RESUMO
Background: Ketamine and esketamine offer a novel approach in the pharmacological treatment of major depressive disorder (MDD). This meta-analysis aimed to investigate the placebo response in double-blind, randomized controlled studies (RCTs) on patients with MDD receiving ketamine or esketamine. Methods: For this systematic review and meta-analysis Medline (PubMed), Cochrane Central Register of Controlled Trials (CENTRAL), PsycInfo and Embase databases were systematically searched for citations published up to March 17, 2023. A total number of 5017 abstracts was identified. Quality of the included trials was assessed with the Cochrane risk-of-bias tool. The meta-analysis was performed using a restricted maximum likelihood model. This study is registered with PROSPERO, number CRD42022377591. Results: A total number of 14 studies and 1100 participants (593 in the medication group and 507 in the placebo group) meeting the inclusion criteria were selected. We estimated the pooled effect sizes of the overall placebo (d pl = -1.85 [CI 95%: -2.9 to -0.79] and overall treatment (dtr = -2.57; [CI 95% -3.36 to -1.78]) response. The overall placebo response accounts for up to 72% of the overall treatment response. Furthermore, we performed subgroup analysis of 8 studies for the for the 7 days post-intervention timepoint. Seven days post-intervention the placebo response (d pl 7d = -1.98 [CI 95%: -3.26 to -0.69]) accounts for 66% of the treatment response (d tr 7d = - 3.01 [CI 95%, -4.28 to -1.74]). Conclusion: Ketamine and esketamine show large antidepressant effects. However, our findings suggest that the placebo response plays a significant role in the antidepressant response and should be used for the benefit of the patients in clinical practice. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42022377591.
RESUMO
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).
