Differences in Adverse Effect Reporting in Placebo Groups in SSRI and Tricyclic Antidepressant Trials: A Systematic Review and Meta-Analysis
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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Significantly more profound adverse effects were reported in TCA-placebo groups compared with SSRI-placebo groups.
“significantly more profound adverse effects were reported in TCA-placebo groups compared with SSRI-placebo groups.”
From Addressing the Side Effects of Contemporary Antidepressant Drugs: A Comprehensive Review (2018) · cites this paper as [106]
Adverse effect profiles between SSRIs and TCAs are prone to systematic expectation influences.
“adverse effect profiles between SSRIs and TCAs are prone to systematic expectation influences.”
From Addressing the Side Effects of Contemporary Antidepressant Drugs: A Comprehensive Review (2018) · cites this paper as [106]
Dry mouth, drowsiness, constipation, and sexual problems were more frequent in the placebo group with the TCAs study than the placebo group of the SSRIs study.
“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) were more frequent in the placebo group with the TCAs study than the placebo group or the SSRIs study.”
From Addressing the Side Effects of Contemporary Antidepressant Drugs: A Comprehensive Review (2018) · cites this paper as [106]
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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
- Semantic Scholar
- 50b250c59bddc89685a35b4cffa7ab9cf1b7a1e4
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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