risk of neuropsychiatric adverse events associated with
TRANSCRIPT
Thomas K H Martin R M Knipe D W Higgins J P T ampGunnell D (2015) Risk of neuropsychiatric adverse eventsassociated with varenicline systematic review and meta-analysisBMJ 350 [h1109] httpsdoiorg101136bmjh1109
Publishers PDF also known as Version of record
Link to published version (if available)101136bmjh1109
Link to publication record in Explore Bristol ResearchPDF-document
University of Bristol - Explore Bristol ResearchGeneral rights
This document is made available in accordance with publisher policies Please cite only thepublished version using the reference above Full terms of use are availablehttpwwwbristolacukredresearch-policypureuser-guidesebr-terms
RESEARCH
1
open access
thethinspbmj | BMJ 2015350h1109 | doi 101136bmjh1109
School of Social and Community Medicine University of Bristol Bristol BS8 2PS UKCorrespondence to K H Thomas kylathomasbristolacukAdditional material is published online only To view please visit the journal online (httpdxdoiorg101136BMJh1109)Cite this as BMJ 2015350h1109doi 101136bmjh1109
Accepted 02 February 2015
Risk of neuropsychiatric adverse events associated with varenicline systematic review and meta-analysisKyla H Thomas Richard M Martin Duleeka W Knipe Julian P T Higgins David Gunnell
AbstrAct
ObjeCtiveTo determine the risk of neuropsychiatric adverse events associated with use of varenicline compared with placebo in randomised controlled trialsDesignSystematic review and meta-analysis comparing study effects using two summary estimates in fixed effects models risk differences and Peto odds ratiosData sOurCesMedline Embase PsycINFO the Cochrane Central Register of Controlled Trials (CENTRAL) and clinicaltrialsgoveligibility Criteria fOr seleCting stuDiesRandomised 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 excludedresultsIn the 39 randomised controlled trials (10 761 participants) there was no evidence of an increased risk of suicide or attempted suicide (odds ratio 167
95 confidence interval 033 to 857) suicidal ideation (058 028 to 120) depression (096 075 to 122) irritability (098 081 to 117) aggression (091 052 to 159) or death (105 047 to 238) in the varenicline users compared with placebo users Varenicline was associated with an increased risk of sleep disorders (163 129 to 207) insomnia (156 136 to 178) abnormal dreams (238 205 to 277) and fatigue (128 106 to 155) but a reduced risk of anxiety (075 061 to 093) 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)COnClusiOnsThis 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 recognisedsystematiC review registratiOnPROSPERO 2014CRD42014009224
IntroductionSmoking is the major avoidable cause of preventable morbidity and premature mortality in the United King-dom and internationally1 2 Researchers have estimated that smoking related illnesses cost the National Health Service (NHS) about pound5bn (euro7bn $8bn) annually3 Varenicline was first licensed in the UK in 2006 Ran-domised controlled trials have shown it to be the most clinically effective drug for short term abstinence in smoking cessation4 Concerns about its neuropsychiat-ric safety however led the Medicines and Healthcare Products Regulatory Agency (MHRA) to issue warnings about varenicline in the UK in 20085 Similarly since 2009 the United States Food and Drug Administration (FDA) has required the addition of a black box warning (the strongest safety warning that can be issued by the agency) to the labelling of varenicline6 These warnings were based on spontaneous reports of adverse drug reactions from the yellow card scheme and the FDA adverse events reporting system
Since the original safety warnings several studies have investigated the neuropsychiatric safety of vareni-cline7ndash10 Most of the studies were observational cohorts7ndash9 although one study examined the risk in a meta-analysis of 17 industry sponsored trials10 None of
WhAt Is AlreAdy knoWn on thIs topIcVarenicline is a commonly prescribed and effective drug for smoking cessation The Medicines and Healthcare Products Regulatory Agency (MHRA) and Food and Drug Administration (FDA) have issued safety warnings regarding suicidal thoughts and depression associated with the use of varenicline based on reports from spontaneous reporting systemsEvidence from previous observational cohort studies and a meta-analysis of 17 trials sponsored by Pfizer have found no evidence of an association with suicide non-fatal self harm or depressionConcerns have been raised about the validity of these findings as observational studies are prone to confounding and industry sponsored trials are more likely than other trials to report outcomes that are favourable to the study sponsor
WhAt thIs pAper AddsOur meta-analysis of all published randomised controlled trials is the most comprehensive meta-analysis of neuropsychiatric adverse events associated with varenicline use to date and reports effects using two summary statistics a relative measure (Peto odds ratio) and an absolute measure (risk difference)There was no evidence of an increased risk of suicide or attempted suicide suicidal ideation depression or death in varenicline users compared with placebo usersVarenicline was associated with an increased risk of sleep disorders insomnia and abnormal dreams side effects that are already well recognised and included in patient information leaflets for varenicline
RESEARCH
2 doi 101136bmjh1109 | BMJ 2015350h1109 | thethinspbmj
the studies found evidence of an increased risk of depression suicide or non-fatal self harm with vareni-cline Two major concerns however have been raised about the validity of these findings Firstly observa-tional studies are prone to confounding by indication11 For example the use of drugs for smoking cessation might seem to be associated with an increased risk of suicide because smokers themselves are at increased risk of mental illness and suicide12 13 Secondly there is evidence that industry sponsored trials are more likely than other trials to report outcomes that are favourable to the study sponsor14 Though the number of prescrip-tion items of varenicline dispensed in England increased from 499 in 2006 to a peak of almost a million in 2011 there was a 25 decrease from 2011 to 201315 This might reflect ongoing fears among prescribers and patients regarding vareniclinersquos safety
We conducted a systematic review and meta-analysis to determine the risk of neuropsychiatric adverse events and death in all published placebo controlled ran-domised controlled trials of varenicline This review deals with some of the limitations of the previous stud-ies and is the most comprehensive published review to date of the neuropsychiatric safety of varenicline
Methodseligibility and literature searchWe sought all placebo controlled randomised con-trolled trials of any duration in humans of varenicline at the maximum dose (1 mg twice daily) as described in the recommended standard titration regimen for varenicline (wwwchantixcom) We included studies in smokers and non-smokers We conducted searches of computer databases and online clinical trial registries (Medline Embase PsycINFO the Cochrane Central Register of Controlled Trials (CENTRAL) and clinicaltri-alsgov) The search strategy is shown in appendix 1 The searches were performed from the inception of each of the databases to 9 May 2014 There were no lan-guage restrictions We manually searched reference lists of relevant research articles and previous system-atic reviews10 16
