SOURCE: Papakostas GI, et al. The nature of placebo response in clinical studies of major depressive disorder. J Clin Psychiatry 2015;76:456-466.

In randomized, placebo-controlled medication trials for depression, meta-analyses indicate that substantial improvement occurs on placebo, averaging about 30% (range = 12-52%). Although one might expect that as placebo response rates rise, active treatment response rates should also increase, this has not been found to be the case. Hence, when placebo-responder rates are high, the likelihood of confirming a favorable response from active treatment diminishes.

Investigation into the factors that affect placebo responses have discerned numerous potential contributors, including illness severity and chronicity, participant age, duration of the trial, and frequency of follow-up. Indeed, it has been posited that persons identified as depressed might be better categorized as “biologic” vs “environmental,” with the latter group demonstrating a more potent response to placebo. There has been some suggestion in the literature that clinical trials in major depression have a substantial (up to 4 weeks) run-in phase, to better identify placebo responders.

Papakostas et al direct out attention to the possibility that we may have committed a statistical Type 2 error in reference to pharmacology trials in depression: we may have dismissed an intervention when indeed it was actually effective, to some degree due to an overly robust placebo response. Clinical trials in major depression may benefit from attending to issues that tend to magnify placebo response.