Assessment of blinding in randomized controlled trials of antidepressants for depressive disorders 2000-2020: A systematic review and meta-analysis

Background In double-blind randomized controlled trials (RCTs) of antidepressants, blinding can be broken due to the apparent side effects, and unsuccessful blinding can lead to overestimation of effect sizes. New generation anti-depressants with less severe side effects may be less susceptible to broken blinding. However, successfulness of blinding in new generation antidepressant trials and its influence on trial effect size estimates remain unclear. Methods Extending a previous systematic review assessing blinding successfulness in psychiatric trials (2000-2010), we searched PubMed/Medline for double-blinded antidepressant RCTs (2010-2020) for trials assessing blinding success. Our primary outcome was the degree of blinding successfulness, measured as kappa statistics between guesses and true allocations. We used random-effects meta-analysis to synthesize studies. We used meta -regression and Pearson's r to examine the relationship between blinding success and effect sizes. This study is regis-tered with PROSPERO (CRD42021249973). Findings Among 154 eligible studies, 11 (7.1%) contained information on blinding assessment between 2010 and 2020. Five studies were added from the previous review, and altogether nine of the 16 studies provided usable data. Agreement in individual studies ranged from k=-0.14 to 0.38. The summary agreement between guesses and the truth was 0.21 (95% CI: 0.14 to 0.28) among patients and 0.17 (95% CI: 0.05 to 0.30) among assessors. Blinding success was not associated with effect size (patients: r= 0.37, p = 0.32; assessors: r= 0.28; p = 0.72). Meta-regression also failed to find a significant relationship between blinding success and depression effect sizes (b=0.06, p = 0.09). Interpretation Less than 10% of the antidepressant RCTs reported blinding assessment. The results in new genera-tion antidepressant trials indicated that patients and assessors were unlikely to be able to judge treatment allocation. There was little evidence that the extent of unblinding biased the effect size estimates of new generation antidepressants.