Drug Safety

, Volume 32, Issue 11, pp 1041–1056

Differences in Adverse Effect Reporting in Placebo Groups in SSRI and Tricyclic Antidepressant Trials

A Systematic Review and Meta-Analysis
  • Winfried Rief
  • Yvonne Nestoriuc
  • Anna von Lilienfeld-Toal
  • Imis Dogan
  • Franziska Schreiber
  • Stefan G. Hofmann
  • Arthur J. Barsky
  • Jerry Avorn
Original Research Article

DOI: 10.2165/11316580-000000000-00000

Cite this article as:
Rief, W., Nestoriuc, Y., von Lilienfeld-Toal, A. et al. Drug-Safety (2009) 32: 1041. doi:10.2165/11316580-000000000-00000

Abstract

Background: Biases in adverse effect reporting in randomized controlled trials (RCTs) [e.g. due to investigator expectations or assessment quality] can be quantified by studying the rates of adverse events reported in the placebo arms of such trials.

Objective: We compared the rates of adverse effects reported in the placebo arms of tricyclic antidepressant (TCA) trials and placebo arms of selective serotonin reuptake inhibitor (SSRI) trials.

Methods: We conducted a literature search for RCTs across PUBMED, Scopus and the Cochrane Central Register of Controlled Trials (CENTRAL). Only studies allowing adverse effect analysis were included. Publication year ranged from 1981 to 2007.

Results: Our systematic review and meta-analysis included 143 placebo-controlled RCTs and data from 12 742 patients. Only 21% of studies used structured and systematic adverse effect ascertainment strategies. The way in which trials recorded adverse events influenced the rate of adverse effects substantially. Systematic assessment led to higher rates than less systematic assessment. Far more adverse effects were reported in TCA-placebo groups compared with SSRI-placebo groups, e.g. dry mouth (odds ratio [OR] = 3.5; 95% CI 2.9, 4.2); drowsiness (OR = 2.7; 95% CI 2.2, 3.4); constipation (OR = 2.7; 95% CI 2.1,3.6); sexual problems (OR =2.3; 95% CI 1.5,3.5). Regression analyses controlling for various influencing factors confirmed the results.

Conclusion: Adverse effect profiles reported in clinical trials are strongly influenced by expectations from investigators and patients. This difference cannot be attributed to ascertainment methods. Adverse effect patterns of the drug group are closely related to adverse effects of the placebo group. These results question the validity of the assumption that adverse effects in placebo groups reflect the ‘drug-unspecific effects’.

Supplementary material

40264_2012_32111041_MOESM1_ESM.pdf (118 kb)
Supplementary material, approximately 121 KB.

Copyright information

© Adis Data Information BV 2009

Authors and Affiliations

  • Winfried Rief
    • 1
  • Yvonne Nestoriuc
    • 1
  • Anna von Lilienfeld-Toal
    • 1
  • Imis Dogan
    • 1
  • Franziska Schreiber
    • 1
  • Stefan G. Hofmann
    • 2
  • Arthur J. Barsky
    • 3
  • Jerry Avorn
    • 4
  1. 1.Clinical Psychology and PsychotherapyPhilipps University of MarburgMarburgGermany
  2. 2.Boston UniversityBostonUSA
  3. 3.Department of Psychiatry, Harvard Medical SchoolBrigham and Women’s HospitalBostonUSA
  4. 4.Division of Pharmacoepidemiology and PharmacoeconomicsBrigham and Women’s Hospital and Harvard Medical SchoolBostonUSA