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Published Online: 10 November 2015

Systematic Review and Meta-Analysis: Dose-Response Relationship of Selective Serotonin Reuptake Inhibitors in Major Depressive Disorder

Ewgeni Jakubovski, M.A., Anjali L. Varigonda, M.D., Nicholas Freemantle, Ph.D., Matthew J. Taylor, Ph.D., and Michael H. Bloch, M.D., M.S.Authors Info & Affiliations
Publication: American Journal of Psychiatry
Volume 173, Number 2
https://doi.org/10.1176/appi.ajp.2015.15030331
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Abstract

Objective:

Previous studies suggested that the treatment response to selective serotonin reuptake inhibitors (SSRIs) in major depressive disorder follows a flat response curve within the therapeutic dose range. The present study was designed to clarify the relationship between dosage and treatment response in major depressive disorder.

Method:

The authors searched PubMed for randomized placebo-controlled trials examining the efficacy of SSRIs for treating adults with major depressive disorder. Trials were also required to assess improvement in depression severity at multiple time points. Additional data were collected on treatment response and all-cause and side effect-related discontinuation. All medication doses were transformed into imipramine-equivalent doses. The longitudinal data were analyzed with a mixed-regression model. Endpoint and tolerability analyses were analyzed using meta-regression and stratified subgroup analysis by predefined SSRI dose categories in order to assess the effect of SSRI dosing on the efficacy and tolerability of SSRIs for major depressive disorder.

Results:

Forty studies involving 10,039 participants were included. Longitudinal modeling (dose-by-time interaction=0.0007, 95% CI=0.0001–0.0013) and endpoint analysis (meta-regression: β=0.00053, 95% CI=0.00018–0.00088, z=2.98) demonstrated a small but statistically significant positive association between SSRI dose and efficacy. Higher doses of SSRIs were associated with an increased likelihood of dropouts due to side effects (meta-regression: β=0.00207, 95% CI=0.00071–0.00342, z=2.98) and decreased likelihood of all-cause dropout (meta-regression: β=–0.00093, 95% CI=–0.00165 to −0.00021, z=−2.54).

Conclusions:

Higher doses of SSRIs appear slightly more effective in major depressive disorder. This benefit appears to plateau at around 250 mg of imipramine equivalents (50 mg of fluoxetine). The slightly increased benefits of SSRIs at higher doses are somewhat offset by decreased tolerability at high doses.

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Information & Authors

Information

Published In

Go to American Journal of Psychiatry
Go to American Journal of Psychiatry
American Journal of Psychiatry
Volume 173 • Number 2 • February 01, 2016
Pages: 174 - 183
PubMed: 26552940

History

Received: 13 March 2015
Revision received: 29 June 2015
Accepted: 2 July 2015
Published online: 10 November 2015
Published in print: February 01, 2016

Authors

Details

Ewgeni Jakubovski, M.A.
From the Yale Child Study Center, New Haven, Conn.; the University of Vermont College of Medicine, Burlington, Vt.; Child Study Center and Department of Psychiatry, Yale University, New Haven, Conn.; the Department of Primary Care and Population Health, University College London; and the Department of Psychosis Studies, King’s College London.
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Anjali L. Varigonda, M.D.
From the Yale Child Study Center, New Haven, Conn.; the University of Vermont College of Medicine, Burlington, Vt.; Child Study Center and Department of Psychiatry, Yale University, New Haven, Conn.; the Department of Primary Care and Population Health, University College London; and the Department of Psychosis Studies, King’s College London.
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Nicholas Freemantle, Ph.D.
From the Yale Child Study Center, New Haven, Conn.; the University of Vermont College of Medicine, Burlington, Vt.; Child Study Center and Department of Psychiatry, Yale University, New Haven, Conn.; the Department of Primary Care and Population Health, University College London; and the Department of Psychosis Studies, King’s College London.
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Matthew J. Taylor, Ph.D.
From the Yale Child Study Center, New Haven, Conn.; the University of Vermont College of Medicine, Burlington, Vt.; Child Study Center and Department of Psychiatry, Yale University, New Haven, Conn.; the Department of Primary Care and Population Health, University College London; and the Department of Psychosis Studies, King’s College London.
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Michael H. Bloch, M.D., M.S.
From the Yale Child Study Center, New Haven, Conn.; the University of Vermont College of Medicine, Burlington, Vt.; Child Study Center and Department of Psychiatry, Yale University, New Haven, Conn.; the Department of Primary Care and Population Health, University College London; and the Department of Psychosis Studies, King’s College London.
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Notes

Address correspondence to Ewgeni Jakubovski ([email protected]).

Funding Information

Dr. Freemantle has received funding as a consultant for Lundbeck. Dr. Taylor has received compensation as a lecturer and for travel expenses from Bristol-Myers Squibb, Lundbeck, and Otsuka; he has served as a consultant to Sunovion; and a member of his family is an employee of GlaxoSmithKline. Dr. Bloch has received grant support from an American Academy of Child and Adolescent Psychiatry/Eli Lilly Junior Investigator Award, NARSAD, the National Institute of Mental Health (K23MH091240), the Rembrandt Foundation, and the Tourette Syndrome Association, as well as grant UL1 RR024139 from the National Center for Research Resources, a component of the National Institutes of Health, and NIH roadmap for Medical Research; he is also partly funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. All other authors report no financial relationships with commercial interests.

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