Artikel
Is the efficacy of selective serotonin reuptake inhibitors influenced by adverse events? Meta-regression and mediation analysis of placebo-controlled trials
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Autoren
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M. Barth
- Klinikum Rechts der Isar/Technische Universität München, München
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L. Kriston
- Institut und Poliklinik für Medizinische Psychologie Universitätsklinikum Hamburg-Eppendorf, Ham-burg
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S. Klostermann
- Institut und Poliklinik für Arbeits-, Sozial- und Umweltmedizin, Klinikum der Univer-sität, Ludwigs-Maximilians-Universität München, München
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C. Barbui
- Department of Public Health and Community Medicine, Section of Psychiatry, University of Verona, Verona
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A. Cipriani
- Department of Psychiatry University of Oxford Warneford Hospital, Oxford
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K. Linde
- Institut für Allgemeinmedizin, Klinikum Rechts der Isar / Technische Universität München, München
| Veröffentlicht: | 4. September 2014 |
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Gliederung
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Importance and objective: It has been suggested that the efficacy of antidepressants might have been overestimated in clinical trials due to the unblinding of drug treatments by adverse events. To investigate the association between adverse events and the efficacy of selective serotonin reuptake inhibitors (SSRIs) in a meta-analysis of double-blind studies with adults with acute major depression.
Material and methods: PubMed, Cochrane Central Register of Controlled Trials and pharmaceutical company clinical trial registers were searched until August 2013. We included randomized placebo-controlled trials of SSRIs, as monotherapy, in the treatment of acute major depression. Two reviewers independently extracted study data and assessed the risk of bias. Random effects meta-analyses were used to calculate pooled estimates for both efficacy and tolerability. We performed meta-regression analyses to investigate the association between adverse events and efficacy. To investigate potential mediation, the Baron and Kenny approach was used. The primary efficacy outcome was the response to treatment, defined as 50% reduction on a standardized rating scale. Change of depressive symptoms from baseline to endpoint was the secondary efficacy outcome. Reporting at least one adverse event or adverse effect was used as indicator of tolerability.
Results: A total of 68 trials (17,646 subjects) were included in the analyses. SSRIs were superior to placebo regarding both dichotomous (odds ratio (OR) 1.62; 95% confidence interval (CI) 1.51, 1.72) and continuous (standardized mean difference -0.27; 95% CI -0.31, 0.23) efficacy outcomes. Significantly more subjects allocated to SSRIs reported adverse events than subjects receiving placebo (OR 1.73; 95% CI 1.58, 1.89). In the meta-regression no statistically significant association between adverse events and efficacy was found (response: β=0.064, P=0.439; change from baseline: β=0.062, P=0.167). There was no indication of adverse events mediating the effect of treatment on response or severity change from baseline.
Conclusions and Relevance: Results from this study clearly do not provide evidence that adverse events may lead to an overestimation of the effect of SSRIs over placebo. Our findings have to be interpreted carefully, as meta-analysis may be prone to bias due to ecological fallacy.
