Selective serotonin reuptake inhibitors versus placebo in patients with major depressive disorder. A systematic review with meta-analysis and Trial Sequential Analysis

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Abstract

Background

The evidence on selective serotonin reuptake inhibitors (SSRIs) for major depressive disorder is unclear.

Methods

Our objective was to conduct a systematic review assessing the effects of SSRIs versus placebo, ‘active’ placebo, or no intervention in adult participants with major depressive disorder. We searched for eligible randomised clinical trials in The Cochrane Library’s CENTRAL, PubMed, EMBASE, PsycLIT, PsycINFO, Science Citation Index Expanded, clinical trial registers of Europe and USA, websites of pharmaceutical companies, the U.S. Food and Drug Administration (FDA), and the European Medicines Agency until January 2016. All data were extracted by at least two independent investigators. We used Cochrane systematic review methodology, Trial Sequential Analysis, and calculation of Bayes factor. An eight-step procedure was followed to assess if thresholds for statistical and clinical significance were crossed. Primary outcomes were reduction of depressive symptoms, remission, and adverse events. Secondary outcomes were suicides, suicide attempts, suicide ideation, and quality of life.

Results

A total of 131 randomised placebo-controlled trials enrolling a total of 27,422 participants were included. None of the trials used ‘active’ placebo or no intervention as control intervention. All trials had high risk of bias. SSRIs significantly reduced the Hamilton Depression Rating Scale (HDRS) at end of treatment (mean difference −1.94 HDRS points; 95% CI −2.50 to −1.37; P < 0.00001; 49 trials; Trial Sequential Analysis-adjusted CI −2.70 to −1.18); Bayes factor below predefined threshold (2.01*10 ⁻²³). The effect estimate, however, was below our predefined threshold for clinical significance of 3 HDRS points. SSRIs significantly decreased the risk of no remission (RR 0.88; 95% CI 0.84 to 0.91; P < 0.00001; 34 trials; Trial Sequential Analysis adjusted CI 0.83 to 0.92); Bayes factor (1426.81) did not confirm the effect). SSRIs significantly increased the risks of serious adverse events (OR 1.37; 95% CI 1.08 to 1.75; P = 0.009; 44 trials; Trial Sequential Analysis-adjusted CI 1.03 to 1.89). This corresponds to 31/1000 SSRI participants will experience a serious adverse event compared with 22/1000 control participants. SSRIs also significantly increased the number of non-serious adverse events. There were almost no data on suicidal behaviour, quality of life, and long-term effects.

Conclusions

SSRIs might have statistically significant effects on depressive symptoms, but all trials were at high risk of bias and the clinical significance seems questionable. SSRIs significantly increase the risk of both serious and non-serious adverse events. The potential small beneficial effects seem to be outweighed by harmful effects.

Systematic review registration

PROSPERO CRD42013004420.

Electronic supplementary material

The online version of this article (doi:10.1186/s12888-016-1173-2) contains supplementary material, which is available to authorized users.

Related collections

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Author and article information

Contributors

Janus Christian Jakobsen: +45 2618 6242 , jcj@ctu.dk

Kiran Kumar Katakam: kiran.katakam@ctu.dk

Anne Schou: anneschou90@gmail.com

Signe Gade Hellmuth: signegh@hotmail.com

Sandra Elkjær Stallknecht: stallknecht.se@gmail.com

Katja Leth-Møller: katja.biering.leth-moeller.01@regionh.dk

Maria Iversen: maraja_i@hotmail.com

Marianne Bjørnø Banke: mar1anne_bb@hotmail.com

Iggiannguaq Juhl Petersen: iggipetersen@live.dk

Sarah Louise Klingenberg: slk@ctu.dk

Jesper Krogh: jesper.krogh@regionh.dk

Sebastian Elgaard Ebert: sebastian.e.ebert@gmail.com

Anne Timm: timm_danmark@hotmail.com

Jane Lindschou: jl@ctu.dk

Christian Gluud: cgluud@ctu.dk

Journal

Journal ID (nlm-ta): BMC Psychiatry

Journal ID (iso-abbrev): BMC Psychiatry

Title: BMC Psychiatry

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-244X

Publication date (Electronic): 8 February 2017

Publication date PMC-release: 8 February 2017

Publication date Collection: 2017

Volume: 17

Electronic Location Identifier: 58

Affiliations

[1 ]ISNI 0000 0004 0646 7373, GRID grid.4973.9, The Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812 Rigshospitalet, , Copenhagen University Hospital, ; Blegdamsvej 9, Rigshospitalet, DK 2100 Copenhagen, Denmark

[2 ]ISNI 0000 0004 0646 8763, GRID grid.414289.2, Department of Cardiology, , Holbæk Hospital, ; Holbæk, Denmark

[3 ]ISNI 0000 0001 0674 042X, GRID grid.5254.6, Mental Health Centre Copenhagen, Faculty of Health Sciences, , University of Copenhagen, ; Copenhagen, Denmark

Article

Publisher ID: 1173

DOI: 10.1186/s12888-016-1173-2

PMC ID: 5299662

PubMed ID: 28178949

SO-VID: ec7a634a-7780-4859-a051-6c5174d19f94

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.