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Original Investigation
November 10, 2021

Association of Single-Blind Placebo Run-in Periods With the Placebo Response in Randomized Clinical Trials of Antidepressants: A Systematic Review and Meta-analysis

Author Affiliations
  • 1School of Psychology, University of Sydney, Sydney, New South Wales, Australia
  • 2Department of Psychology, eCentreClinic, Macquarie University, Sydney, New South Wales, Australia
JAMA Psychiatry. Published online November 10, 2021. doi:10.1001/jamapsychiatry.2021.3204
Key Points

Question  Is the use of a placebo run-in (PRI) period associated with different outcomes among randomized clinical trials (RCTs) of antidepressants?

Findings  In this systematic review and meta-analysis of 347 RCTs of antidepressants comprising 89 183 participants, the use of PRI periods was associated with a lower placebo and drug response but was not associated with the drug-placebo difference.

Meaning  This study suggests that the use of PRI periods is common in RCTs of antidepressants, despite offering no apparent benefits to RCT outcomes; given the risks and costs of PRI periods, their practice should be ceased.

Abstract

Importance  Single-blind placebo run-in (PRI) periods are common in randomized clinical trials (RCTs) of treatment for depression. They aim to increase sensitivity to detect drug effects; however, the association of PRI periods with study outcomes remains unclear. This is concerning given the costs of PRI periods to patients and investigators.

Objective  To examine the association of the use of PRI periods with the placebo response, drug response, and drug-placebo difference among RCTs of antidepressants.

Data Sources  MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and PsycINFO, as well as repositories of unpublished studies, were systematically searched up to July 2021.

Study Selection  Included studies were double-blind, placebo-controlled RCTs of antidepressant medication among adults with depressive disorders.

Data Extraction and Synthesis  Data were extracted into a coding sheet, including the characteristics of studies, the characteristics of PRI periods, and the outcomes of studies.

Main Outcomes and Measures  Study outcomes were the primary depression symptom measure reported by the RCT. These outcomes were used to calculate effect sizes (Hedges g) of the within-group drug response and placebo response as well as the drug-placebo difference. Random-effects meta-analysis was used to calculate effect sizes, and subgroup analyses were used to compare outcomes depending on use of PRI periods.

Results  A total of 347 trials (representing 89 183 participants) were included; 174 studies (50%) reported using a single-blind PRI period. Response outcome data were available for 189 studies. Studies using PRI periods reported a smaller placebo response (g= 1.05 [95% CI, 0.98-1.11]; I2 = 82%) than studies that did not use a PRI period (g= 1.15 [95% CI, 1.09-1.21]; I2 = 81%; P = .02). Subgroup analysis showed a larger drug response size among studies that did not use a PRI period (g= 1.55 [95% CI, 1.49-1.61]; I2 = 85%) than those that did use a PRI period (g= 1.42 [95% CI, 1.36-1.48]; I2 = 81%; P = .001). The drug-placebo difference did not differ by use of PRI periods (g= 0.33 [95% CI, 0.29-0.38]; I2 = 47% for use of a PRI period vs g= 0.34 [95% CI, 0.30-0.38]; I2 = 54% for no use of PRI periods; P = .92). The likelihood of response to drug vs placebo also did not differ between studies that used a PRI period (odds ratio, 1.89 [95% CI, 1.76-2.03]) and those that did not use a PRI period (odds ratio, 1.77 [95% CI, 1.65-1.89]; P = .18).

Conclusions and Relevance  This study suggests that RCTs using PRI periods yield smaller within-group changes across both placebo and drug groups compared with RCTs without PRI periods. The reduction in effect size across groups was equivalent in magnitude. Consequently, PRI studies do not observe larger drug-placebo differences, suggesting that they do not increase trial sensitivity. As such, given the resources and probable deception required and risk to external validity, the practice of using PRI periods in RCTs of antidepressants should be ended.

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