Outcome measuresOur primary outcome measures were neuropsychiatric adverse events comprising suicide attempted suicide suicidal ideation and depression Secondary outcomes included other neuropsychiatric outcomes (abnormal dreams aggression anxiety fatigue insomnia irrita-bility sleep disorders somnolence) and death We included all deaths regardless of whether or not we believed they were related to drug treatment
Data extraction and managementTwo reviewers (KHT and DWK) independently screened the identified studies by title and abstract against the eligibility criteria We then obtained full reports of stud-ies for a second round of screening We identified dupli-cate publications for exclusion by examining the study name authors study population location and the dates of duration of the study A third reviewer (DG)
reviewed all excluded studies and studies when there was disagreement regarding inclusion or exclusion
KHT (all papers) and DG and RMM (papers equally shared) performed double data extraction to collect information on the study design (duration of treatment description of allocation concealment and blinding) study participants (inclusion and exclusion criteria country region population studied and baseline char-acteristics such as ethnicity sex smoking history) description of the intervention and placebo groups pri-mary and secondary outcomes measures of efficacy of treatment losses to follow-up and study sponsor KHT contacted authors of all studies to verify the accuracy of the extracted data
assessment of risk of biasThe Cochrane tool for assessing the risk of bias was used to assess whether there was high low or unclear risk of bias in the following domains random sequence generation allocation concealment blinding of partic-ipants and personnel blinding of outcome assess-ment incomplete outcome data selective outcome reporting and other sources of bias17 KHT (all papers) and DG and RMM (papers equally shared) assessed the risk of bias Discrepancies were resolved by referring to the original publications and discussion among all three reviewers KHT also contacted study authors to obtain study protocols and additional information that might not have been published to aid with assessment of the risk of bias
statistical analysisWe described study characteristics according to sample size characteristics of study participants study dura-tion duration of treatment and source of funding For trials with more than two intervention groups we extracted data for the maximum dose of varenicline (that is 1 mg twice daily) and the placebo group The ldquometanrdquo command in Stata (version 13 StataCorp USA) was used to conduct all of the meta-analyses18 Because our outcomes of interest are rare we followed recom-mendations of Bradburn and colleagues19 and used Peto odds ratios to compare the varenicline and placebo groups We also undertook meta-analyses using Man-tel-Haenszel risk differences We report results includ-ing 95 confidence intervals and forest plots for both measures so that findings can be compared Statistical heterogeneity was assessed with the I2 statistic20
For sensitivity analyses we used inverse variance methods under fixed and random effects models for the outcomes with the largest number of treatment events random effects models can be problematic for meta-analyses of rare events21 We report subgroup analyses for the primary outcomes by age (lt40 v ge40) sex (lt50 male v ge50 male) ethnicity (lt50 white v ge50 white) presence or absence of psychiatric ill-ness smoking status (smokers including smokeless tobacco users v majority non-smokers (gt60 non-smokers)) and whether or not the study was sponsored by a pharmaceutical company Studies were not categorised as sponsored by a pharmaceutical
RESEARCH
3thethinspbmj | BMJ 2015350h1109 | doi 101136bmjh1109
company if the drug was provided at no cost by the manufacturer andor if the research was investigator initiatedmdashthat is the drug and some funding was provided by the manufacturer although there was no other involvement in study conduct or publication and data were independently held by the researchers Tests for subgroup differences were performed Funnel plot asymmetry was assessed for two outcomemdashdepression and insomniamdashwith Harbordrsquos modified test for small study effects with the ldquometafunnelrdquo and ldquometabiasrdquo commands in Stata22 23
resultsstudy characteristicsFigure 1 summarises the selection of studies The search strategy identified 1089 studies from the com-puterised databases (476 from Medline 517 from Psy-cINFO and 96 from Embase) One additional trial was identified from CENTRAL and clinicaltrialsgov Out of the 1090 studies 130 were duplicates and 905 were excluded based on screening of titles and abstracts therefore 55 papers met the criteria for further screen-ing After the second round of screening 42 trials were identified for further data extraction24ndash65 Two addi-tional studies were identified when the search was repeated for the week beginning Monday 4 August 201466 67 Forty four studies were included in the sys-tematic review We received responses from study authors for 33 studies (75)
Table 1 and appendix 2 describe study characteris-tics The trials included 11 146 participants (6015 patients were randomised to receive a maximum of varenicline 1 mg twice daily and 5131 patients received a placebo) Of these randomised patients 10 998 were
evaluable for adverse events (5931 in the varenicline group and 5067 in the placebo group) The duration of treatment ranged from one week to 52 weeks while study duration ranged from eight days to 53 weeks Eighteen trials (613 of all participants) included cigarette smokers from the general population with no history of psychiatric illnesses (Table 2) In trials that included cigarette smokers (39 trials) participants smoked an average of 20 cigarettes a day for 266 years in the varenicline group and 20 cigarettes a day for 262 years in the placebo group Loss to follow-up ranged from 0 to 60 in both groups (appendix 2) In 12 trials losses to follow-up were higher in the varenicline group than the placebo group whereas in 17 trials losses to follow-up were higher in the placebo group than the varenicline group
Table 3 shows the assessment of risk of bias We excluded five trials from the meta-analysis as the risk of bias was unclear in four or more of the six domains47 52 60 or because no data were reported in the published papers and the study authors did not respond to our requests for data48 49 52 This resulted in exclusion of 114 patients (19) from the varenicline group and 123 patients (24) from the placebo group 10 761 patients were included in the meta-analyses (5817 in the varenicline group and 4944 in the placebo group) In three trials39 41 42 there were high losses to follow-up 537 60 and 452 respectively These studies were assessed as low risk of bias because of incomplete outcome data and were not excluded They were all small trials (combined total of n=92 in the varenicline group (16 of all people ran-domised to varenicline in our meta-analysis) and n=86 in the placebo group (17 of all people randomised to pla-cebo)) In addition only nine out of 178 patients (51) were lost to follow-up because of adverse events and these were mostly gastrointestinal in nature (such as nausea and vomiting)39 42 41
