Comparative efficacy of placebos in short-term antidepressant trials for major depression: a secondary meta-analysis of placebo-controlled trials

BACKGROUND: The issue of unblinded outcome-assessors and patients has repeatedly been stressed as a flaw in allegedly double-blind antidepressant trials. Unblinding bias can for example result from a drug‘s marked side effects. If such unblinding bias is present for a given drug, then it might be expected that the placebos of that drug are rated significantly less effective than that of other antidepressants. METHODS: To test this hypothesis, the present exploratory analysis conducted a Bayesian network meta-analysis (NMA) comparing the efficacy of 19 different placebos in placebo-controlled trials provided in the dataset by Cipriani et al. (Lancet 2018; 391: 1357–66). Primary outcome was efficacy (continuous) estimated on the standardized mean difference (SMD) scale and defined as the pre-post change on the Hamilton Depression scale (HAMD-17), on which information was available in N = 258 trials. RESULTS: Comparative placebo ranking suggested mirtazapine-placebo (SMD -2.0 [− 5.0–1.0 95% CrI]) to be the most, and amitriptyline- (SMD 1.2 [− 1.6–3.9 95% CrI]) and trazodone- (SMD 2.1 [− 0.9–5.2 95% CrI]) placebos to be the least effective placebos. Other placebos suggested to be more effective than amitriptyline- and trazodone-placebos (based on 95% CrIs excluding zero) were citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, sertraline, and venlafaxine placebos. These NMA results were corroborated by the observation that the relative efficacy between drug and placebo was considerably larger for amitriptyline and trazodone than for instance mirtazapine, duloxetine, and venlafaxine, supported by a small and insignificant correlation between drug-efficacy and placebo-efficacy (r = − 0.202, p = 0.408). DISCUSSION: The present exploratory NMA indicates that distinguishable side effects of older drugs may unblind outcome-assessors thus resulting in overestimation of the average drug-placebo difference and underrating bias in placebo-arms, particularly for the older antidepressant drugs amitriptyline and trazodone. If confirmed in prospective studies, these findings suggest that efficacy rankings for antidepressants are susceptible to bias and should be considered unreliable or misleading. The analysis is limited by the focus on the single-comparison placebos (76%, i.e., placebos assessed in two-arm trials), since double-comparison placebos (25%, i.e., placebos assessed in three-arm trials) are hard to interpret and therefore not included in the present interpretation. Another limitation is the problem of multiplicity, which was only approximately accounted for in the Bayesian NMA by modelling treatment effects as exchangeable.