title: Efficacy of selective serotonin reuptake inhibitors and adverse events: meta-regression and mediation analysis of placebo-controlled trials.
abstract: BACKGROUND
  It has been suggested that the efficacy of antidepressants has been overestimated in clinical trials owing to unblinding of drug treatments by adverse events.
  
  
  OBJECTIVE
  To investigate the association between adverse events and the efficacy of selective serotonin reuptake inhibitors (SSRIs).
  
  
  METHODS
  The literature was searched to identify randomised, double-blind, placebo-controlled trials of SSRIs in the treatment of major depression. Efficacy outcomes were response to treatment and change in depressive symptoms. Reporting of adverse events was used as an indicator of tolerability. Random effects meta-analyses were used to calculate pooled estimates. Meta-regression analyses were performed to investigate the association between adverse events and efficacy. Potential mediation was investigated with the Baron & Kenny approach.
  
  
  RESULTS
  A total of 68 trials (n = 17 646) were included in the analyses. In meta-analysis SSRIs were superior to placebo in terms of efficacy (odds ratio, OR = 1.62, 95% CI 1.51-1.72). More patients allocated to SSRIs reported adverse events than did patients receiving placebo (OR = 1.73, 95% CI 1.58-1.89). Meta-regression analyses did not find an association between adverse events and efficacy (P = 0.439). There was no indication of adverse events mediating the effect of SSRI treatment.
  