risk of neuropsychiatric adverse events and deathTwo people died by suicide (both in the varenicline arms) and four attempted to do so (two in the vareni-cline arm and two in the placebo arm) Table 4 sum-marises the Peto odds ratios risk differences and 95 confidence interval for the primary and secondary out-comes Because of the small numbers of events we combined suicide and attempted suicide into a single outcome Thirty one trials reported suicide and suicide attempt the Peto odds ratio for varenicline versus pla-cebo was 167 (95 confidence interval 033 to 857 P=054 I2=103) and the risk difference was 00003 (minus0002 to 0003 P=081 I2=00) Twenty trials reported suicidal ideation (figs 2 and 3) the Peto odds ratio was 058 (028 to 120 P=014 I2=00) and the risk difference was minus0003 (minus0009 to 0002 P=024 I2=00) Thirty one trials reported on depression (figs 4 and 5) the Peto odds ratio was 096 (075 to 122 P=074 I2=00) and the risk difference was minus0001 (minus001 to 001 P=074 I2=00) Death was reported in 36 trials (total 135760 in the varenicline group and 114887 in the placebo group) The Peto odds ratio for death was 105 (047 to 238 P=09 I2=387) and
Boxes (n=)Articles identied through literature search on 9 May 2014 (n=1090) Computerised databases (n=1089) Medline (n=476) Embase (n=96) PsycINFO (n=517) Additional trials identied from Cochrane database of randomised controlled trials or Clinicaltrialsgov (n=1)
Screening of titles and abstracts (n=1090)
Full text articles for second round of screening (n=55)
Eligible trials aer second round of screening (n=42)
Included in systematic review (n=44)
Additional trials published aer search (n=2)Drug manufacturer conrmed no furthertrials underway for publication in 2014
Duplicates (n=130)Excluded (n=905)
Excluded (n=13) Crossover trials (n=8) No monitoring of adverse eventssingle doseltmax dose varenicline (n=4) Second paper on same trial with no additional information (n=1)
fig 1 | flow chart showing selection of randomised controlled trials for inclusion in systematic review of varenicline
RESEARCH
4 doi 101136bmjh1109 | BMJ 2015350h1109 | thethinspbmj
there was no evidence of an increased risk of death in the varenicline group compared with the placebo group (risk difference 00001 minus0003 to 0003 P=094 I2=00) (Table 4) The forest plots for the secondary outcomes are shown in appendix 3
We found no evidence of an increased risk of irritabil-ity (odds ratio 098 05 confidence interval 081 to 117 P=079 I2=00) aggression (091 052 to 159 P=075 I2=208) or somnolence (123 094 to 162 P=013 I2=104) as the confidence intervals included the null value of 1 Varenicline was associated with an increased risk of sleep disorders (163 129 to 207 Plt0001 I2=00) insomnia (156 136 to 178 Plt0001 I2=00) abnormal dreams (238 205 to 277 Plt0001 I2=223)
and fatigue (128 106 to 155 P=001 I2=63) with some evidence of a reduced risk of anxiety (075 061 to 093 P=0008 I2=57) Consistent findings were observed for the risk differences (table 4)
sensitivity analysesThere were minimal differences in the effect measures and 95 confidence intervals with Peto fixed effects and random effects odds ratios (Table 5)
subgroup analysesThe subgroup analyses are shown in appendix 4 for the primary outcomes of depression and suicidal ideation Subgroup tests showed no evidence of a variation in the
table 1 | Characteristics of randomised controlled trials of varenicline 1mg twice daily included in systematic review
studyDuration (weeks) sample size mean age (years) men whitestudy treatment varenicline Placebo varenicline Placebo varenicline Placebo varenicline Placebo
Anthenelli 201324 52 12 256 269 454 471 379 368 NA NABolliger 201125 24 12 394 199 431 439 577 657 303 313Brandon 201126 22 22 56 58 458 412 609 611 541 648Burstein 200627 13 13 8 8 681 679 75 50 50 375Chengappa 201466 24 12 31 29 457 462 29 345 645 724Cinciripini 201328 24 12 86 106 438 452 616 632 581 717Ebbert 201129 24 12 38 38 407 41 100 100 100 100Evins 201430 64 40 40 47 514 457 60 66 75 72Faessel 200931 26 2 14 7 154 154 571 571 857 714Fagerstrom 201032 26 12 213 218 439 439 89 90 99 100Fatemi 201333 12 12 6 9 404 414 833 778 50 889Garza 201134 16 12 55 55 334 338 60 727 80 709Gonzales 200635 52 12 352 344 425 426 50 541 795 762Gonzales 201467 52 12 251 247 477 473 498 494 948 914Hughes 201136 24 8 107 111 44 412 605 572 914 919Jorenby 200637 52 12 344 341 446 423 552 581 855 85Litten 201338 16 13 97 101 46 45 732 683 619 703McClure 201339 5 5 54 50 45 43 40 59 32 36McKee 200940 11 1 10 10 342 353 80 80 40 90Meszaros 201341 12 8 5 5 42 44 80 60 40 60Mitchell 201242 16 12 33 31 29 25 55 65 73 64Nakamura 200743 52 12 156 154 401 399 792 76 NA NANiaura 200844 40 12 160 160 415 421 503 535 93 884Nides 200645 52 7 127 127 419 416 504 52 856 878Oncken 200646 52 12 259 129 422 43 485 519 808 721Plebani 201247 9 8 18 19 NA NA 696 75 11 33Plebani 201348 13 12 19 21 448 481 789 905 421 714Poling 201049 12 11 13 18 365 344 846 778 462 722Rennard 201250 24 12 493 166 439 432 60 596 68 681Rigotti 201051 52 12 355 359 57 559 752 822 803 808Shim 201252 8 8 60 60 399 399 38 45 0 0Stein 201353 24 24 137 45 392 406 46 622 825 756Steinberg 201154 24 12 40 39 NA NA 60 59 77 67Tashkin 201155 52 12 250 254 572 571 625 622 819 841Tonnesen 201356 52 12 70 69 536 556 429 493 NA NATonstad 200657 52 12 603 607 454 453 502 483 967 97Tsai 200758 24 12 126 124 397 409 849 927 0 0Wang 200959 24 12 165 168 39 385 964 97 0 0Weiner 201160 12 12 4 5 NA NA NA NA NA NAWilliams 200761 53 52 251 126 482 466 506 484 869 921Williams 201262 26 12 84 43 402 43 774 767 595 581Wong 201263 52 12 151 135 519 533 55 504 NA NAZesiewicz 201264 8 8 10 10 474 538 44 67 NA NAZhao 201165 37 3 14 10 71 73 429 50 100 90NA=not applicable
RESEARCH
5thethinspbmj | BMJ 2015350h1109 | doi 101136bmjh1109
side effects of depression and suicidal ideation by age group (P=0391 and P=0933 respectively for interac-tion) percentage of men in the study (P=0418 and P=0925) percentage of white people in the study (P=0685 and P=0254) presence or absence of psychi-atric illness (P=0126 and P=0304) smoking status (P=0906 for depression but not calculated for suicidal ideation as there were no reports of suicidal ideation in studies that included non-smokers) and whether the trial was industry sponsored or not (P=0386 and P=0380) The effect estimates (odds ratio) for the trials in which all participants had psychiatric illnesses com-pared with those where none of the participants had psychiatric illness were 149 (95 confidence interval 084 to 265) versus 091 (069 to 121) for depression and 079 (032 to 193) versus 034 (009 to 129) for suicidal ideation
table 2 | summary of characteristics of patients enrolled in 44 randomised controlled trials of vareniclineCharacteristics of trial participants no of trialsSmokers from general population 18Smokers with psychiatric illness 8Heavy drinking smokersalcohol dependence 4People dependent on cocaine or opioid dependent 3Smokeless tobacco users 2Smokers with mild to moderate COPD 1Smokers with cardiovascular disease 1Smokers about to undergo surgery 1Patients with spinocerebellar ataxia type 3 1Adolescent smokers 1Elderly non-smokers 1Smokers in hospital 1Smokers previously treated with varenicline 1Ex-smokers on long term NRT 1COPD=chronic obstructive pulmonary disease NRT=nicotine replacement therapy
table 3 | risk of bias assessment for each trial of varenicline using Cochrane risk of assessment of bias tool
studyrandom sequence generation
allocation concealment used
blindingincomplete outcome data
selective reporting Other bias
Participants and personnel
Outcome assessment
