title: Nocebo effects in the treatment of major depression: results from an individual study participant-level meta-analysis of the placebo arm of duloxetine clinical trials.
abstract: BACKGROUND
  The nocebo effect, when a harmless substance creates harmful effects in a person who takes it, is a clinically salient yet seldom studied phenomenon that may be associated with poorer treatment outcomes, perceived adverse events, and treatment discontinuation. The covert presence of nocebo responders in clinical trials may contribute to outcome variance in both placebo and active treatment arms for important primary and secondary endpoints. Nocebo effects are thought to be driven by expectancy and conditioning.
  
  
  METHODS
  This study analyzed pooled clinical trial data in the placebo arms of controlled trials of antidepressant medications to investigate variables associated with the emergence of adverse outcomes in placebo-treated participants (N = 2,457). Specifically, we examined treatment-emergent adverse events (TEAEs) and discontinuation in placebo-treated individuals. Trials were commenced between 1993 and 2010 as studies of duloxetine versus active comparator and/or placebo.
  
  
  RESULTS
  TEAEs were reported by 1,569 placebo-treated participants (63.9%), with 115 (4.7%) discontinuing from the studies due to TEAEs and 274 (11.2%) showing worsening of Hamilton Depression Rating Scale total score during placebo treatment. There was specifically no evidence to support the expectancy hypothesis, that reported TEAEs were influenced by adverse effects described in the clinical trials participant information and consent forms, or the conditioning hypothesis, that reported TEAEs would be influenced by adverse effect profiles of previous antidepressant medications used by these study participants. There was some evidence to suggest that people who had previously used complementary medications were more likely to report TEAEs. Variables specific to individual studies were the strongest predictors of TEAEs.
  
  
  CONCLUSIONS
  In this study, TEAEs were very common among placebo-treated clinical trial participants. Unexpectedly, there was no evidence to associate TEAEs with adverse clinical outcomes, nor were the conditioning or expectancy hypotheses supported by these data.
  
  
  CONCLUSIONS
  The nocebo effect is a common, covert, and poorly understood driver of clinical outcomes that requires further investigation.
authors.affiliation: Swanston Centre-Barwon Health, PO Box 281, Geelong, Victoria 3220, Australia seetald@barwonhealth.org.au.
authors.forename: Seetal
authors.initials: S
authors.lastname: Dodd
authors.forename: Alexander
authors.initials: A
authors.lastname: Schacht
authors.forename: Katarina
authors.initials: K
authors.lastname: Kelin
authors.forename: Héctor
authors.initials: H
authors.lastname: Dueñas
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Reed
authors.forename: Lana J
authors.initials: LJ
authors.lastname: Williams
authors.forename: Frances H
authors.initials: FH
authors.lastname: Quirk
authors.forename: Gin S
authors.initials: GS
authors.lastname: Malhi
authors.forename: Michael
authors.initials: M
authors.lastname: Berk
mesh_terms: D000928:Antidepressive Agents / Q000627:therapeutic use*; D018849:Controlled Clinical Trials as Topic / Q000706:statistics & numerical data*; D003865:Major Depressive Disorder / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D000068736:Duloxetine Hydrochloride; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D064786:Nocebo Effect; D013876:Thiophenes / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000928:Antidepressive Agents; D013876:Thiophenes; D000068736:Duloxetine Hydrochloride