Beyond control in psychiatric research: systematic review and meta-analysis of placebo treatment responses across major psychiatric conditions in citalopram and escitalopram RCTs

Vollständiger Abstract

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Background Placebos have historically been used as comparative tools in randomised controlled trials (RCTs), but their therapeutic effect, particularly in psychiatric conditions, warrant a more detailed exploration to improve research design and clinical practice. Aims This systematic review and meta-analysis examines the factors influencing placebo treatment effects across major psychiatric disorders, including depression, anxiety disorders, obsessive–compulsive disorder (OCD) and post-traumatic stress disorder (PTSD). Method This PROSPERO registered systematic review and meta-analysis followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to identify RCTs with at least one placebo and one medication arm (citalopram or escitalopram), across four major groups of psychiatric conditions. Data extraction focused on study characteristics, methodology, target condition, participant demographics and outcome measurements. Cohen’s d effect sizes for placebo and medication groups were calculated, with random-effects model meta-analyses performed to assess heterogeneity and their correlates. Results The review included 80 studies with 312 outcome measures, involving 19 776 participants (7 to 91 years old). A large placebo response was observed (effect size: 1.01; 95% CI: 0.93–1.10) with significant heterogeneity ( I 2 : 99.61%). Significant differences in placebo responses were noted across clinical conditions, independent of the medication type. PTSD and depressive disorders exhibited the highest placebo effect size (1.14 and 1.02, respectively), whereas OCD showed the lowest (effect size: 0.62, P < 0.01). Anxiety disorders displayed a moderately large placebo effect size (0.86), with significant variability among anxiety disorder subclasses, specifically noting the lowest placebo effect size in specific phobia (0.23, P < 0.01). The medication effect size (1.43) also demonstrated considerable heterogeneity ( I 2 : 99.76%) but was not significantly different across psychiatric conditions ( P = 0.61). Placebo response magnitude was larger in studies with more study arms ( b : 0.181, P < 0.01) and younger mean age of the participant ( b : −0.010, P < 0.01). Moreover, clinician-rated outcomes versus patient self-reports (effect size: 1.07 v . 0.76, P < 0.01), multicentre studies ( p < 0.01) and using intention-to-treat data (effect size: 1.08 v . 0.86, P = 0.01) were associated with larger placebo effect size. Conclusions This study used a unique approach to examine placebo responses from the same interventions across multiple major psychiatric disorders. We found substantial placebo responses across psychiatric conditions and significant heterogeneity, influenced by a range of study-related and demographic factors. The findings underscore the complexity of placebo responses and highlight the importance of considering these variances in both research design and clinical translation.