Anthenelli 201324 Low Low Low Low Low Low LowBolliger 201125 Low Low Low Low Low Low LowBrandon 201126 Low Low Low Low Low Low LowBurstein 200627 Low Low Low Low Low Low LowChengappa 201466 Low Low Low Low Low Low LowCinciripini 201328 Low Low Low Low Low Low LowEbbert 201129 Low Unclear Low Low Low Low LowEvins 201430 Low Low Low Low Low Low LowFaessel 200931 Low Low Low Low Low Low LowFagerstrom 201032 Low Low Low Low Low Low LowFatemi 201333 Unclear Low Low Low Low Low LowGarza 201134 Unclear Low Low Low Low Low LowGonzales 206635 Low Low Low Low Low Low LowGonzales 201467 Low Low Low Low Low Low LowHughes 201136 Low Low Low Low Low Unclear LowJorenby 200637 Low Low Low Low Low Low LowLitten 201338 Low Low Low Low Low Low LowMcClure 201339 Low Low Low Low Low Low LowMcKee 200940 Unclear Unclear Low Unclear Low Low LowMeszaros 201341 Low Low Low Low Low Low LowMitchell 201242 Low Low Low Low Low Low LowNakamura 200743 Low Low Low Low Low Low LowNiaura 200844 Low Low Low Low Low Low LowNides 200645 Low Low Low Low Low Low LowOncken 200646 Low Low Low Low Low Low LowPlebani 201247 Unclear Unclear Unclear Unclear Low Unclear LowPlebani 201348 Low Low Low Unclear Unclear Unclear LowPoling 201049 Low Unclear Low Unclear Low Low LowRennard 201250 Low Low Low Low Low Low LowRigotti 201051 Low Low Low Low Low Low LowShim 201252 Unclear Unclear Low Unclear Unclear Unclear UnclearStein 201353 Low Low Low Low Low Low LowSteinberg 201154 Low Low Low Low Low Low LowTashkin 201155 Low Low Low Low Low Low LowTonnesen 201356 Low Unclear Low Low Low Low LowTonstad 200657 Low Low Low Low Low Low LowTsai 200758 Low Low Low Low Low Low LowWang 200959 Low Low Low Low Low Low UnclearWeiner 201160 Unclear Unclear Unclear Unclear Low Unclear UnclearWilliams 200761 Low Low Low Low Low Low LowWilliams 201262 Low Low Low Low Low Low LowWong 201263 Low Low Low Low Low Low LowZesiewicz 201264 Low Low Low Low Low Low LowZhao 201165 Low Low Low Low Low Low Unclear
RESEARCH
6 doi 101136bmjh1109 | BMJ 2015350h1109 | thethinspbmj
small study effectsThe funnel plots for depression and insomnia are shown in appendix 5 The P values for funnel plot asym-metry were 053 for depression and 093 for insomnia (that is there was no evidence against the null hypoth-esis of no small study effects)
discussionThis meta-analysis of 39 randomised controlled trials involving 5817 patients prescribed varenicline 1 mg twice daily and 4944 patients prescribed placebo found no increased risk of suicide or attempted suicide
suicidal ideation depression or death in individuals treated with varenicline Almost half of the trial partici-pants were chronic heavy smokers (that is they had smoked on average 20 cigarettes a day for 26 years) Five separate trials (including 1281 participants randomised to varenicline and 1143 to placebo) reported a suicide andor suicide attempt (see appendix 3) one reported suicide only three reported attempted suicide only and one reported both suicide and attempted suicide Two suicides and two attempts occurred in the varenicline group of the trials (008) and two attempts occurred in the placebo group (005) Use of the maximum dose of varenicline (1 mg twice daily) was associated with a 28 increased risk of fatigue a 56 increased risk of insomnia a 63 increased risk of sleep disorders and more than twice the risk of abnormal dreams There was evidence of a 25 reduction in the risk of anxiety When we used risk differences for every 1000 patients there were an additional 10 cases of fatigue 40 cases of insomnia 20 cases of sleep disorders and 60 cases of abnormal dreams in those prescribed varenicline com-pared with placebo Similarly there were 10 fewer epi-sodes of anxiety per 1000 participants in the varenicline group compared with the placebo group (risk difference minus001 95 confidence interval minus002 to minus00003) There was no evidence of a variation in depression and sui-cidal ideation by age sex ethnicity presence or absence of psychiatric illness or type of study sponsor
Comparison with other studiesA recent study by Kishi and Iwata examined the effects of varenicline for smoking cessation in people with schizo-phrenia in a meta-analysis of seven randomised con-trolled trials68 With the exception of the study by Hong and colleagues69 we included all their randomised con-trolled trials in the current analysis Similar to our find-ings Kishi and Iwata found no significant differences in depression and suicidal ideation between the vareni-cline and placebo groups They reported however that varenicline use was associated with a lower risk of abnor-mal dreamsnightmares than placebo (relative risk 047 95 confidence interval 022 to 099 P=005)68
table 4 | summary of Peto odds ratios risk differences and 95 confidence intervals for neuropsychiatric events in people treated with varenicline
neuropsychiatric adverse eventno of eventsno treated
Odds ratio (95 Ci) P value risk difference (95 Ci) P valuevarenicline group Placebo groupPrimary outcomesDepression 1635356 1394487 096 (075 to 122) 074 minus0001 (minus001 to 001) 074Suicidal ideation 152799 182191 058 (028 to 120) 014 minus0003 (minus0009 to 0002) 024Attempted suicide 22184 21842 075 (010 to 565) 078 minus00003 (minus0005 to 0004) 091Suicide and attempted suicide 45352 24478 167 (033 to 857) 054 00003 (minus0002 to 0003) 081secondary outcomesAbnormal dreams 6035606 2244741 238 (205 to 277) lt0001 006 (005 to 007) lt0001Aggression 394276 243524 091 (052 to 159) 075 minus0001 (minus0005 to 0004) 079Anxiety 2094999 2264457 075 (061 to 093) 0008 minus001 (minus002 to minus00003) 001Death 135760 114887 105 (047 to 238) 09 00001 (minus0003 to 0003) 094Fatigue 2835502 2024701 128 (106 to 155) 001 001 (0002 to 002) 001Insomnia 6795621 3794762 156 (136 to 178) lt0001 004 (003 to 005) lt0001Irritability 2935406 2664615 098 (081 to 117) 079 minus0001 (minus001 to 0008) 079Sleep disorders 2115081 1234284 163 (129 to 207) lt0001 002 (001 to 002) lt0001Somnolence 1395360 914542 123 (094 to 162) 013 0005 (minus0001 to 001) 013
Jorenby 2006 Hughes 2011 Bolliger 2011 Tashkin 2011 Williams 2012 Rennard 2012 Mitchell 2012 Stein 2013 Cinciripini 2013 Meszaros 2013 Anthenelli 2013 Evins 2014 Chengappa 2014 Zhao 2011 Brandon 2011 Ebbert 2011 Steinberg 2011 Wong 2012 McClure 2013 Gonzales 2014Overall I2=0 P=0621
013 (000 to 676)014 (000 to 708)
453 (024 to 8523)014 (000 to 690)084 (019 to 380)011 (001 to 151)013 (000 to 641)
366 (003 to 38784)016 (000 to 842)
100 (009 to 1103)014 (001 to 136)118 (016 to 875)
186 (019 to 1864)ExcludedExcludedExcludedExcludedExcludedExcludedExcluded
058 (028 to 120)
3363
2383239
1013100000000
100
0001 001 01 1 10 100 1000
Study
Favourstreatment
Favoursplacebo
Odds ratio(95 CI)
Odds ratio(95 CI)
Weight()
0343010723900248584
1486033
111108625
0256240231014046038040
0151041
024915799
Treatment
1340111101981251343
2165131033
110625
3269247129110054038039
0135042
0245182191
ControlNo of eventstotal
fig 2 | forest plot of risk of suicidal ideation events (Peto odds ratio) associated with varenicline use in 20 placebo controlled randomised trials
RESEARCH
7thethinspbmj | BMJ 2015350h1109 | doi 101136bmjh1109
This discrepancy with our findings could be explained by the small sample size of their study (288 from four randomised controlled trials versus 10 347 from 35 ran-domised controlled trials in our analysis)
Gibbons and Mann used pooled data from 17 ran-domised controlled trials sponsored by Pfizer to exam-ine neuropsychiatric adverse events associated with varenicline10 Our study included industry and non- industry sponsored trials and more than twice the num-ber of trials that they included Their findings of no increased risk of suicidal events depression and agita-tion are consistent with our study Although the authors did not include references to the published literature for their included studies (which made cross referenc-ing difficult) it is likely that we included most of their studies in our analysis
