Influence of baseline severity on the effects of SSRIs in depression: an item-based, patient-level post-hoc analysis
Abstract
Background Reports claiming that antidepressants are effective only in patients with severe depression have affected treatment guidelines but these reports usually use a disputed measure of improvement, a decrease in the sum-score of the 17-item Hamilton Depression Rating Scale (HDRS-17), and are based on group-level rather than patient-level data.Method In this item-based, patient-level, post-hoc analysis, we pooled data from all completed, acute-phase, placebo-controlled, industry-sponsored, HDRS-based trials of the SSRIs citalopram, paroxetine, or sertraline in adult major depression. Patient-level data were pooled and subjected to item-based post-hoc analyses to assess the effect of baseline severity of depression on the response to treatment as assessed with HDRS-17 sum score, the depressed mood item of the HDRS, a six-item HDRS subscale (HDRS-6), and the remaining 11 HDRS items not included in this subscale (non-HDRS-6). Patients were defined as having non-severe depression if they had a baseline HDRS-17 sum score of 18 points or less and as having severe depression if they had a score of 27 points or more.Findings Our study population consisted of 8262 patients from 28 placebo-controlled SSRI trials. Participants were treated with either citalopram (n=744), paroxetine (n=2981), sertraline (n=1202), fluoxetine (active-control group; n=754), or placebo (n=2581). 654 patients were defined as having non-severe depression and 1377 as having severe depression. Patients with non-severe and severe depression did not differ with respect to SSRI-induced decrease in depressed mood and other HDRS symptoms belonging to the HDRS-6 subscale. However, after exclusion of patients with rare extreme baseline values, a positive association was seen between severity and efficacy when using HDRS-17 sum score as the effect parameter. This result was largely due to a more pronounced response to treatment with respect to non-HDRS-6 items in patients with severe depression than in those with non-severe depression. This outcome could be explained by non-HDRS-6 items, more so than HDRS-6 items, being more severe and prevalent at baseline in severe than in non-severe cases; hence, less room was left for improvement in these areas in patients with non-severe depression.Interpretation The use of an outcome measure that includes symptoms that rate low at baseline in patients with non-severe depression might result in the interpretation that SSRIs are ineffective in these patients. With respect to alleviation of HDRS-6 items, SSRIs appear to be as effective in patients with non-severe depression as in those with severe depression.Funding Swedish Medical Research Council, AFA Insurance, Swedish Brain Foundation, Sahlgrenska University Hospital (Avtal om Läkarutbildning och Forskning), Bertil Hållsten's Foundation, and Söderberg's Foundation.
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A more recent study found that the differential response of patients with different severity was due to larger improvement on non-core symptoms, and that baseline severity did not affect the efficacy for core depression symptoms.
“However, a more recent study (28) found that the differential response of patients with different severity was due to larger improvement on non-core symptoms, and that baseline severity did not affect the efficacy for core depression symptoms.”
Cites
Kirsch, I., Deacon, B. J., Huedo-Medina, T. B., Scoboria, A., Moore, T. J., & Johnson, B. T. (2008) · PLoS Medicine · doi:10.1371/journal.pmed.0050045 · Cited by 2,442 · see citing works
Antidepressant Drug Effects and Depression Severity: A Patient-Level Meta-analysis
Fournier, J. C., DeRubeis, R. J., Hollon, S. D., Dimidjian, S., Amsterdam, J. D., Shelton, R. C., & Fawcett, J. (2010) · JAMA · doi:10.1001/jama.2009.1943 · Cited by 2,009 · see citing works
The Hamilton Depression Rating Scale: Has the Gold Standard Become a Lead Weight?
