Study protocol for a randomized controlled trial comparing mindfulness-based cognitive therapy with maintenance anti-depressant treatment in the prevention of depressive relapse/recurrence: the PREVENT trial

Background

The total effect of a medication is the sum of its drug effect, placebo effect (meaning response), and their possible interaction. Current interpretation of clinical trials' results assumes no interaction. Demonstrating such an interaction has been difficult due to lack of an appropriate study design.

Methods

180 adults were randomized to caffeine (300 mg) or placebo groups. Each group received the assigned intervention described by the investigators as caffeine or placebo, in a randomized crossover design. 4-hour-area-under-the-curve of energy, sleepiness, nausea (on 100 mm visual analog scales), and systolic blood pressure levels as well as caffeine pharmacokinetics (in 22 volunteers nested in the caffeine group) were determined. Caffeine drug, placebo, placebo-plus-interaction, and total effects were estimated by comparing outcomes after, receiving caffeine described as placebo to receiving placebo described as placebo, receiving placebo described as caffeine or placebo, receiving caffeine described as caffeine or placebo, and receiving caffeine described as caffeine to receiving placebo described as placebo, respectively.

Results

The placebo effect on area-under-the-curve of energy (mean difference) and sleepiness (geometric mean ratio) was larger than placebo-plus-interaction effect (16.6 95% CI, 4.1 to 29.0] vs. 8.4 -4.2 to 21.0] mm*hr and 0.58 0.39 to 0.86] vs. 0.69 0.49 to 0.97], respectively), similar in size to drug effect (20.8 3.8 to 37.8] mm*hr and 0.49 0.30 to 0.91], respectively), and its combination with the later was larger than total caffeine effect (29.5 11.9 to 47.1] mm*hr and 0.37 0.22 to 0.64]). Placebo-plus-interaction effect increased caffeine terminal half-life by 0.40 0.12 to 0.68] hr (P = 0.007).

Conclusions

Drug and placebo effects of a medication may be less than additive, which influences the interpretation of clinical trials. The placebo effect may increase active drug terminal half-life, a novel mechanism of placebo action.

Trial Registration

ClinicalTrials.gov identification number - NCT00426010.