Another meta-analysis examined the long term effi-cacy and safety of varenicline in trials with a minimum follow-up period of 12 months70 A meta-analysis of the main psychiatric related adverse effects (which com-bined depressed mood other mood disorders bipolar disorder delirium suicidal and self injurious behaviours adjustment disorders and abnormal think-ing into a single outcome) did not show a ldquosignificant increase of psychiatric side effects for varenicline com-pared with placebordquo70 This meta-analysis however included only three trials and the combined psychiat-ric outcome was non-specific The authors reported an increased risk of insomnia (relative risk 165 95 confi-dence interval 129 to 211) abnormal dreams (278 207 to 373) and sleep disturbance (209 162 to 269) but no
increased risk of irritability (114 075 to 173) which is consistent with our findings70
A previous Cochrane review examined the efficacy and tolerability of nicotine receptor partial agonists including varenicline16 Trials were excluded if partici-pants used smokeless tobacco or if there was less than six months of follow-up In addition to the efficacy out-comes meta-analyses were performed for the most commonly reported adverse events nausea insomnia abnormal dreams and headache Findings were consis-tent with our study for insomnia (relative risk 162 95 confidence interval 140 to 188) and abnormal dreams (291 234 to 362)16 The Cochrane review did not report any treatment emergent deaths Although we used a broader definition of deaths in our analysis by includ-ing all deaths irrespective of whether or not we thought they were related to treatment we did not find an increased risk of death in the varenicline group
strengths and limitationsTo the best of our knowledge this is the most compre-hensive published systematic review (and meta-analy-sis) of neuropsychiatric effects associated with use of varenicline Compared with the previous Cochrane review16 our analysis included 16 additional trials for the meta-analysis of the risk of insomnia events and 23 addi-tional trials for the pooled analysis of abnormal dreams
The choice of summary statistics for meta-analyses of rare events caused controversy (about whether the Peto odds ratio should be reported instead of risk differ-ences) when it led to conflicting findings from two sys-tematic reviews examining the risk of cardiovascular side effects associated with varenicline use71 72 We pres-ent results using both measures a relative measure (Peto odds ratio and sensitivity analyses with fixed and random effects odds ratios) as well as an absolute mea-sure (risk difference) Findings were consistent for all examined outcomes
Many study authors did not specify the actual dates that adverse events were reported so we included all reported events this decision would have increased the likelihood of obtaining reports of rare adverse events We contacted authors for all of our included trials to check the data extracted on adverse events and for study protocols and other information to adequately assess the risk of bias in the studies We had a high response rate (75)
There are some limitations Firstly in this analysis we used study level data instead of individual level data so we were unable to determine whether differences in the adverse events were because of greater quit rates in the varenicline group relative to placebo Secondly because of the small number of suicides and attempted suicide reported (n=6) we cannot rule out major beneficial or adverse effects of varenicline for this outcome (Peto odds ratio 167 95 confidence interval 033 to 857) Thirdly there was potential for heterogeneity in the reporting of adverse events Authors used a range of methods to record adverse events including self report open ended questions structured questionnaires side effect check-lists and case reports coded to the Medical Dictionary for
Jorenby 2006 Hughes 2011 Zhao 2011 Brandon 2011 Ebbert 2011 Steinberg 2011 Bolliger 2011 Tashkin 2011 Williams 2012 Rennard 2012 Mitchell 2012 Wong 2012 McClure 2013 Stein 2013 Cinciripini 2013 Meszaros 2013 Anthenelli 2013 Evins 2014 Chengappa 2014 Gonzales 2014Overall I2=0 P=0995
-000 (-001 to 001)-001 (-003 to 002)000 (-015 to 015)000 (-004 to 004)000 (-005 to 005)000 (-005 to 005)001 (-001 to 002)000 (-001 to 001)-001 (-010 to 008)-001 (-003 to 001)-003 (-012 to 005)000 (-001 to 001)000 (-005 to 005)001 (-004 to 005)-001 (-004 to 002)000 (-061 to 061)-001 (-003 to 000)001 (-008 to 010)003 (-008 to 014)000 (-001 to 001)-000 (-001 to 000)
1551222
11112
1016224lt11121
10100
-05 0 05
Study
Favourstreatment
Favoursplacebo
Odds ratio(95 CI)
Odds ratio(95 CI)
Weight()
03430107014046038040
23900248584
1486033
0151041
111108625
0256240231
0249152799
Treatment
13401111010054038039
01981251343
2165131
0135042033
110625
3269247129
0245182191
ControlNo of eventstotal
fig 3 | forest plot of risk of suicidal ideation events (mantel-Haenszel risk difference) associated with varenicline use in 20 placebo controlled randomised trials
RESEARCH
8 doi 101136bmjh1109 | BMJ 2015350h1109 | thethinspbmj
Regulatory Activities (MedDRA wwwmeddraorg) All of the industry sponsored trials coded adverse events using MedDRA Fourthly we excluded two studies69 73 from the review as the maximum dose of varenicline used in these studies was only 1 mg once a daymdashthat is half of the rec-ommended maximum dose Hong and colleagues exam-ined varenicline treatment in 20 smokers and 15 non-smokers with schizophrenia or schizoaffective disor-der and found no evidence that varenicline worsened psychiatric symptoms in these patients69 Mocking and colleagues studied the effects of varenicline on emotional and cognitive processing in 21 healthy adult non-smokers and concluded that it did not cause problems in emo-tional processing or impulsivity providing less support for a possible depressogenic effect of varenicline73 Fur-thermore a secondary analysis which included all doses of varenicline in the original trials and these two excluded randomised controlled trials produced similar findings to our main analysis (see appendix 6)
We tried to minimise reporting bias by including all events (such as deaths) reported regardless of whether or
not we considered them to be related to treatment It is still possible however that reporting bias could have occurred as for certain trials where the corresponding authors did not respond to our requests for additional information we could not determine whether a lack of reporting of deaths in the published paper was synonymous with no deaths It was difficult to interpret the funnel plots to assess whether publication bias might be present as most trials were efficacy trials and were not performed solely to deter-mine the incidence of psychiatric adverse events
Additionally smoking cessation has been shown to have a positive impact on mental health outcomes with a reduction in depression and anxiety compared with those who continue to smoke74 Patients prescribed varenicline were reported to have an approximately threefold increased chance of quitting smoking com-pared with those given placebo (odds ratio 288 95 confidence interval 240 to 347)4 this could explain the reduction in anxiety observed in this meta-analysis
Lastly half of the trials were sponsored by Pfizer the manufacturers of varenicline Although previous research with nicotine replacement therapy has shown that industry sponsored trials were more likely than other trials to report outcomes that were favourable to the study sponsor14 we did not find any evidence for differences in depression and suicidal ideation for industry versus non industry sponsored trials (P=0386 and P=0380 respectively for interaction) In addition all of the industry sponsored trials were assessed over-all as having a low risk of bias
