Re-evaluation of Significance and the Implications of Placebo Effect in Antidepressant Therapy.

Abstract

Placebo was conceived as an epistemological tool to control for incidental factors that could influence investigated outcomes (1, 2). As a phenomenon, placebo has been conceptualized in many different ways, both theoretically and practically, although a generally accepted definition is still to be devised (3). In clinical research setting it is, however, helpful to distinguish placebo response from placebo effect. Placebo response is considered to be the composite change observed in individuals after administration of placebo, consisting of different aspects, such as natural course of the disease and methodological artifacts, as well as the placebo effect itself (4, 5). Placebo effect would therefore be the change observed in individuals after controlling for natural course of the disorder, methodological aspects, and the effect linked to treatment-specific features (i.e., antidepressant verum) (1). In other words, placebo responses may or may not include placebo effect as genuine psychobiosocial effect that is usually attributed to various features of treatment situation and contexts (5). Recent findings consistently show a modest average effect (a mean effect size of d = 0.30) of antidepressants above placebo in short-term treatment of adult depression (6, 7). This could be interpreted as strong evidence of a modest effect. Whether this effect on outcome measures, that are rather limited and subjective, is clinically meaningful remains an open question (8). Issues of true long-term efficacy, safety and cost-effectiveness of antidepressant drugs still loom over the horizon (8–11). Still, these recent findings pose interesting questions, since similarly consistent findings have been published showing a large and highly variable placebo effect in studies aiming to prove true efficacy of antidepressants (12, 13). In other words, participants in antidepressant studies that are receiving, at least from a theoretical point, a supposedly inherently neutral intervention (one that should be lacking known, relevant, and specific features), show substantial and consistent improvement across different study designs and contexts.