Cited by 202Meta-analysis and systematic reviewsPharmaceutical industry and healthcareStatistical Methods in Clinical Trials

Differences in Adverse Effect Reporting in Placebo Groups in SSRI and Tricyclic Antidepressant Trials: A Systematic Review and Meta-Analysis

Rief, Winfried, Nestoriuc, Yvonne, von Lilienfeld-Toal, Anna, Dogan, Imis, Schreiber, Franziska, Hofmann, Stefan G., Barsky, Arthur J., Avorn, Jerry·2009·Drug Safety

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 placebocontrolled 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'.

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Crossref · 10.2165/11316580-000000000-00000

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Authors
Rief, W., Nestoriuc, Y., von Lilienfeld-Toal, A., Dogan, I., Schreiber, F., Hofmann, S. G., Barsky, A. J., & Avorn, J.
Affiliations
  • Philipps University of Marburg (DE)
  • Boston University (US)
  • Brigham and Women's Hospital (US)
Corresponding author
Rief, Winfried
Venue
Drug Safety
Published
2009-11
Volume
32
Issue
11
Pages
1041-1056
ISSN
0114-5916 (ISSN-L)
OpenAlex
W59643826
Cited by
202
References
192
Citations by year
2026: 3 · 2025: 6 · 2024: 11 · 2023: 6 · 2022: 15 · 2021: 14 · 2020: 12 · 2019: 18 · 2018: 16 · 2017: 11 · 2016: 17 · 2015: 15 · 2014: 16 · 2013: 11 · 2012: 16
FWCI
12.82
Type
journal article
Language
en
Open access
closed
Locations
  • Drug Safety (publishedVersion)
  • PubMed (publishedVersion)
  • Radboud Repository (Radboud University) (submittedVersion)
Topics
  • Social Sciences › Decision Sciences › Statistics, Probability and Uncertainty › Meta-analysis and systematic reviews
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmaceutical industry and healthcare
  • Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Clinical Trials
Keywords
placebo group, selective serotonin reuptake inhibitors, tricyclic antidepressants, investigator bias, xerostomia, sleepiness, constipation, sexual dysfunction, antidepressant trials
MeSH terms
Antidepressive Agents, Tricyclic, Humans, Regression Analysis, Research Personnel, Bias, Randomized Controlled Trials as Topic, Selective Serotonin Reuptake Inhibitors, Antidepressive Agents, Second-Generation, Research Subjects

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