Conclusions and clinical implicationsBased on this comprehensive systematic review of pub-lished randomised controlled trials there is no evi-dence of an increased risk of depression suicidal behaviour (that is suicide or attempted suicide sui-cidal ideation) and death from any cause associated with treatment with varenicline Varenicline users however have an increased risk of abnormal dreams insomnia and sleep disturbances which are consistent with findings from other studies and previously docu-mented commonly reported side effects of varenicline (wwwchantixcom) We reported our findings using two summary statistics (a relative measure and an abso-lute measure) and observed consistency with both methods This meta-analysis adds to previous research (observational and experimental) that found no evi-dence for increased suicidal behaviour or depression with varenicline the most effective drug for smoking cessation4 The dangers of smoking are well docu-mented and the health benefits of stopping smoking are well known Our analysis suggests that the benefits of varenicline for smoking cessation outweigh the as yet unproved risks of suicidal behaviour In the UK vareni-cline is recommended alongside bupropion and nico-tine replacement therapy as first line treatment for smoking cessation75 Therefore the reduction in vareni-cline prescribing in the UK should be as much a cause for concern to clinicians regulatory agencies and policy makers as the unfounded fears regarding vareni-clinersquos association with suicidal behaviour
Nides 2006 Tonstad 2006 Jorenby 2006 Onken 2006 Gonzales 2006 Williams 2007 Tsai 2007 Niaura 2008 Rigotti 2010 Fagerstrom 2010 Hughes 2011 Garza 2011 Ebbert 2011 Steinberg 2011 Bolliger 2011 Tashkin 2011 Williams 2012 Rennard 2012 Wong 2012 Zesiewicz 2012 McClure 2013 Stein 2013 Litten 2013 Cinciripini 2013 Meszaros 2013 Anthenelli 2013 Evins 2014 Chengappa 2014 Gonzales 2014 Faessel 2009 Brandon 2011Overall I2=0 P=0631
193 (020 to 1870)088 (044 to 178)
419 (095 to 1855)070 (018 to 267)057 (017 to 186)148 (051 to 428)050 (005 to 488)148 (025 to 864)164 (041 to 661)043 (010 to 191)053 (005 to 514)
100 (006 to 1619)014 (000 to 682)097 (013 to 719)102 (030 to 340)122 (037 to 402)066 (013 to 326)020 (004 to 090)089 (089 to 642)012 (012 to 208)078 (078 to 185)066 (066 to 185)123 (123 to 378)051 (020 to 130)
100 (005 to 1991)140 (067 to 292)
118 (007 to 1932)381 (099 to 1467)234 (053 to 1040)
ExcludedExcluded
096 (075 to 122)
1123345123311lt1144232186571
1113300
100
0001 001 01 1 10 100 1000
Study
Favourstreatment
Favoursplacebo
Odds ratio(95 CI)
Odds ratio(95 CI)
Weight()
212515602634362534349
1225111263157535322131107155038240
83906248484
44862151
091741
1711179768615
17256140831
5249014046
1635356
Treatment
112317604134041217344412621242155335052182111155138239
41985251343
51652135
292042733
610114106
1513269
147229
224507
0541394487
ControlNo of eventstotal
fig 4 | forest plot of risk of depression events (Peto odds ratio) associated with varenicline use in 31 placebo controlled randomised trials
RESEARCH
9thethinspbmj | BMJ 2015350h1109 | doi 101136bmjh1109
We are grateful to the corresponding authors of the trials and Cristina Russ of Pfizer (for the Pfizer sponsored trials) for their support with providing access to the data on psychiatric adverse events and death used in this studyContributors KHT DG and RMM conceived the study KHT conducted the literature search KHT and DWK screened the abstracts with assistance from DG KHT DG and RMM were responsible for data extraction and the risk of bias assessment KHT did the statistical analysis with support from JPH KHT wrote the paper with contributions from all authors All authors have approved the final draft of the manuscript KHT is study guarantor had full access to all of the data (including statistical reports and tables) and can take responsibility for the integrity of the data and the accuracy of the data analysisFunding KHT is currently funded by a clinical lectureship from the National Institute for Health Research Part of this work was undertaken while KHT was on a National Institute for Health Research doctoral research fellowship (DRF-2010-03-138) DWK is funded by a Wellcome Trust four year studentship (WT099874MA) DG is an NIHR senior investigator The views expressed in this publication are those of the authors and not necessarily those of the NHS the National Institute for Health Research or the Department of HealthCompeting interests All authors have completed the Unified Competing Interest form at wwwicmjeorgcoi_disclosurepdf (available on request from the corresponding author) and declare RMM had specified relationship with the MHRA in the past (was a member of the MHRArsquos Independent Scientific Advisory Committee for CPRD research and received expenses and a small fee for meeting attendance and preparation for meetings) DG had specified relationship with the MHRA in the past (was a member of the MHRArsquos Pharmacovigilance Expert Advisory Group and received travel expenses and a small fee for meeting attendance and preparation for meetings)Ethics approval Not requiredData sharing No additional data are availableTransparency declaration KHT affirms that this manuscript is an honest accurate and transparent account of the study being reported that no important aspects of the study have been omitted and that any discrepancies from the study as planned (and if relevant registered) have been explainedThis is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 40) license which permits others to distribute remix adapt build upon this work non-commercially and license their derivative works on different terms provided the original work is properly cited and the use is non-commercial See httpcreativecommonsorglicensesby-nc401 Peto R Darby S Deo H Silcocks P Whitley E Doll R Smoking
smoking cessation and lung cancer in the UK since 1950 combination of national statistics with two case-control studies BMJ 2000321323ndash9
2 Jha P Peto R Global effects of smoking of quitting and of taxing tobacco N Engl J Med 201437060ndash8
3 Allender S Balakrishnan R Scarborough P Webster P Rayner M The burden of smoking-related ill health in the UK Tob Control 200918262ndash67
4 Cahill K Stevens S Perera R Lancaster T Pharmacological interventions for smoking cessation an overview and network meta-analysis Cochrane Database Syst Rev 20135CD009329
5 Medicines and Healthcare Products Regulatory Agency Varenicline adverse psychiatric reactions including depression Drug Safety Update 200822ndash3
6 US Food and Drug Administration Information for healthcare professionals varenicline (marketed as Chantix) and bupropion (marketed as Zyban Wellbutrin and generics) FDA Drug Safety Newsletter 2009
7 Gunnell D Irvine D Wise L Davies C Martin RM Varenicline and suicidal behaviour a cohort study based on data from the General Practice Research Database BMJ 2009339b3805
8 Meyer TE Taylor LG Xie S Graham DJ Mosholder AD Williams JR et al Neuropsychiatric events in varenicline and nicotine replacement patch users in the Military Health System Addiction 2013108203ndash10
9 Thomas KH Martin RM Davies N Metcalfe C Windmeijer F Gunnell D Smoking cessation treatment and the risk of depression suicide and self-harm in the Clinical Practice Research Datalink prospective cohort study BMJ 2013347f5704
10 Gibbons RD Mann JJ Varenicline smoking cessation and neuropsychiatric adverse events Am J Psychiatry 20131701460ndash7
11 Walker AM Confounding by indication Epidemiology 19967335ndash612 Miller M Hemenway D Bell NS Yore MM Amoroso PJ Cigarette
smoking and suicide a prospective study of 300000 male active-duty Army soldiers Am J Epidemiol 20001511060ndash3
