Magnitude of the Placebo Response Across Treatment Modalities Used for Treatment-Resistant Depression in Adults

et al. 2021

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“…The well-established 1.5 interquartile range (IQR) rule was used to define outlier IIV assessments as individual test scores falling outside quartile 3 + 1.5 IQR. The approach of identifying and removing patients who demonstrate highly variable assessment responses has been previously employed to examine treatment effects in mental illness, including schizophrenia and major depressive disorder [ 33 , 34 ].…”

Section: Methodsmentioning

confidence: 99%

Effectiveness of KarXT (xanomeline-trospium) for cognitive impairment in schizophrenia: post hoc analyses from a randomised, double-blind, placebo-controlled phase 2 study

Sauder¹,

Allen

Baker

et al. 2022

Transl Psychiatry

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The muscarinic receptor agonist xanomeline improved cognition in phase 2 trials in Alzheimer’s disease and schizophrenia. We present data on the effect of KarXT (xanomeline–trospium) on cognition in schizophrenia from the 5-week, randomised, double-blind, placebo-controlled EMERGENT-1 trial (NCT03697252). Analyses included 125 patients with computerised Cogstate Brief Battery (CBB) subtest scores at baseline and endpoint. A post hoc subgroup analysis evaluated the effects of KarXT on cognitive performance in patients with or without clinically meaningful cognitive impairment at baseline, and a separate outlier analysis excluded patients with excessive intraindividual variability (IIV) across cognitive subdomains. ANCOVA models assessed treatment effects for completers and impairment subgroups, with or without removal of outliers. Sample-wide, cognitive improvement was numerically but not statistically greater with KarXT (n = 60) than placebo (n = 65), p = 0.16. However, post hoc analyses showed 65 patients did not exhibit clinically meaningful cognitive impairment at baseline, while eight patients had implausibly high IIV at one or both timepoints. Significant treatment effects were observed after removing outliers (KarXT n = 54, placebo n = 63; p = 0.04). Despite the small sample size, a robust (d = 0.50) and significant effect was observed among patients with cognitive impairment (KarXT n = 23, placebo n = 37; p = 0.03). These effects did not appear to be related to improvement in PANSS total scores (linear regression, R2 = 0.03). Collectively, these findings suggest that KarXT may have a separable and meaningful impact on cognition, particularly among patients with cognitive impairment.

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“…Variables found to contribute to the placebo response include year of publication, baseline severity, probability of being allocated to placebo arm, number of clinic centres, dosing schedule, length of trial, the magnitude of active response, early score fluctuations and inflation of baseline severity. [2][3][4][5][6][7][8][9][10] The largest metaanalysis to date (252 studies, pooled n=26 324) reported that the placebo response rate of antidepressant medications has been stable over the last thirty years and ranges between 35% and 40%. 11 While the placebo response is extensively investigated in non-TRD, there is a paucity of research into the magnitude of the placebo response in TRD.…”

Section: Introductionmentioning

confidence: 99%

“…There have been several studies attempting to determine patient and study variables contributing to the placebo response in non-treatment-resistant depression (TRD). Variables found to contribute to the placebo response include year of publication, baseline severity, probability of being allocated to placebo arm, number of clinic centres, dosing schedule, length of trial, the magnitude of active response, early score fluctuations and inflation of baseline severity 2–10. The largest meta-analysis to date (252 studies, pooled n=26 324) reported that the placebo response rate of antidepressant medications has been stable over the last thirty years and ranges between 35% and 40% 11.…”

Section: Introductionmentioning

confidence: 99%

Protocol for a systematic review and meta-analysis of the placebo response in treatment-resistant depression: comparison of multiple treatment modalities

et al. 2021

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IntroductionThe high placebo response in depression treatment trials is a major contributing factor for randomised control trial failure to establish efficacy of novel or repurposed treatments in treatment-resistant depression (TRD) and major depressive disorder in general. Though there have been a number of meta-analyses and primary research studies evaluating the placebo response in non-TRD, placebo response in TRD is poorly understood. It is important to understand the placebo response of TRD as treatments are only moderately effective and up to 1/3 of patients will experience TRD.Methods and analysisWe will conduct a search of electronic databases (MEDLINE and PsychINFO) from inception to 24th January 2020 including randomised, placebo-controlled trials of pharmacological, somatic and psychological interventions for adults with TRD. TRD will be defined as a failure to respond to at least two interventions of adequate dose or duration. We will also search reference lists from review articles. We will perform several meta-analyses to quantify the placebo response for each treatment modality. Regression analysis will explore potential contributing demographic and clinical variables to the placebo response. We will use Cochrane risk of bias tool.Ethics and disseminationThere is no research ethics board approval required. The dissemination plan is to publish results in a peer-reviewed academic journal.PROSPERO registration number190 465.

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Early score fluctuation and placebo response in a study of major depressive disorder

Cited by 11 publications

References 37 publications

Magnitude of the Placebo Response Across Treatment Modalities Used for Treatment-Resistant Depression in Adults

Magnitude of the Placebo Response Across Treatment Modalities Used for Treatment-Resistant Depression in Adults

Effectiveness of KarXT (xanomeline-trospium) for cognitive impairment in schizophrenia: post hoc analyses from a randomised, double-blind, placebo-controlled phase 2 study

Protocol for a systematic review and meta-analysis of the placebo response in treatment-resistant depression: comparison of multiple treatment modalities

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