<p>The goal of this paper is to explore a set of epistemological and ontological issues regarding the historical and philosophical role of placebos in the contested history of antidepressants. Starting from an account of the dual nature of the placebo as both an epistemic and a therapeutic tool, and against the background of the heated debates on the efficacy of second-generation antidepressants, I propose two related arguments. First, I argue that placebos as controls played a crucial but paradoxical role in the rise of so-called evidence-based approaches to depression. Second, I discuss how current research on placebo effects puts into question some of the most crucial assumptions of psychiatric technoscience regarding the ontology of affective experiences. Ultimately, this paper aims to probe discussions around placebos, placebo effects, and the status of depression both as a diagnostic category and a lived experience.</p>