title: Risk of neuropsychiatric adverse events associated with varenicline: systematic review and meta-analysis.
abstract: OBJECTIVE
  To determine the risk of neuropsychiatric adverse events associated with use of varenicline compared with placebo in randomised controlled trials.
  
  
  METHODS
  Systematic review and meta-analysis comparing study effects using two summary estimates in fixed effects models, risk differences, and Peto odds ratios.
  
  
  METHODS
  Medline, Embase, PsycINFO, the Cochrane Central Register of Controlled Trials (CENTRAL), and clinicaltrials.gov.
  
  
  METHODS
  Randomised controlled trials with a placebo comparison group that reported on neuropsychiatric adverse events (depression, suicidal ideation, suicide attempt, suicide, insomnia, sleep disorders, abnormal dreams, somnolence, fatigue, anxiety) and death. Studies that did not involve human participants, did not use the maximum recommended dose of varenicline (1 mg twice daily), and were cross over trials were excluded.
  
  
  RESULTS
  In the 39 randomised controlled trials (10,761 participants), there was no evidence of an increased risk of suicide or attempted suicide (odds ratio 1.67, 95% confidence interval 0.33 to 8.57), suicidal ideation (0.58, 0.28 to 1.20), depression (0.96, 0.75 to 1.22), irritability (0.98, 0.81 to 1.17), aggression (0.91, 0.52 to 1.59), or death (1.05, 0.47 to 2.38) in the varenicline users compared with placebo users. Varenicline was associated with an increased risk of sleep disorders (1.63, 1.29 to 2.07), insomnia (1.56, 1.36 to 1.78), abnormal dreams (2.38, 2.05 to 2.77), and fatigue (1.28, 1.06 to 1.55) but a reduced risk of anxiety (0.75, 0.61 to 0.93). Similar findings were observed when risk differences were reported. There was no evidence for a variation in depression and suicidal ideation by age group, sex, ethnicity, smoking status, presence or absence of psychiatric illness, and type of study sponsor (that is, pharmaceutical industry or other).
  
  
  CONCLUSIONS
  This meta-analysis found no evidence of an increased risk of suicide or attempted suicide, suicidal ideation, depression, or death with varenicline. These findings provide some reassurance for users and prescribers regarding the neuropsychiatric safety of varenicline. There was evidence that varenicline was associated with a higher risk of sleep problems such as insomnia and abnormal dreams. These side effects, however, are already well recognised.
  
  
  BACKGROUND
  PROSPERO 2014:CRD42014009224.
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol BS8 2PS, UK kyla.thomas@bristol.ac.uk.
authors.forename: Kyla H
authors.initials: KH
authors.lastname: Thomas
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol BS8 2PS, UK.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Martin
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol BS8 2PS, UK.
authors.forename: Duleeka W
authors.initials: DW
authors.lastname: Knipe
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol BS8 2PS, UK.
authors.forename: Julian P T
authors.initials: JP
authors.lastname: Higgins
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol BS8 2PS, UK.
authors.forename: David
authors.initials: D
authors.lastname: Gunnell
mesh_terms: D000374:Aggression / Q000187:drug effects; D001552:Benzazepines / Q000009:adverse effects*; D003863:Depression / Q000139:chemically induced; D006801:Humans; D001523:Mental Disorders / Q000139:chemically induced*; D011810:Quinoxalines / Q000009:adverse effects*; D012307:Risk Factors; D012893:Sleep Wake Disorders / Q000139:chemically induced*; D013405:Suicide / Q000706:statistics & numerical data; D013406:Suicide, Attempted / Q000706:statistics & numerical data; D061485:Tobacco Use Cessation Devices / Q000009:adverse effects*; D000068580:Varenicline
chemical_list: D001552:Benzazepines; D011810:Quinoxalines; D000068580:Varenicline