Declining differences in response rates with antidepressants versus placebo: a modest proposal for another contributing cause

J Psychiatr Pract. 2013 May;19(3):227-33. doi: 10.1097/01.pra.0000430506.37144.d1.


This column discusses declining differences in response rates between sequentially introduced selective serotonin reuptake inhibitors (SSRI) and placebo. Although discussions of this phenomenon in the literature have largely focused on increasing placebo response rates, the author proposes that another factor may be responsible. That factor is an order effect, meaning that response rates have been declining as a function of the number of SSRIs on the market when the next SSRI is in development. The rationale is that the pool of potential clinical trial participants likely to respond to a drug with this mechanism of action (MOA) becomes progressively smaller with the introduction of each new agent with the same MOA, because many patients will already have been treat- ed and responded to an earlier member of the class. This phenomenon is not limited to the SSRIs but generalizes to any class of treatments that shares the same MOA.

Publication types

  • Review

MeSH terms

  • Antidepressive Agents / supply & distribution
  • Antidepressive Agents / therapeutic use*
  • Depressive Disorder / diagnosis
  • Depressive Disorder / drug therapy*
  • Depressive Disorder / psychology
  • Depressive Disorder, Treatment-Resistant / diagnosis
  • Depressive Disorder, Treatment-Resistant / drug therapy
  • Depressive Disorder, Treatment-Resistant / psychology
  • Drug Approval
  • Drug Substitution
  • Drug Utilization / statistics & numerical data
  • Humans
  • Placebo Effect
  • Randomized Controlled Trials as Topic
  • Serotonin Uptake Inhibitors / supply & distribution
  • Serotonin Uptake Inhibitors / therapeutic use*
  • Treatment Outcome
  • United States
  • United States Food and Drug Administration


  • Antidepressive Agents
  • Serotonin Uptake Inhibitors