Beyond Control in Psychiatric Research: A Systematic Review and Meta-Analysis of Placebo Treatment Responses across Major Psychiatric Conditions in Citalopram and Escitalopram RCTs

Background: Placebos have historically been used as comparative tools in Randomized Clinical Trials (RCTs), but their therapeutic effect, particularly in psychiatric conditions, warrant a more detailed exploration to improve research design and clinical practice. 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). Methods: This PROSPERO registered systematic review and meta-analysis followed PRISMA guidelines to identify RCTs with at least one placebo and one medication arm (citalopram or escitalopram), across four major group 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 314 outcome measures, involving 19,441 participants (7 to 91 years old). A large placebo response was observed (ES: 1.01; 95% CI: 0.93-1.10) with significant heterogeneity (I2: 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 ES (1.14 and 1.02, respectively), whereas OCD showed the lowest (ES: 0.62, P<0.01). Anxiety disorders displayed a moderately large placebo ES (0.86), with significant variability among anxiety disorder sub-classes, specifically noting the lowest placebo ES in Specific Phobia (0.23, P<0.01). The medication effect size (ES: 1.43) also demonstrated considerable heterogeneity (I2: 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 vs. patient self-reports (ES: 1.07 vs. 0.76, P<0.01) and using intention-to-treat data (Es: 1.08 vs. 0.86, P=0.01) were associated with larger placebo ES. Conclusion: 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.