Bagby, R. M., Ryder, A. G., Schuller, D. R., & Marshall, M. B. (2004) · American Journal of Psychiatry · doi:10.1176/appi.ajp.161.12.2163 · Cited by 1,148 · see citing works
THE TREATMENT OF DEPRESSIVE STATES WITH G 22355 (IMIPRAMINE HYDROCHLORIDE)
Kuhn, R. (1958) · American Journal of Psychiatry · doi:10.1176/ajp.115.5.459 · Cited by 615 · see citing works
QUANTITATIVE RATING OF DEPRESSIVE STATES
Bech, P., Gram, L. F., Dein, E., Jacobsen, O., Vitger, J., & Bolwig, T. G. (1975) · Acta Psychiatrica Scandinavica · doi:10.1111/j.1600-0447.1975.tb00002.x · Cited by 489 · see citing works
Khan, A., Leventhal, R. M., Khan, S. R., & Brown, W. A. (2002) · Journal of Clinical Psychopharmacology · doi:10.1097/00004714-200202000-00007 · Cited by 456 · see citing works
A Comparison of Depression Rating Scales
Kearns, N. P., Cruickshank, C. A., McGuigan, K. J., Riley, S., Shaw, S. P., & Snaith, R. P. (1982) · The British Journal of Psychiatry · doi:10.1192/bjp.141.1.45 · Cited by 273 · see citing works
Gibbons, R. D., Hur, K., Brown, C. H., Davis, J. M., & Mann, J. J. (2012) · Archives of General Psychiatry · doi:10.1001/archgenpsychiatry.2011.2044 · Cited by 271 · see citing works
Hieronymus, F., Emilsson, J. F., Nilsson, S., & Eriksson, E. (2015) · Molecular Psychiatry · doi:10.1038/mp.2015.53 · Cited by 204 · see citing works
Self-citationDepression, sleep physiology, and antidepressant drugs
Winokur, A., Gary, K. A., Rodner, S., Rae-Red, C., Fernando, A. T., & Szuba, M. P. (2001) · Depression and Anxiety · doi:10.1002/da.1043 · Cited by 176 · see citing works
Licht, R. W., Qvitzau, S., Allerup, P., & Bech, P. (2005) · Acta Psychiatrica Scandinavica · doi:10.1111/j.1600-0447.2004.00440.x · Cited by 120 · see citing works
Melander, H., Salmonson, T., Abadie, E., & van Zwieten-Boot, B. (2008) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2008.06.003 · Cited by 117 · see citing works
Hieronymus, F., Nilsson, S., & Eriksson, E. (2016) · Translational Psychiatry · doi:10.1038/tp.2016.104 · Cited by 100 · see citing works
Self-citationA study comparing paroxetine placebo and imipramine in depressed patients.
Feighner, J., Cohn, J., Fabre, L., Fieve, R., Mendels, J., Shrivastava, R., & Dunbar, G. (1993) · Journal of Affective Disorders · doi:10.1016/0165-0327(93)90035-i · Cited by 82 · see citing works
No role for initial severity on the efficacy of antidepressants: results of a multi-meta-analysis
Fountoulakis, K. Ν., Veroniki, A. A., Siamouli, M., & Möller, H. (2013) · Annals of General Psychiatry · doi:10.1186/1744-859x-12-26 · Cited by 66 · see citing works
Furukawa, T. A., Maruo, K., Noma, H., Tanaka, S., Imai, H., Shinohara, K., Ikeda, K., Yamawaki, S., Levine, S. Z., Goldberg, Y., et al. (2018) · Acta Psychiatrica Scandinavica · doi:10.1111/acps.12886 · Cited by 60 · see citing works
Rabinowitz, J., Werbeloff, N., Mandel, F. S., Ménard, F., Marangell, L. B., & Kapur, S. (2016) · The British Journal of Psychiatry · doi:10.1192/bjp.bp.115.173906 · Cited by 59 · see citing works
Not as golden as standards should be: Interpretation of the Hamilton Rating Scale for Depression
Kriston, L., & von Wolff, A. (2011) · Journal of Affective Disorders · doi:10.1016/j.jad.2010.07.011 · Cited by 55 · see citing works
Hieronymus, F., Lisinski, A., Nilsson, S., & Eriksson, E. (2017) · Molecular Psychiatry · doi:10.1038/mp.2017.147 · Cited by 44 · see citing works
