Placebo run-in periods offer no benefits to antidepressant RCTs

Randomized clinical trials of antidepressants often contain placebo run-in periods despite their apparent lack of benefits to outcome, according to results of a systematic review and meta-analysis published in JAMA Psychiatry.

“Placebo run-in periods [PRIs] have been used for many decades; however, their theoretical and/or empirical basis is unclear,” Amelia J. Scott, PhD, of the School of Psychology at the University of Sydney in New South Wales, and colleagues wrote. “Early studies suggest that the use of PRI periods was based largely on intuition; some presumed that eliminating early placebo responders would lower placebo response rates after randomization, thereby increasing the difference between placebo and active treatments.”

The researchers aimed to investigate the link between the use of PRI periods and placebo response, drug response and the drug-placebo difference among randomized clinical trials (RCTs) of antidepressants. They systematically searched up to July three databases and repositories of unpublished studies, and they included double-blind, placebo-controlled RCTs of antidepressants among adults with depressive disorders. Primary depression symptoms measure reported via the RCT served as the study outcomes, which the researchers used to calculate effect sizes of the within-group drug response and placebo response, in addition to the drug-placebo difference. Further, they used random-effects meta-analysis to calculate effect sizes and subgroup analyses to compare outcomes depending on PRI period use.

Scott and colleagues included 347 trials featuring 89,183 participants, with 174 studies (50%) reporting using a single-blind PRI period. A total of 189 studies had response outcome data available. Those that used PRI periods had a smaller placebo response than those that did not use them. Subgroup analysis revealed a larger drug response size among studies that did not have a PRI period compared with those that did. Use of PRI periods did not appear to affect the drug-placebo difference. Studies that used a PRI period vs. those that did not did not differ in the likelihood of response to drug vs. placebo.

“Although our results reveal that the use of PRI periods in RCTs of antidepressants carries no benefits, they also provide strong reassurance that eliminating this practice comes at no cost to trial outcomes,” Scott and colleagues wrote. “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.”