The effects of esketamine and treatment expectation in acute major depressive disorder (Expect): study protocol for a pharmacological fMRI study using a balanced placebo design

BACKGROUND: Major depressive disorder (MDD) is a highly prevalent (8–15%), severely disabling disorder and is associated with enormous socioeconomic impact. Antidepressant medication for the treatment of MDD has proven effective in RCTs; however, placebo response is also substantial. Given the potential benefits of modulating the placebo response in patient care and pharmacological research, understanding the mechanisms underlying placebo response is of high clinical relevance. The placebo response is mediated by treatment expectation, i.e. an individual’s belief about whether and how much they will improve as a consequence of their treatment. The mechanisms and moderators of treatment expectation effects in MDD are poorly understood. Initial brain imaging studies on placebo responses in MDD point towards the relevance of the lateral prefrontal cortex and the rostral anterior cingulate cortex (rACC). In this project, we will investigate the neural mechanisms underlying the antidepressant effects of treatment expectation associated with the fast-acting antidepressant esketamine in patients with MDD. Esketamine is an NMDA receptor antagonist inducing antidepressant effects within hours. METHODS: We will employ a fully balanced placebo design with the factors “treatment” (i.v. esketamine / placebo) and verbally induced “expectation” (high / low) combined with fMRI (resting state, emotion and reward processing paradigms) to investigate the psychological and neural mechanisms underlying the antidepressant effects of expectation, and how these interact with the pharmacological effects of esketamine. DISCUSSION: The insights gained by this project promise fundamental implications for clinical treatment and future drug trials. Unraveling the mechanisms underlying expectation effects on antidepressant treatment may inform (1) strategies to modulate these effects and thus improve assay sensitivity in RCTs and (2) novel treatment regiments aiming to maximize the synergistic effects of expectation and pharmacological treatment in the clinical care of patients with MDD. TRIAL REGISTRATION: This trial has been prospectively registered with the EU Clinical Trials Register: EudraCT-No.: 2020–000784-23 (November 17, 2020).