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Single-Blind Placebo Run-In Periods Do Not Increase Trial Sensitivity

Utilizing placebo run-in (PRI) periods improves trial sensitivity, researchers found in a systematic review and meta-analysis published in JAMA Psychiatry.

The researchers searched MEDLINE, Embase, PsycINFO, and Cochrane databases through July 2021 for original double-blind, placebo-controlled randomized controlled trials of approved, regulated antidepressants that included adult participants with depressive disorder. They excluded studies of individuals with bipolar depression and those that involved adjunctive medication.

They identified 347 studies (89,183 participants) that met their criteria. Half used a single-blind PRI period, and 189 provided response outcome data.

Overall within-group Hedges g for drug response was 1.49 (I2  =84.27 τ2 = 0.10). Studies that did not use PRI period had larger drug response size (g = 1.55) compared with those that did (g = 1.42 P =.001).

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For placebo response, Hedges g was 1.10 (I2 = 82.29 τ2 = 0.07). It was higher among studies that did not use a PRI period (g = 1.15) than among those that did (g = 1.05 P =.02).

There was no significant difference in pooled drug response, placebo response or drug-placebo difference between studies that used a PRI period and those that did not.

“This systematic review and meta-analysis provides evidence to suggest that the use of PRI periods has no scientific basis in trials of antidepressants,” the researchers said.

“At the same time, PRI periods carry numerous costs and risks. Although our results reveal that the use of PRI periods in RCTs [Randomized Clinical Trials] of antidepressants carries no benefits, they also provide strong reassurance that eliminating this practice comes at no cost to trial outcomes. Our results highlight the importance of ongoing investigations into the conduct of RCTs and the risks associated with practices based merely on precedent or intuition.”


Scott AJ, Sharpe L, Quinn V, Colagiuri B. Association of single-blind placebo run-in periods with the placebo response in randomized clinical trials of antidepressants: a systematic review and meta-analysis. JAMA Psychiatry. Published online November 10, 2021. doi:10.1001/jamapsychiatry.2021.3204

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Source: Psychiatry Advisor