Assessment of blinding in randomized controlled trials of antidepressants for depressive disorders 2000-2020: A systematic review and meta-analysis
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Yi-Hsuan Lin1, Ethan Sahker1,2, Kiyomi Shinohara1
1Department of Health Promotion and Human Behavior, Kyoto University Graduate School of Medicine and School of Public Health, Kyoto, Japan.
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 antidepressants 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 registered 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 κ=-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 (β=0·06, p = 0·09).
Interpretation:
Less than 10% of the antidepressant RCTs reported blinding assessment. The results in new generation 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.
Funding:
None.
Insights
Blinding in antidepressant trials is often unsuccessful, but this does not appear to bias effect size estimates for new generation antidepressants. Less than 10% of studies assessed blinding success.
Area of Science:
- Psychiatry
- Clinical Trials
- Pharmacology
Background:
- Blinding in double-blind randomized controlled trials (RCTs) of antidepressants can be compromised by side effects, potentially inflating effect sizes.
- Newer antidepressants with milder side effects might be less prone to unblinding.
- The success rate of blinding in trials of new generation antidepressants and its impact on effect size estimates require further investigation.
Purpose of the Study:
- To assess the success of blinding in double-blind antidepressant RCTs published between 2010 and 2020.
- To determine the relationship between blinding success and effect size estimates in these trials.
Main Methods:
- A systematic review of PubMed/Medline was conducted for antidepressant RCTs (2010-2020) that assessed blinding success.
- Blinding success was measured using kappa statistics, with random-effects meta-analysis and meta-regression used to synthesize data and examine relationships.
- Data from a previous review (2000-2010) were incorporated.
Main Results:
- Only 7.1% of eligible studies (11 out of 154) reported blinding assessment.
- Summary agreement between guessed and true treatment allocations was low (kappa=0.21 for patients, kappa=0.17 for assessors).
- No significant association was found between blinding success and antidepressant effect sizes (patients: r=0.37, p=0.32; assessors: r=0.28, p=0.72; meta-regression: β=0.06, p=0.09).
Conclusions:
- A low proportion of antidepressant RCTs report blinding assessments.
- Patients and assessors in new generation antidepressant trials demonstrated limited ability to accurately guess treatment allocation.
- Evidence suggests that the degree of unblinding in these trials does not significantly bias effect size estimates.
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