Nides 2006 Tonstad 2006 Jorenby 2006 Onken 2006 Gonzales 2006 Williams 2007 Tsai 2007 Niaura 2008 Faessel 2009 Rigotti 2010 Fagerstrom 2010 Hughes 2011 Garza 2011 Brandon 2011 Ebbert 2011 Steinberg 2011 Bolliger 2011 Tashkin 2011 Williams 2012 Rennard 2012 Wong 2012 Zesiewicz 2012 McClure 2013 Stein 2013 Litten 2013 Cinciripini 2013 Meszaros 2013 Anthenelli 2013 Evins 2014 Chengappa 2014 Gonzales 2014Overall I2=0 P=0783
001 (-002 to 003)-000 (-002 to 001)001 (-000 to 003)-001 (-005 to 003)-001 (-003 to 001)-002 (-002 to 006)001 (-004 to 002)001 (-002 to 003)000 (-019 to 019)001 (-001 to 002)-001 (-004 to 001)-001 (-004 to 002)000 (-005 to 005)000 (-004 to 004)-003 (-010 to 004)-000 (-010 to 010)000 (-002 to 002)000 (-002 to 003)-002 (-011 to 007)-002 (-005 to 001)-000 (-003 to 003)-022 (-052 to 008)-006 (-027 to 015)-006 (-021 to 010)001 (-006 to 008)-006 (-015 to 002)000 (-050 to 050)002 (-002 to 006)000 (-006 to 007)019 (001 to 037)001 (-001 to 003)-000 (-001 to 001)
313737433lt1752111165153lt11122lt16115
100
-05 0 05
Study
Favourstreatment
Favoursplacebo
Odds ratio(95 CI)
Odds ratio(95 CI)
Weight()
212515602634362534349
1225111263157014
535322131107155046038240
83906248484
44862151
091741
1711179768615
17256140831
52491635356
Treatment
112317604134041217344412621242155
07335052182111155054138239
41985251343
51652135
292042733
610114106
1513269
147229
22451394487
ControlNo of eventstotal
fig 5 | forest plot of risk of depression events (mantel-Haenszel risk difference) associated with varenicline use in 31 placebo controlled randomised trials
table 5 | Comparison of Peto fixed effects and random effects odds ratios (Or) for insomnia sleep disorders and abnormal dreams in people treated with varenicline
neuropsychiatric adverse event
no of eventsno treatedOdds ratio (95 Ci)
test for heterogeneity ()varenicline group Placebo group
insomniaPeto OR 6795621 3794762 156 (136 to 178) 0Fixed effects OR 6795621 3794762 156 (135 to 179) 0Random effects OR 6795621 3794762 156 (135 to 179) 0sleep disordersPeto OR 2115081 1234284 163 (129 to 207) 0Fixed effects OR 2115081 1234284 157 (122 to 203) 0Random effects OR 2115081 1234284 157 (122 to 203) 0abnormal dreams Peto OR 6035606 2244741 238 (205 to 277) 223Fixed effects OR 6035606 2244741 237 (199 to 282) 316Random effects OR 6035606 2244741 236 (187 to 298) 316All Plt0001
RESEARCH
10 doi 101136bmjh1109 | BMJ 2015350h1109 | thethinspbmj
13 Miller M Hemenway D Rimm E Cigarettes and suicide a prospective study of 50000 men Am J Public Health 200090768ndash73
14 Etter JF Burri M Stapleton J The impact of pharmaceutical company funding on results of randomized trials of nicotine replacement therapy for smoking cessation a meta-analysis Addiction 2007102815ndash22
15 Prescribing and Primary Care team Health and Social Care Information Centre Prescription cost analysis England 2013 Health and Social Care Information Centre 2014
16 Cahill K Stead LF Lancaster T Nicotine receptor partial agonists for smoking cessation Cochrane Database Syst Rev 20124CD006103
17 Higgins JPT Altman DG Assessing risk of bias in included studies Cochrane handbook for systematic reviews of interventions John Wiley 2008187ndash241
18 Harris R Bradburn M Deeks J Harbord R Altman D Sterne J metan fixed- and random-effects meta-analysis Stata J 200883ndash28
19 Bradburn MJ Deeks JJ Berlin JA Russell Localio A Much ado about nothing a comparison of the performance of meta-analytical methods with rare events Stat Med 20072653ndash77
20 Higgins JP Thompson SG Deeks JJ Altman DG Measuring inconsistency in meta-analyses BMJ 2003327557ndash60
21 Higgins JPT Deeks JJ Altman DG Special topics in statistics Cochrane handbook for systematic reviews of interventions John Wiley 2008481ndash529
22 Sterne JAC Harbord RM Funnel plots in meta-analysis Stata J 20044127ndash41
23 Harbord RM Harris RJ Sterne JAC Updated tests for small-study effects in meta-analyses Stata J 20099197ndash210
24 Anthenelli RM Morris C Ramey TS Dubrava SJ Tsilkos K Russ C et al Effects of varenicline on smoking cessation in adults with stably treated current or past major depression a randomized trial Ann Intern Med 2013159390ndash400
25 Bolliger CT Issa JS Posadas-Valay R Safwat T Abreu P Correia EA et al Effects of varenicline in adult smokers a multinational 24-week randomized double-blind placebo-controlled study Clin Ther 201133465ndash77
26 Brandon TH Drobes DJ Unrod M Heckman BW Oliver JA Roetzheim RC et al Varenicline effects on craving cue reactivity and smoking reward Psychopharmacology (Berl) 2011218391ndash403
27 Burstein AH Fullerton T Clark DJ Faessel HM Pharmacokinetics safety and tolerability after single and multiple oral doses of varenicline in elderly smokers J Clin Pharmacol 2006461234ndash40
28 Cinciripini PM Robinson JD Karam-Hage M Minnix JA Lam C Versace F et al Effects of varenicline and bupropion sustained-release use plus intensive smoking cessation counseling on prolonged abstinence from smoking and on depression negative affect and other symptoms of nicotine withdrawal JAMA Psychiatry 201370522ndash33
29 Ebbert JO Croghan IT Severson HH Schroeder DR Hays JT A pilot study of the efficacy of varenicline for the treatment of smokeless tobacco users in Midwestern United States Nicotine Tob Res 201113820ndash6
30 Evins AE Cather C Pratt SA Pachas GN Hoeppner SS Goff DC et al Maintenance treatment with varenicline for smoking cessation in patients with schizophrenia and bipolar disorder a randomized clinical trial JAMA 2014311145ndash54
31 Faessel H Ravva P Williams K Pharmacokinetics safety and tolerability of varenicline in healthy adolescent smokers a multicenter randomized double-blind placebo-controlled parallel-group study Clin Ther 200931177ndash89
32 Fagerstrom K Gilljam H Metcalfe M Tonstad S Messig M Stopping smokeless tobacco with varenicline randomised double blind placebo controlled trial BMJ 2010341c6549
33 Fatemi SH Yousefi MK Kneeland RE Liesch SB Folsom TD Thuras PD Antismoking and potential antipsychotic effects of varenicline in subjects with schizophrenia or schizoaffective disorder a double-blind placebo and bupropion-controlled study Schizophr Res 2013146376ndash8
34 Garza D Murphy M Tseng LJ Riordan HJ Chatterjee A A double-blind randomized placebo-controlled pilot study of neuropsychiatric adverse events in abstinent smokers treated with varenicline or placebo Biol Psychiatry 2011691075ndash82
35 Gonzales D Rennard SI Nides M Oncken C Azoulay S Billing CB et al Varenicline an alpha4beta2 nicotinic acetylcholine receptor partial agonist vs sustained-release bupropion and placebo for smoking cessation a randomized controlled trial JAMA 200629647ndash55
36 Hughes JR Rennard SI Fingar JR Talbot SK Callas PW Fagerstrom KO Efficacy of varenicline to prompt quit attempts in smokers not currently trying to quit a randomized placebo-controlled trial Nicotine Tob Res 201113955ndash64
37 Jorenby DE Hays JT Rigotti NA Azoulay S Watsky EJ Williams KE et al Efficacy of varenicline an alpha4beta2 nicotinic acetylcholine receptor partial agonist vs placebo or sustained-release bupropion for smoking cessation a randomized controlled trial JAMA 200629656ndash63
38 Litten RZ Ryan ML Fertig JB Falk DE Johnson B Dunn KE et al A double-blind placebo-controlled trial assessing the efficacy of varenicline tartrate for alcohol dependence J Addict Med 20137277ndash86
39 McClure EA Vandrey RG Johnson MW Stitzer ML Effects of varenicline on abstinence and smoking reward following a programmed lapse Nicotine Tob Res 201315139ndash48
40 McKee SA Harrison EL OrsquoMalley SS Krishnan-Sarin S Shi J Tetrault JM et al Varenicline reduces alcohol self-administration in heavy-drinking smokers Biol Psychiatry 200966185ndash90
41 Meszaros ZS Abdul-Malak Y Dimmock JA Wang D Ajagbe TO Batki SL Varenicline treatment of concurrent alcohol and nicotine dependence in schizophrenia a randomized placebo-controlled pilot trial J Clin Psychopharmacol 201333243ndash7
