A mega-analysis of fixed-dose trials reveals dose-dependency and a rapid onset of action for the antidepressant effect of three selective serotonin reuptake inhibitors
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The possible dose-dependency for the antidepressant effect of selective serotonin reuptake inhibitors (SSRIs) remains controversial. We believe we have conducted the first comprehensive patient-level mega-analysis exploring this issue, one incentive being to address the possibility that inclusion of low-dose arms in previous meta-analyses may have caused an underestimation of the efficacy of these drugs. All company-sponsored, acute-phase, placebo-controlled, fixed-dose trials using the Hamilton Depression Rating Scale (HDRS) and conducted to evaluate the effect of citalopram, paroxetine or sertraline in adult major depression were included (11 trials, n=2859 patients). The single-item depressed mood, which has proven a more sensitive measure to detect an antidepressant signal than the sum score of all HDRS items, was designated the primary effect parameter. Doses below or at the lower end of the usually recommended dose range (citalopram: 10-20 mg, paroxetine: 10 mg; sertraline: 50 mg) were superior to placebo but inferior to higher doses, hence confirming a dose-dependency to be at hand. In contrast, among doses above these, there was no indication of a dose-response relationship. The effect size (ES) after exclusion of suboptimal doses was of a more respectable magnitude (0.5) than that usually attributed to the antidepressant effect of the SSRIs. In conclusion, the observation that low doses are less effective than higher ones challenges the oft-cited view that the effect of the SSRIs is not dose-dependent and hence not caused by a specific, pharmacological antidepressant action. Moreover, we suggest that inclusion of suboptimal doses in previous meta-analyses has led to an underestimation of the efficacy of these drugs.
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The validity of the HDRS has been extensively criticized.
“and its validity has been extensively criticized (42, 43).”
From Total Sleep Deprivation Followed by Bright Light Therapy as Rapid Relief for Depression: A Pragmatic Randomized Controlled Trial (2021) · cites this paper as [42]
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- Authors
- Hieronymus, F., Nilsson, S., & Eriksson, E.
- Affiliations
- University of Gothenburg (SE)
- Chalmers University of Technology (SE)
- Corresponding author
- Eriksson, E
- Venue
- Translational Psychiatry
- Published
- 2016-06-07
- Volume
- 6
- Issue
- 6
- Pages
- e834-e834
- ISSN
- 2158-3188 (ISSN-L)
- PMC
- PMC4931602
- OpenAlex
- W2412709103
- Cited by
- 100
- References
- 31
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 7 · 2023: 6 · 2022: 10 · 2021: 18 · 2020: 13 · 2019: 15 · 2018: 5 · 2017: 8 · 2016: 5
- FWCI
- 8.90
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Translational Psychiatry (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Chalmers Publication Library (Chalmers University of Technology) (submittedVersion)
- Chalmers Research (Chalmers University of Technology) (submittedVersion)
- Funders
- Pfizer
- Sahlgrenska Universitetssjukhuset
- H. Lundbeck A/S
- Medical Research Council
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- selective serotonin reuptake inhibitors, antidepressant efficacy, dose-response relationship, major depressive disorder, citalopram, paroxetine, sertraline, onset of action, depressive mood, Hamilton Depression Rating Scale
- MeSH terms
- Adult, Depressive Disorder, Major, Major Depressive Disorder, Dose-Response Relationship, Drug, Humans, Citalopram, Randomized Controlled Trials as Topic, Treatment Outcome, Selective Serotonin Reuptake Inhibitors, Paroxetine, Sertraline
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