In double-blind randomized trials of ketamine and esketamine for major depressive disorder, the placebo response accounts for up to 72% of the overall treatment response. Across 14 studies with 1100 participants, the pooled effect size for placebo was -1.85, while the treatment effect was -2.57. Seven days after treatment, the placebo response accounted for 66% of the treatment response. Ketamine and esketamine show large antidepressant effects, but the placebo response plays a significant role and should be leveraged in clinical practice.
A study will investigate how treatment expectation influences the antidepressant effects of esketamine in patients with major depressive disorder (MDD). Using a fully balanced placebo design with factors of treatment (esketamine or placebo) and verbally induced expectation (high or low), combined with fMRI, the research aims to uncover the neural mechanisms—particularly in the lateral prefrontal cortex and rostral anterior cingulate cortex—underlying expectation effects and their interaction with esketamine's pharmacology. Insights may inform strategies to modulate placebo response in clinical trials and optimize treatment regimens that leverage expectation and drug synergy.