Is superiority to placebo the most appropriate measure of efficacy in trials of novel psychotropic medications?

Huneke, Nathan T. M.

doi:10.1016/j.euroneuro.2022.06.003

Cited by 6 publications

(7 citation statements)

References 10 publications

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“…Additionally, there is evidence that the administration of placebos can lead to genuine physiological changes in biological systems, including the immune, dopaminergic, and endogenous opioid systems ( De La Fuente-Fernandez, 2001 ; Benedetti et al, 2011 ; Albring et al, 2012 ; Wager and Atlas, 2015 ). Since placebo effect size is changeable and factors that influence it are not fully understood, it is currently challenging to predict how large it will be in any given clinical trial ( Huneke, 2022 ). This can affect the ability of a clinical trial to distinguish efficacy of active treatment from placebo, hindering psychotropic drug development over time ( Enck et al, 2013 ; Huneke et al, 2020a ; Huneke, 2022 ; Correll et al, 2023 ).…”

Section: Introductionmentioning

confidence: 99%

“…Since placebo effect size is changeable and factors that influence it are not fully understood, it is currently challenging to predict how large it will be in any given clinical trial ( Huneke, 2022 ). This can affect the ability of a clinical trial to distinguish efficacy of active treatment from placebo, hindering psychotropic drug development over time ( Enck et al, 2013 ; Huneke et al, 2020a ; Huneke, 2022 ; Correll et al, 2023 ). Therefore, improved understanding of the mechanisms that contribute to placebo responses in anxiety disorders is needed.…”

Section: Introductionmentioning

confidence: 99%

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Placebo Effects Are Small on Average in the 7.5% CO2 Inhalational Model of Generalized Anxiety

Huneke,

Cross,

Fagan

et al. 2024

International Journal of Neuropsychopharmacology

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Background Anxiety disorders are highly prevalent and socio-economically costly. Novel pharmacological treatments for these disorders are needed as many patients do not respond to current agents or experience unwanted side-effects. However, a barrier to treatment development is the variable and large placebo response rate seen in trials of novel anxiolytics. Despite this, the mechanisms that drive placebo responses in anxiety disorders have been little investigated, possibly due to low availability of convenient experimental paradigms. We aimed to develop and test a novel protocol for inducing placebo anxiolysis in the 7.5% CO2 inhalational model of generalised anxiety in healthy volunteers. Methods Following a baseline 20-minute CO2 challenge, 32 healthy volunteers were administered a placebo intranasal spray labelled as either the anxiolytic ‘lorazepam’ or ‘saline’. Following this, participants surreptitiously underwent a 20-minute inhalation of normal air. Post-conditioning, a second dose of the placebo was administered, after which participants completed another CO2 challenge. Results Participants administered sham ‘lorazepam’ reported significant positive expectations of reduced anxiety (p = 0.001) but there was no group-level placebo effect on anxiety following CO2 challenge post-conditioning (p’s > 0.350). Surprisingly, we found many participants exhibited unexpected worsening of anxiety, despite positive expectations. Conclusions Contrary to our hypothesis, our novel paradigm did not induce a placebo response, on average. It is possible that effects of 7.5% CO2 inhalation on prefrontal cortex function, or behaviour in line with a Bayesian predictive coding framework, attenuated the effect of expectations on subsequent placebo response. Future studies are needed to explore these possibilities.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Placebo Effects Are Small on Average in the 7.5% CO2 Inhalational Model of Generalized Anxiety

Huneke,

Cross,

Fagan

et al. 2024

International Journal of Neuropsychopharmacology

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“…Given the high prevalence of mental health disorders and their significant socioeconomic burden,29–31 there is a need to develop more effective and safer treatments. However, the magnitude of the placebo response in randomised controlled trials (RCTs) may be substantial, which can affect their interpretation 32 33. As an example, approximately 35%–40% of patients in antidepressant trials respond to placebo 34.…”

Section: Introductionmentioning

confidence: 99%

Placebo effects in mental health disorders: protocol for an umbrella review

Huneke,

Amin,

Baldwin

et al. 2023

BMJ Open

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IntroductionGiven the high prevalence of mental health disorders and their significant socioeconomic burden, there is a need to develop improved treatments, and to evaluate them through placebo-controlled trials. However, the magnitude of the placebo response in randomised controlled trials to test medications may be substantial, affecting their interpretation. Therefore, improved understanding of the patient, trial and mental disorder factors that influence placebo responses would inform clinical trial design to better detect active treatment effects. There is a growing literature exploring the placebo response within specific mental health disorders, but no overarching synthesis of this research has been produced to date. We present a protocol for an umbrella review of systematic reviews and/or meta-analyses in which we aim to understand the effect size and potential predictors of placebo response within, and across, mental health disorders.Methods and analysisWe will systematically search databases (Medline, PsycINFO, EMBASE+EMBASE Classic, Web of Knowledge) for systematic reviews and/or meta-analyses that report placebo effect size in clinical trials in patients with mental health disorders (initial search date 23 October 2022). Screening of abstracts and full texts will be done in pairs. We will extract data to qualitatively examine how placebo effect size varies across mental health disorders. We also plan to qualitatively summarise predictors of increased placebo response identified either quantitatively (eg, through meta-regression) or qualitatively. Risk of bias will be assessed using the AMSTAR-2 tool. We aim to not only summarise the current literature but also to identify gaps in knowledge and generate further hypotheses.Ethics and disseminationWe do not believe there are any specific ethical considerations relevant to this study. We will publish the results in a peer-reviewed journal.

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“…Sponsors should be prepared to justify their exclusion criteria, focusing on comorbidities that are expected to complicate interpretation of the study or decrease the likelihood of detecting an effect (e.g., active substance use disorders). The paper suggests requiring post-marketing studies to examine drug efficacy in "real world" patients; however, the FDA does not have the statutory authority to require such studies 7 .…”

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confidence: 99%

“…Nevertheless, some hurdles are still there. An obvious one is the increasing difficulties in signal detection with placebo‐controlled trials 7 and the limited alternatives to placebo‐controlled designs 8 , as well as problems related to the representativeness of the patients enrolled in those trials and the generalizability of the findings 9 . Regulatory agencies are not consistent across the world in their requirements for marketing approval of medications, and this carries increased costs and inequalities.…”

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confidence: 99%

Tough times never last too long: the future of psychopharmacology

Vieta

2023

World Psychiatry

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Is superiority to placebo the most appropriate measure of efficacy in trials of novel psychotropic medications?

Cited by 6 publications

References 10 publications

Placebo Effects Are Small on Average in the 7.5% CO2 Inhalational Model of Generalized Anxiety

Placebo Effects Are Small on Average in the 7.5% CO2 Inhalational Model of Generalized Anxiety

Placebo effects in mental health disorders: protocol for an umbrella review

Tough times never last too long: the future of psychopharmacology

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