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Review
, 17 (1), 58

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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Review

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 et al. BMC Psychiatry.

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; Systematic review.

Figures

Fig. 1
Fig. 1
PRISMA flowchart
Fig. 2
Fig. 2
Random-effects meta-analysis of the results on the Hamilton depression rating scale
Fig. 3
Fig. 3
Risk of bias in the included randomized clinical trials
Fig. 4
Fig. 4
Subgroup analysis comparing trials assessing the effects of different selective serotonin reuptake inhibitors
Fig. 5
Fig. 5
Subgroup analysis comparing trials randomising elderly participants to trials randomising non-elderly participants
Fig. 6
Fig. 6
Subgroup analysis comparing trials using a placebo-washout period to trials not using a placebo-washout period
Fig. 7
Fig. 7
Trial Sequential Analysis of the results of selective serotonin reuptake inhibitors on Hamilton depression rating scale
Fig. 8
Fig. 8
Funnel plot of the random-effects meta-analysis of the effect of selective serotonin reuptake inhibitors on Hamilton depression rating scale
Fig. 9
Fig. 9
Random-effects meta-analysis of the results of selective serotonin reuptake inhibitors on remission of depression
Fig. 10
Fig. 10
Trial Sequential Analysis of the results of selective serotonin reuptake inhibitors on remission of depression
Fig. 11
Fig. 11
Random-effects meta-analysis of the results of selective serotonin reuptake inhibitors on serious adverse events
Fig. 12
Fig. 12
Trial Sequential Analysis of the results of selective serotonin reuptake inhibitors on serious adverse events

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