Why Has the Antidepressant–Placebo Difference in Antidepressant Clinical Trials Diminished over the Past Three Decades?
Open accessAbstract
The increasing rate of failure of antidepressant clinical trials has led to the assertion that antidepressants do not have meaningful clinical benefits. Our hypothesis was that the decrease in antidepressant–placebo differences in antidepressant clinical trials over the past three decades could be explained by changes in research design features rather than a lack of potency of the antidepressants being tested. We collected data from 130 double blind placebo controlled antidepressant clinical trials conducted between 1981 and 2008 that included 35,122 depressed patients with 23,157 patients assigned to antidepressants and 11,965 assigned to placebo. We conducted a hierarchical regression analysis of change in HAM‐D scores in antidepressant and placebo groups separately with year of publication, and research design features as independent variables. We found that antidepressant–placebo differences in antidepressant clinical trials have declined markedly over the past three decades. Decline in change scores in the antidepressant group was related to mean total baseline HAM‐D scores in the trial, the version of HAM‐D used, and duration of trial. Similarly, decline in change scores in the placebo group was related to mean total baseline HAM‐D scores, duration of trial, and year of publication. Overall, we found that antidepressant–placebo differences were statistically significantly higher in trials that used HAM‐D 21 rather than HAM‐D 17 and in trials that lasted 6 weeks or less. These data suggest that, apart from the efficacy of the antidepressant being tested, factors such as baseline HAM‐D scores, version of HAM‐D used and duration of trial have a significant impact on outcome. As such a clinician's assessment of the usefulness of antidepressants should not be based solely on the results of such clinical trials. In the meantime there is a need for continuing research to improve the methodology of antidepressant clinical trials. These data suggest that many aspects of the design of antidepressant trials have a significant impact on outcome. Further, these data suggest that the results of more recent placebo controlled trials do not adequately inform clinicians about the potential utility of antidepressants.
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Antidepressant-placebo response differences have decreased over the past few decades, in part due to recruitment of less severely ill patients into trials.
“For instance, antidepressant–placebo response differences have decreased over the past few decades, in part due to recruitment of less severely ill patients into trials (Khan et al. 2010).”
From Predicting relapse after antidepressant withdrawal – a systematic review (2017) · cites this paper as Khan et al. 2010
The Discussion reports that antidepressant–placebo differences declined and that lower mean baseline HAM-D severity could contribute to the decline. But it cautions that newer trials used different HAM-D versions and says the analysis could not assess changes in trial populations; it does not establish that recruitment of less severely ill patients caused the decline. (LLM, conf=0.84)
Experimental — accuracy not yet measuredMethodological issues have been previously proposed as possible reasons for negative clinical trials in MDD.
“methodological issues, including aspects of study design and conduct (i.e., issues with identifying appropriate patients, large multi-site trials, multiple raters) that have been previously proposed as possible reasons for negative clinical trials in MDD”
From A randomized, double-blind, duloxetine-referenced study comparing efficacy and tolerability of 2 fixed doses of vortioxetine in the acute treatment of adults with MDD (2015) · cites this paper as Khan et al., 2010
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“For instance, antidepressant–placebo response differences have decreased over the past few decades, in part due to recruitment of less severely ill patients into trials (Khan et al. 2010).”
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- Authors
- Khan, A., Bhat, A., Kolts, R., Thase, M. E., & Brown, W.
- Affiliations
- Northwest Clinical Research Center (US)
- Eastern Washington University (US)
- University of Pennsylvania (US)
- Brown University (US)
- Corresponding author
- Khan, Arif
- Venue
- CNS Neuroscience & Therapeutics
- Publisher
- Wiley
- Published
- 2010-07
- Volume
- 16
- Issue
- 4
- Pages
- 217-226
- ISSN
- 1755-5930 (ISSN-L)
- 1755-5949
- PMC
- PMC6493812
- OpenAlex
- W2159271064
- Cited by
- 78
- References
- 16
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 2 · 2023: 1 · 2022: 3 · 2021: 6 · 2020: 6 · 2019: 4 · 2018: 9 · 2017: 1 · 2016: 7 · 2015: 13 · 2014: 6 · 2013: 2 · 2012: 6
- FWCI
- 3.29
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- public-domain
- onlinelibrary.wiley.com/termsAndConditions#vor (vor)
- Locations
- CNS Neuroscience & Therapeutics (publishedVersion, public-domain)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cognitive Neuroscience › Pain Management and Placebo Effect
- Social Sciences › Psychology › Clinical Psychology › Psychotherapy Techniques and Applications
- Keywords
- antidepressants, clinical trial design, depression, Hamilton Depression Rating Scale, HAM-D-17, trial duration, baseline depression severity, placebo response
- MeSH terms
- Antidepressive Agents, Clinical Trials as Topic, Depression, Humans, Placebos, Psychiatric Status Rating Scales, Regression Analysis, Retrospective Studies, Treatment Outcome
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