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

Janus Christian Jakobsen; Kiran Kumar Katakam; Anne Schou; Signe Gade Hellmuth; Sandra Elkjær Stallknecht; Katja Leth-Møller; Maria Iversen; Marianne Bjørnø Banke; Iggiannguaq Juhl Petersen; Sarah Louise Klingenberg; Jesper Krogh; Sebastian Elgaard Ebert; Anne Timm; Jane Lindschou; Christian Gluud

doi:10.1186/s12888-016-1173-2

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

Janus Christian Jakobsen^*, Kiran Kumar Katakam, Anne Schou, Signe Gade Hellmuth, Sandra Elkjær Stallknecht, Katja Leth-Møller, Maria Iversen, Marianne Bjørnø Banke, Iggiannguaq Juhl Petersen, Sarah Louise Klingenberg, Jesper Krogh, Sebastian Elgaard Ebert, Anne Timm, Jane Lindschou, Christian Gluud

^*Corresponding author for this work

Department of Biomedical Sciences

132 Citations (Scopus)

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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.

Original language	English
Article number	58
Journal	BMC Psychiatry
Volume	17
Issue number	1
Number of pages	28
ISSN	1471-244X
DOIs	https://doi.org/10.1186/s12888-016-1173-2
Publication status	Published - 8 Feb 2017

Keywords

Depression
SSRI

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Selective serotonin reuptake inhibitors versus placebo in patients with major depressive disorder. A systematic review with meta-analysis and Trial Sequential AnalysisFinal published version, 3.79 MBLicence: CC BY

Cite this

Jakobsen, J. C., Katakam, K. K., Schou, A., Hellmuth, S. G., Stallknecht, S. E., Leth-Møller, K., Iversen, M., Banke, M. B., Petersen, I. J., Klingenberg, S. L., Krogh, J., Ebert, S. E., Timm, A., Lindschou, J., & Gluud, C. (2017). Selective serotonin reuptake inhibitors versus placebo in patients with major depressive disorder. A systematic review with meta-analysis and Trial Sequential Analysis. BMC Psychiatry, 17(1), [58]. https://doi.org/10.1186/s12888-016-1173-2

Selective serotonin reuptake inhibitors versus placebo in patients with major depressive disorder. A systematic review with meta-analysis and Trial Sequential Analysis. / Jakobsen, Janus Christian; Katakam, Kiran Kumar; Schou, Anne et al.

In: BMC Psychiatry, Vol. 17, No. 1, 58, 08.02.2017.

Research output: Contribution to journal › Journal article › Research › peer-review

Jakobsen, JC, Katakam, KK, Schou, A, Hellmuth, SG, Stallknecht, SE, Leth-Møller, K, Iversen, M, Banke, MB, Petersen, IJ, Klingenberg, SL, Krogh, J, Ebert, SE, Timm, A, Lindschou, J & Gluud, C 2017, 'Selective serotonin reuptake inhibitors versus placebo in patients with major depressive disorder. A systematic review with meta-analysis and Trial Sequential Analysis', BMC Psychiatry, vol. 17, no. 1, 58. https://doi.org/10.1186/s12888-016-1173-2

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

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.",

keywords = "Depression, SSRI",

author = "Jakobsen, {Janus Christian} and Katakam, {Kiran Kumar} and Anne Schou and Hellmuth, {Signe Gade} and Stallknecht, {Sandra Elkj{\ae}r} and Katja Leth-M{\o}ller and Maria Iversen and Banke, {Marianne Bj{\o}rn{\o}} and Petersen, {Iggiannguaq Juhl} and Klingenberg, {Sarah Louise} and Jesper Krogh and Ebert, {Sebastian Elgaard} and Anne Timm and Jane Lindschou and Christian Gluud",

year = "2017",

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doi = "10.1186/s12888-016-1173-2",

language = "English",

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journal = "B M C Psychiatry",

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TY - JOUR

T1 - Selective serotonin reuptake inhibitors versus placebo in patients with major depressive disorder. A systematic review with meta-analysis and Trial Sequential Analysis

AU - Jakobsen, Janus Christian

AU - Katakam, Kiran Kumar

AU - Schou, Anne

AU - Hellmuth, Signe Gade

AU - Stallknecht, Sandra Elkjær

AU - Leth-Møller, Katja

AU - Iversen, Maria

AU - Banke, Marianne Bjørnø

AU - Petersen, Iggiannguaq Juhl

AU - Klingenberg, Sarah Louise

AU - Krogh, Jesper

AU - Ebert, Sebastian Elgaard

AU - Timm, Anne

AU - Lindschou, Jane

AU - Gluud, Christian

PY - 2017/2/8

Y1 - 2017/2/8

N2 - 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.

AB - 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.

KW - Depression

KW - SSRI

U2 - 10.1186/s12888-016-1173-2

DO - 10.1186/s12888-016-1173-2

M3 - Journal article

C2 - 28178949

AN - SCOPUS:85012101620

SN - 1471-244X

VL - 17

JO - B M C Psychiatry

JF - B M C Psychiatry

IS - 1

M1 - 58

ER -

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

Abstract

Keywords

UN SDGs

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