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

Abstract

BackgroundThe evidence on selective serotonin reuptake inhibitors (SSRIs) for major depressive disorder is unclear.MethodsOur 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.ResultsA 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.ConclusionsSSRIs 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 registrationPROSPERO CRD42013004420.Electronic supplementary materialThe online version of this article (doi:10.1186/s12888-016-1173-2) contains supplementary material, which is available to authorized users.

Former suicidal inpatients’ experiences of treatment and care in psychiatric wards in Norway

“…In a recent systematic review, Jakobsen et al (2017) concluded that the potentially limited beneficial effects of antidepressants (SSRIs) appear to be outweighed by harmful effects. Critical voices have been raised against diagnostic practices and the potential adverse effects of psychiatric medication (Gøtzsche, 2013; Whitaker, 2010), and several authors have questioned the overreliance on biomedical models with regard to how we understand and manage suicidality (Cutcliffe & Santos, 2012; Hjelmeland, Dieserud, Dyregrov, Knizek, & Rasmussen, 2014; Marsh, 2016; Webb, 2010).…”

Do not blame the SSRIs: blame the Hamilton Depression Rating Scale

“…Furthermore, it is my hope that Jakobsen et al (1) will see this comment on their work as an encouragement to reanalyse their data using the HDRS 6 total score as outcome measure. This would be a highly clinically relevant contribution to the literature.…”

“…For the reasons outlined above, I strongly suggest that not only independent researchers like Jakobsen et al (1), but also organisations like the NICE, the pharmaceutical industry, and the pharmaceutical evaluation authorities, such as the US Food and Drug Administration and the European Medicines Agency, will no longer consider the total score on the HDRS (or the MADRS or BDI for that reason) as being a valid outcome measure in studies of antidepressants -because this practice is in conflict with the results of a very large body of literature based on clinical psychometric research. Furthermore, it is my hope that Jakobsen et al (1) will see this comment on their work as an encouragement to reanalyse their data using the HDRS 6 total score as outcome measure.…”

“…Therefore, the total score of the HDRS cannot be considered as a clinically valid measure of the severity of depression (5,16). As the conclusions made by Jakobsen et al (1) are based on the results of analyses of HDRS total scores, it entails that they are not clinically valid either.…”

Antidepressiver mot akutt depresjon

“…Vaaler sier at studien må ses i sammenheng med en metaanalyse publisert i fjor av 131 studier med over 27 000 pasienter om bruk av selektive serotoninreopptakshemmere (SSRI) (2). Forfatterne av den studien konkluderte med at SSRI-legemidler ikke hadde klinisk meningsfull effekt på depressive symptomer og at legemidlene økte risikoen for alvorlige og ikke-alvorlige bivirkninger.…”