Open-Label Placebo Effects in Reducing Depression Severity Among Adults with Major Depressive Disorder: A Systematic Review and Meta-Analysis of Early Evidence
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Abstract
Background: Open-label placebo (OLP) represents an intervention where patients knowingly receive inert treatments associated with clinical benefits. This approach has demonstrated efficacy across multiple medical conditions. Meanwhile, major depressive disorder (MDD) affects 280 million people worldwide, yet three-quarters receive no treatment, urging non-pharmacological approaches. Despite this high prevalence, there is scarce data on the potential of OLP intervention for MDD.
Objective: To determine whether OLP can meaningfully reduce depression scores in adults with MDD.
Methods: Following Cochrane methodology and PRISMA guidelines, six databases (Cochrane, PsycNet, PMC, ClinicalTrials.gov, Scopus, PubMed) were systematically reviewed including studies from up to May 5, 2025. Inclusion criteria encompassed randomized controlled trials (RCTs) examining OLP interventions in adults with MDD, measuring depression severity using validated scales. Studies were independently screened by multiple reviewers. Risk of bias was assessed using RoB2. A meta-analysis was conducted using post-intervention mean scores and standard deviations.
Results: From 1,886 screened records, 3 randomized controlled trials (n = 118; mean age 46.8 years; 78% female) met the inclusion. Trials were conducted in the USA, Israel, and Austria between 2012 and 2022, with sample sizes ranging from 20–60 participants. All compared open-label placebo (OLP) to treatment-as-usual or waitlist controls, using validated depression scales (HAM-D-17, QIDS-SR, BDI-II). Individual trial findings were mixed: one trial found significant symptom reduction with OLP plus cognitive-behavioral therapy, though the effect was small; two trials reported no overall between-group differences, although one showed improvement in patients with early-onset depression. A meta-analysis of two small trials at 4 weeks suggested a modest reduction in depressive symptoms favoring OLP (Hedges’s g = –0.43, 95% CI –0.83 to –0.04), although both individual trials were underpowered and did not reach statistical significance. Given the limited number of studies and high risk of bias, these findings should be interpreted as preliminary. Risk of bias was rated as some concerns in one study and high in two, primarily due to outcome measurement and missing data.
Conclusions: Current evidence from three small RCTs suggests that open-label placebo may be associated with modest short-term symptom improvement in adults with MDD; however, the evidence base is limited, heterogeneous, and at risk of bias. These findings should be considered preliminary and hypothesis-generating, and larger, methodologically rigorous trials are required before clinical recommendations can be made.