Self-citationRandomized clinical trials underestimate the efficacy of antidepressants in less severe depression
Isacsson, G., & Adler, M. (2011) · Acta Psychiatrica Scandinavica · doi:10.1111/j.1600-0447.2011.01815.x · Cited by 40 · see citing works
Interpreting meta‐regression: application to recent controversies in antidepressants’ efficacy
Petkova, E., Tarpey, T., Huang, L., & Deng, L. (2013) · Statistics in Medicine · doi:10.1002/sim.5766 · Cited by 28 · see citing works
Simple Options for Improving Signal Detection in Antidepressant Clinical Trials
Mallinckrodt, C. H., PhD, Meyers, A. L., MS, Prakash, A., BA, Faries, D. E., PhD, Detke, A. M. J., MD, et al. (2025) · Psychopharmacology Bulletin · doi:10.64719/pb.4124 · Cited by 25 · see citing works
Näslund, J., Hieronymus, F., Emilsson, J. F., Lisinski, A., Nilsson, S., & Eriksson, E. (2017) · Acta Psychiatrica Scandinavica · doi:10.1111/acps.12784 · Cited by 22 · see citing works
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Luo, Y., Kataoka, Y., Ostinelli, E. G., Cipriani, A., & Furukawa, T. A. (2020) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2020.00035 · Cited by 206 · see citing works
Lewis, G., Duffy, L., Ades, A., Amos, R., Araya, R., Brabyn, S., Button, K. S., Churchill, R., Derrick, C., Dowrick, C., et al. (2019) · The Lancet Psychiatry · doi:10.1016/s2215-0366(19)30366-9 · Cited by 120 · see citing works
Hengartner, M. P., & Plöderl, M. (2022) · BMJ Evidence-Based Medicine · doi:10.1136/bmjebm-2020-111600 · Cited by 114 · see citing works
Hershenberg, R., McDonald, W. M., Crowell, A., Riva-Posse, P., Craighead, W. E., Mayberg, H. S., & Dunlop, B. W. (2020) · Journal of Affective Disorders · doi:10.1016/j.jad.2020.01.108 · Cited by 40 · see citing works
- Authors
- Hieronymus, F., Lisinski, A., Nilsson, S., & Eriksson, E.
- Affiliations
- University of Gothenburg (SE)
- Chalmers University of Technology (SE)
- Corresponding author
- Eriksson, Elias
- Venue
- The Lancet Psychiatry
- Publisher
- Elsevier BV
- Published
- 2019-09
- Volume
- 6
- Issue
- 9
- Pages
- 745-752
- ISSN
- 2215-0366 (ISSN-L)
- OpenAlex
- W2959164882
- Cited by
- 73
- References
- 23
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 11 · 2023: 7 · 2022: 7 · 2021: 13 · 2020: 11 · 2019: 9
- FWCI
- 6.19
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Lancet Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Chalmers Research (Chalmers University of Technology) (submittedVersion)
- Funders
- Vetenskapsrådet
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
- Social Sciences › Psychology › Social Psychology › Mental Health Treatment and Access
- Keywords
- baseline depression severity, selective serotonin reuptake inhibitors, major depressive disorder, antidepressant efficacy, Hamilton Depression Rating Scale, citalopram, paroxetine, sertraline, fluoxetine, treatment response, individual patient data, depressive mood
- MeSH terms
- Antidepressive Agents, Clinical Trials as Topic, Depression, Major Depressive Disorder, Fluoxetine, Humans, Longitudinal Studies, Placebos, Psychiatric Status Rating Scales, Severity of Illness Index, Reproducibility of Results, Citalopram, Outcome Assessment, Health Care, Selective Serotonin Reuptake Inhibitors, Paroxetine, Sertraline
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