  
  CONCLUSIONS
  Our results do not support, but also do not unequivocally disprove, the hypothesis that adverse events lead to an overestimation of the effect of SSRIs over placebo.
authors.affiliation: Michael Barth, MSc, Institute of General Practice, Klinikum rechts der Isar, Technische Universität München, Munich; Levente Kriston, PhD, Department of Medical Psychology, University Medical Centre Hamburg-Eppendorf, Hamburg; Swaantje Klostermann, MPH, Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, University Hospital of Munich (Ludwig-Maximilians-University), Munich, Germany; Corrado Barbui, MD, World Health Organization (WHO) Collaborating Centre for Research and Training in Mental Health and Service Evaluation, Department of Public Health and Community Medicine, Section of Psychiatry, University of Verona, Italy; Andrea Cipriani, MD, WHO Collaborating Centre for Research and Training in Mental Health and Service Evaluation, Department of Public Health and Community Medicine, Section of Psychiatry, University of Verona, Italy, and Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK; Klaus Linde, MD, Institute of General Practice, Klinikum rechts der Isar, Technische Universität München, Munich, Germany michael.barth@tum.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Barth
authors.affiliation: Michael Barth, MSc, Institute of General Practice, Klinikum rechts der Isar, Technische Universität München, Munich; Levente Kriston, PhD, Department of Medical Psychology, University Medical Centre Hamburg-Eppendorf, Hamburg; Swaantje Klostermann, MPH, Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, University Hospital of Munich (Ludwig-Maximilians-University), Munich, Germany; Corrado Barbui, MD, World Health Organization (WHO) Collaborating Centre for Research and Training in Mental Health and Service Evaluation, Department of Public Health and Community Medicine, Section of Psychiatry, University of Verona, Italy; Andrea Cipriani, MD, WHO Collaborating Centre for Research and Training in Mental Health and Service Evaluation, Department of Public Health and Community Medicine, Section of Psychiatry, University of Verona, Italy, and Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK; Klaus Linde, MD, Institute of General Practice, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Levente
authors.initials: L
authors.lastname: Kriston
authors.affiliation: Michael Barth, MSc, Institute of General Practice, Klinikum rechts der Isar, Technische Universität München, Munich; Levente Kriston, PhD, Department of Medical Psychology, University Medical Centre Hamburg-Eppendorf, Hamburg; Swaantje Klostermann, MPH, Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, University Hospital of Munich (Ludwig-Maximilians-University), Munich, Germany; Corrado Barbui, MD, World Health Organization (WHO) Collaborating Centre for Research and Training in Mental Health and Service Evaluation, Department of Public Health and Community Medicine, Section of Psychiatry, University of Verona, Italy; Andrea Cipriani, MD, WHO Collaborating Centre for Research and Training in Mental Health and Service Evaluation, Department of Public Health and Community Medicine, Section of Psychiatry, University of Verona, Italy, and Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK; Klaus Linde, MD, Institute of General Practice, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Swaantje
authors.initials: S
authors.lastname: Klostermann
authors.affiliation: Michael Barth, MSc, Institute of General Practice, Klinikum rechts der Isar, Technische Universität München, Munich; Levente Kriston, PhD, Department of Medical Psychology, University Medical Centre Hamburg-Eppendorf, Hamburg; Swaantje Klostermann, MPH, Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, University Hospital of Munich (Ludwig-Maximilians-University), Munich, Germany; Corrado Barbui, MD, World Health Organization (WHO) Collaborating Centre for Research and Training in Mental Health and Service Evaluation, Department of Public Health and Community Medicine, Section of Psychiatry, University of Verona, Italy; Andrea Cipriani, MD, WHO Collaborating Centre for Research and Training in Mental Health and Service Evaluation, Department of Public Health and Community Medicine, Section of Psychiatry, University of Verona, Italy, and Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK; Klaus Linde, MD, Institute of General Practice, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Corrado
authors.initials: C
authors.lastname: Barbui
authors.affiliation: Michael Barth, MSc, Institute of General Practice, Klinikum rechts der Isar, Technische Universität München, Munich; Levente Kriston, PhD, Department of Medical Psychology, University Medical Centre Hamburg-Eppendorf, Hamburg; Swaantje Klostermann, MPH, Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, University Hospital of Munich (Ludwig-Maximilians-University), Munich, Germany; Corrado Barbui, MD, World Health Organization (WHO) Collaborating Centre for Research and Training in Mental Health and Service Evaluation, Department of Public Health and Community Medicine, Section of Psychiatry, University of Verona, Italy; Andrea Cipriani, MD, WHO Collaborating Centre for Research and Training in Mental Health and Service Evaluation, Department of Public Health and Community Medicine, Section of Psychiatry, University of Verona, Italy, and Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK; Klaus Linde, MD, Institute of General Practice, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cipriani
authors.affiliation: Michael Barth, MSc, Institute of General Practice, Klinikum rechts der Isar, Technische Universität München, Munich; Levente Kriston, PhD, Department of Medical Psychology, University Medical Centre Hamburg-Eppendorf, Hamburg; Swaantje Klostermann, MPH, Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, University Hospital of Munich (Ludwig-Maximilians-University), Munich, Germany; Corrado Barbui, MD, World Health Organization (WHO) Collaborating Centre for Research and Training in Mental Health and Service Evaluation, Department of Public Health and Community Medicine, Section of Psychiatry, University of Verona, Italy; Andrea Cipriani, MD, WHO Collaborating Centre for Research and Training in Mental Health and Service Evaluation, Department of Public Health and Community Medicine, Section of Psychiatry, University of Verona, Italy, and Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK; Klaus Linde, MD, Institute of General Practice, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Linde
mesh_terms: D000928:Antidepressive Agents / Q000009:adverse effects* / Q000627:therapeutic use*; D015283:Citalopram / Q000627:therapeutic use; D003863:Depression / Q000188:drug therapy*; D003865:Major Depressive Disorder / Q000188:drug therapy*; D006801:Humans; D017374:Paroxetine / Q000627:therapeutic use; D011569:Psychiatric Status Rating Scales; D016032:Randomized Controlled Trials as Topic; D017367:Selective Serotonin Reuptake Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use*
chemical_list: D000928:Antidepressive Agents; D015283:Citalopram; D017374:Paroxetine; D017367:Selective Serotonin Reuptake Inhibitors