title: Suicidality and aggression during antidepressant treatment: systematic review and meta-analyses based on clinical study reports.
abstract: OBJECTIVE
  To study serious harms associated with selective serotonin and serotonin-norepinephrine reuptake inhibitors.Design Systematic review and meta-analysis.
  
  
  METHODS
  Mortality and suicidality. Secondary outcomes were aggressive behaviour and akathisia.
  
  
  METHODS
  Clinical study reports for duloxetine, fluoxetine, paroxetine, sertraline, and venlafaxine obtained from the European and UK drug regulators, and summary trial reports for duloxetine and fluoxetine from Eli Lilly's website.
  
  
  METHODS
  Double blind placebo controlled trials that contained any patient narratives or individual patient listings of harms.
  
  
  METHODS
  Two researchers extracted data independently; the outcomes were meta-analysed by Peto's exact method (fixed effect model).
  
  
  RESULTS
  We included 70 trials (64,381 pages of clinical study reports) with 18,526 patients. These trials had limitations in the study design and discrepancies in reporting, which may have led to serious under-reporting of harms. For example, some outcomes appeared only in individual patient listings in appendices, which we had for only 32 trials, and we did not have case report forms for any of the trials. Differences in mortality (all deaths were in adults, odds ratio 1.28, 95% confidence interval 0.40 to 4.06), suicidality (1.21, 0.84 to 1.74), and akathisia (2.04, 0.93 to 4.48) were not significant, whereas patients taking antidepressants displayed more aggressive behaviour (1.93, 1.26 to 2.95). For adults, the odds ratios were 0.81 (0.51 to 1.28) for suicidality, 1.09 (0.55 to 2.14) for aggression, and 2.00 (0.79 to 5.04) for akathisia. The corresponding values for children and adolescents were 2.39 (1.31 to 4.33), 2.79 (1.62 to 4.81), and 2.15 (0.48 to 9.65). In the summary trial reports on Eli Lilly's website, almost all deaths were noted, but all suicidal ideation events were missing, and the information on the remaining outcomes was incomplete.
  
  
  CONCLUSIONS
  Because of the shortcomings identified and having only partial access to appendices with no access to case report forms, the harms could not be estimated accurately. In adults there was no significant increase in all four outcomes, but in children and adolescents the risk of suicidality and aggression doubled. To elucidate the harms reliably, access to anonymised individual patient data is needed.
authors.affiliation: Nordic Cochrane Centre, Rigshospitalet, Copenhagen, Denmark University of Copenhagen, Faculty of Health and Medical Sciences, Denmark ts@cochrane.dk.
authors.forename: Tarang
authors.initials: T
authors.lastname: Sharma
authors.affiliation: Nordic Cochrane Centre, Rigshospitalet, Copenhagen, Denmark University of Copenhagen, Faculty of Health and Medical Sciences, Denmark.
authors.forename: Louise Schow
authors.initials: LS
authors.lastname: Guski
authors.affiliation: Nordic Cochrane Centre, Rigshospitalet, Copenhagen, Denmark University of Copenhagen, Faculty of Health and Medical Sciences, Denmark.
authors.forename: Nanna
authors.initials: N
authors.lastname: Freund
authors.affiliation: Nordic Cochrane Centre, Rigshospitalet, Copenhagen, Denmark University of Copenhagen, Faculty of Health and Medical Sciences, Denmark.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Gøtzsche
mesh_terms: D000928:Antidepressive Agents / Q000008:administration & dosage / Q000009:adverse effects*; D003866:Depressive Disorder / Q000188:drug therapy*; D004311:Double-Blind Method; D006801:Humans; D011595:Psychomotor Agitation / Q000209:etiology* / Q000523:psychology; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D059020:Suicidal Ideation; D013405:Suicide / Q000523:psychology; D000092864:Suicide Prevention
chemical_list: D000928:Antidepressive Agents; D017367:Selective Serotonin Reuptake Inhibitors
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