Abstract
BackgroundAssumptions underlying placebo controlled trials include that the placebo effect impacts on all study arms equally, and that treatment effects are additional to the placebo effect. However, these assumptions have recently been challenged, and different mechanisms may potentially be operating in the placebo and treatment arms. The objective of the current study was to explore the nature of placebo versus pharmacological effects by comparing predictors of the placebo response with predictors of the treatment response in a randomised, placebo-controlled trial of a phytotherapeutic combination for the treatment of menopausal symptoms. A substantial placebo response was observed but no significant difference in efficacy between the two arms.MethodsA post hoc analysis was conducted on data from 93 participants who completed this previously published study. Variables at baseline were investigated as potential predictors of the response on any of the endpoints of flushing, overall menopausal symptoms and depression. Focused tests were conducted using hierarchical linear regression analyses. Based on these findings, analyses were conducted for both groups separately. These findings are discussed in relation to existing literature on placebo effects.ResultsDistinct differences in predictors were observed between the placebo and active groups. A significant difference was found for study entry anxiety, and Greene Climacteric Scale (GCS) scores, on all three endpoints. Attitude to menopause was found to differ significantly between the two groups for GCS scores. Examination of the individual arms found anxiety at study entry to predict placebo response on all three outcome measures individually. In contrast, low anxiety was significantly associated with improvement in the active treatment group. None of the variables found to predict the placebo response was relevant to the treatment arm.ConclusionThis study was a post hoc analysis of predictors of the placebo versus treatment response. Whilst this study does not explore neurobiological mechanisms, these observations are consistent with the hypotheses that 'drug' effects and placebo effects are not necessarily additive, and that mutually exclusive mechanisms may be operating in the two arms. The need for more research in the area of mechanisms and mediators of placebo versus active responses is supported.Trial RegistrationInternational Clinical Trials Registry ISRCTN98972974.
Highlights
Assumptions underlying placebo controlled trials include that the placebo effect impacts on all study arms and that treatment effects are additional to the placebo effect
Overall menopausal symptoms measured on the Greene climacteric scale (GCS) and depressive symptoms measured on the Hamilton Depression Inventory (HDI), both well-validated widely available tools
A significant difference was found in the predictive ability of anxiety at study entry between the two arms for all three endpoints, flushes R2 = 0.41, Std. β = 0.43, p = 0.001; Greene Climacteric Scale (GCS) R2 = 0.29, Std. β = 0.45, p = 0.002; Hamilton Depression Inventory 17-item scale (HDI-17) scale R2 = 0.30, Std. β = 0.63, p < 0.001
Summary
Assumptions underlying placebo controlled trials include that the placebo effect impacts on all study arms and that treatment effects are additional to the placebo effect. It has been argued by Kirsch and colleagues [1] that it is not a logical necessity for the effects of the active treatment to be additive, or composed of the two components – the placebo effect and the specific treatment effect (see Figure 1) In support of their position they suggest that, if drug effects and placebo effects are additive, the pharmacological effect of antidepressant drugs must be quite small [1], since meta-analyses of antidepressant drugs have found that 65% – 80% of the response to the drug is duplicated in the placebo arm, including in long-term maintenance studies [2,3,4]. They proposed that the effects may be non-additive or only partially additive [1], suggesting different underlying mechanisms may be operating in the placebo and pharmacological treatment arms
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