A regulatory Apologia--a review of placebo-controlled studies in regulatory submissions of new-generation antidepressants

Eur Neuropsychopharmacol. 2008 Sep;18(9):623-7. doi: 10.1016/j.euroneuro.2008.06.003. Epub 2008 Jul 14.


Data on percentage of patients experiencing a relevant response (>50% reduction of the baseline Hamilton Depression Scale (HAMD) score), average baseline severity and sample size were retrieved for all placebo-controlled studies in regulatory submissions of SSRIs and SNRIs between 1984 and 2003. Overall there was 16%-units (95% CI: 12; 20) more responders on active drug compared to placebo. There was no evidence of a diminishing magnitude of effect with lower severity at baseline. With one exception significant differences varying between 13.5 and 19.3%-units were demonstrated for the individual antidepressants. Statistically significant mean differences versus placebo in change in HAMD are not a proper basis for evaluation of clinical relevance and are not sufficient for approval. Differences in the percentage of patients experiencing a clinically relevant response should also be demonstrated. In this respect, the approved SSRIs and SNRIs were found superior to placebo, independent of severity of depression.

MeSH terms

  • Antidepressive Agents / standards
  • Antidepressive Agents / therapeutic use*
  • Clinical Trials as Topic / methods*
  • Depression / drug therapy*
  • Drug Approval / methods
  • Drug Approval / statistics & numerical data*
  • Humans
  • Placebos / therapeutic use*
  • Selective Serotonin Reuptake Inhibitors / therapeutic use
  • Serotonin Antagonists / therapeutic use
  • Severity of Illness Index


  • Antidepressive Agents
  • Placebos
  • Serotonin Antagonists
  • Serotonin Uptake Inhibitors