Selective serotonin reuptake inhibitors versus placebo in patients with major depressive disorder. A systematic review with meta-analysis and Trial Sequential Analysis.
The evidence on selective serotonin reuptake inhibitors (SSRIs) for major depressive disorder is unclear.



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.



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.



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.



PROSPERO CRD42013004420.
The Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812 Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, Rigshospitalet, DK 2100, Copenhagen, Denmark. jcj@ctu.dk.|Department of Cardiology, Holbæk Hospital, Holbæk, Denmark. jcj@ctu.dk.
Janus Christian
JC
Jakobsen
The Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812 Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, Rigshospitalet, DK 2100, Copenhagen, Denmark.
Kiran Kumar
KK
Katakam
The Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812 Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, Rigshospitalet, DK 2100, Copenhagen, Denmark.
Anne
A
Schou
The Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812 Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, Rigshospitalet, DK 2100, Copenhagen, Denmark.
Signe Gade
SG
Hellmuth
The Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812 Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, Rigshospitalet, DK 2100, Copenhagen, Denmark.
Sandra Elkjær
SE
Stallknecht
The Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812 Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, Rigshospitalet, DK 2100, Copenhagen, Denmark.
Katja
K
Leth-Møller
The Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812 Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, Rigshospitalet, DK 2100, Copenhagen, Denmark.
Maria
M
Iversen
The Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812 Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, Rigshospitalet, DK 2100, Copenhagen, Denmark.
Marianne Bjørnø
MB
Banke
The Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812 Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, Rigshospitalet, DK 2100, Copenhagen, Denmark.
Iggiannguaq Juhl
IJ
Petersen
The Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812 Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, Rigshospitalet, DK 2100, Copenhagen, Denmark.
Sarah Louise
SL
Klingenberg
Mental Health Centre Copenhagen, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
Jesper
J
Krogh
The Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812 Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, Rigshospitalet, DK 2100, Copenhagen, Denmark.
Sebastian Elgaard
SE
Ebert
The Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812 Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, Rigshospitalet, DK 2100, Copenhagen, Denmark.
Anne
A
Timm
The Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812 Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, Rigshospitalet, DK 2100, Copenhagen, Denmark.
Jane
J
Lindschou
The Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812 Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, Rigshospitalet, DK 2100, Copenhagen, Denmark.
Christian
C
Gluud
D000328:Adult; D018687:Antidepressive Agents, Second-Generation / Q000627:therapeutic use*; D003866:Depressive Disorder / Q000188:drug therapy*; D006801:Humans; D010919:Placebos; D011788:Quality of Life; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use*; D059020:Suicidal Ideation
D018687:Antidepressive Agents, Second-Generation; D010919:Placebos; D017367:Selective Serotonin Reuptake Inhibitors
Depression; SSRI; Systematic review