42 Mitchell JM Teague CH Kayser AS Bartlett SE Fields HL Varenicline decreases alcohol consumption in heavy-drinking smokers Psychopharmacology (Berl) 2012223299ndash306
43 Nakamura M Oshima A Fujimoto Y Maruyama N Ishibashi T Reeves KR Efficacy and tolerability of varenicline an alpha4beta2 nicotinic acetylcholine receptor partial agonist in a 12-week randomized placebo-controlled dose-response study with 40-week follow-up for smoking cessation in Japanese smokers Clin Ther 2007291040ndash56
44 Niaura R Hays JT Jorenby DE Leone FT Pappas JE Reeves KR et al The efficacy and safety of varenicline for smoking cessation using a flexible dosing strategy in adult smokers a randomized controlled trial Curr Med Res Opin 2008241931ndash41
45 Nides M Oncken C Gonzales D Rennard S Watsky EJ Anziano R et al Smoking cessation with varenicline a selective alpha4beta2 nicotinic receptor partial agonist results from a 7-week randomized placebo- and bupropion-controlled trial with 1-year follow-up Arch Intern Med 20061661561ndash8
46 Oncken C Gonzales D Nides M Rennard S Watsky E Billing CB et al Efficacy and safety of the novel selective nicotinic acetylcholine receptor partial agonist varenicline for smoking cessation Arch Intern Med 20061661571ndash7
47 Plebani JG Lynch KG Yu Q Pettinati HM OrsquoBrien CP Kampman KM Results of an initial clinical trial of varenicline for the treatment of cocaine dependence Drug Alcohol Depend 2012121163ndash6
48 Plebani JG Lynch KG Rennert L Pettinati HM OrsquoBrien CP Kampman KM Results from a pilot clinical trial of varenicline for the treatment of alcohol dependence Drug Alcohol Depend 2013133754ndash8
49 Poling J Rounsaville B Gonsai K Severino K Sofuoglu M The safety and efficacy of varenicline in cocaine using smokers maintained on methadone a pilot study Am J Addict 201019401ndash8
50 Rennard S Hughes J Cinciripini PM Kralikova E Raupach T Arteaga C et al A randomized placebo-controlled trial of varenicline for smoking cessation allowing flexible quit dates Nicotine Tob Res 201214343ndash50
51 Rigotti NA Pipe AL Benowitz NL Arteaga C Garza D Tonstad S Efficacy and safety of varenicline for smoking cessation in patients with cardiovascular disease a randomized trial Circulation 2010121221ndash9
52 Shim JC Jung DU Jung SS Seo YS Cho DM Lee JH et al Adjunctive varenicline treatment with antipsychotic medications for cognitive impairments in people with schizophrenia a randomized double-blind placebo-controlled trial Neuropsychopharmacology 201237660ndash8
53 Stein MD Caviness CM Kurth ME Audet D Olson J Anderson BJ Varenicline for smoking cessation among methadone-maintained smokers a randomized clinical trial Drug Alcohol Depend 2013133486ndash93
54 Steinberg MB Randall J Greenhaus S Schmelzer AC Richardson DL Carson JL Tobacco dependence treatment for hospitalized smokers a randomized controlled pilot trial using varenicline Addic Behav 2011361127ndash32
55 Tashkin DP Rennard S Hays JT Ma W Lawrence D Lee TC Effects of varenicline on smoking cessation in patients with mild to moderate COPD a randomized controlled trial Chest 2011139591ndash9
56 Tonnesen P Mikkelsen K Varenicline to stop long-term nicotine replacement use a double-blind randomized placebo-controlled trial Nicotine Tob Res 201315419ndash27
57 Tonstad S Tonnesen P Hajek P Williams KE Billing CB Reeves KR et al Effect of maintenance therapy with varenicline on smoking cessation a randomized controlled trial JAMA 200629664ndash71
58 Tsai ST Cho HJ Cheng HS Kim CH Hsueh KC Billing CB Jr et al A randomized placebo-controlled trial of varenicline a selective alpha4beta2 nicotinic acetylcholine receptor partial agonist as a new therapy for smoking cessation in Asian smokers Clin Ther 2007291027ndash39
59 Wang C Xiao D Chan KPW Pothirat C Garza D Davies S Varenicline for smoking cessation A placebo-controlled randomized study Respirology 200914384ndash92
60 Weiner E Buchholz A Coffay A Liu F McMahon RP Buchanan RW et al Varenicline for smoking cessation in people with schizophrenia a double blind randomized pilot study Schizophr Res 201112994ndash5
RESEARCH
11thethinspbmj | BMJ 2015350h1109 | doi 101136bmjh1109
61 Williams K Reeves K Billing C Pennington A Gong J A double-blind study evaluating the long-term safety of varenicline for smoking cessation Curr Med Res Opin 200723793ndash801
62 Williams JM Anthenelli RM Morris CD Treadow J Thompson JR Yunis C et al A randomized double-blind placebo-controlled study evaluating the safety and efficacy of varenicline for smoking cessation in patients with schizophrenia or schizoaffective disorder J Clin Psychiatry 201273654ndash60
63 Wong J Abrishami A Yang Y Zaki A Friedman Z Selby P et al A perioperative smoking cessation intervention with varenicline a double-blind randomized placebo-controlled trial Anesthesiology 2012117755ndash64
64 Zesiewicz TA Greenstein PE Sullivan KL Wecker L Miller A Jahan I et al A randomized trial of varenicline (Chantix) for the treatment of spinocerebellar ataxia type 3 Neurology 201278545ndash50
65 Zhao Q Schwam E Fullerton T OrsquoGorman M Burstein AH Pharmacokinetics safety and tolerability following multiple oral doses of varenicline under various titration schedules in elderly nonsmokers J Clin Pharmacol 201151492ndash501
66 Chengappa KN Perkins KA Brar JS Schlicht PJ Turkin SR Hetrick ML et al Varenicline for smoking cessation in bipolar disorder a randomized double-blind placebo-controlled study J Clin Psychiatry 201475765ndash72
67 Gonzales D Hajek P Pliamm L Nackaerts K Tseng LJ McRae TD et al Retreatment with varenicline for smoking cessation in smokers who have previously taken varenicline a randomized placebo-controlled trial Clin Pharmacol Ther 201496390ndash6
68 Kishi T Iwata N Varenicline for smoking cessation in people with schizophrenia systematic review and meta-analysis Eur Arch Psychiatry Clin Neurosci 2014 Oct 5 [Epub ahead of print]
69 Hong LE Thaker GK McMahon RP Summerfelt A Rachbeisel J Fuller RL et al Effects of moderate-dose treatment with varenicline on neurobiological and cognitive biomarkers in smokers and nonsmokers with schizophrenia or schizoaffective disorder Arch Gen Psychiatry 2011681195ndash206
70 Huang Y Li W Yang L Jiang Y Wu Y Long-term efficacy and safety of varenicline for smoking cessation a systematic review and
meta-analysis of randomized controlled trials J Public Health 201220355ndash65
71 Singh S Loke YK Spangler JG Furberg CD Risk of serious adverse cardiovascular events associated with varenicline a systematic review and meta-analysis CMAJ 20111831359ndash66
72 Prochaska JJ Hilton JF Risk of cardiovascular serious adverse events associated with varenicline use for tobacco cessation systematic review and meta-analysis BMJ 2012344e2856
73 Mocking RJ Patrick Pflanz C Pringle A Parsons E McTavish SF Cowen PJ et al Effects of short-term varenicline administration on emotional and cognitive processing in healthy non-smoking adults a randomized double-blind study Neuropsychopharmacology 201338476ndash84
74 Taylor G McNeill A Girling A Farley A Lindson-Hawley N Aveyard P Change in mental health after smoking cessation systematic review and meta-analysis BMJ 2014348g1151
75 Smoking cessation services in primary care pharmacies local authorities and workplaces particularly for manual working groups pregnant women and hard to reach communities NICE public health guidance 10 National Institute for Health and Care Excellence 2008
copy BMJ Publishing Group Ltd 2015
Appendix 1 Search strategy to identify relevant articles in MedlineAppendix 2 Further characteristics of included ran-domised controlled trialsAppendix 3 Forest plots for secondary outcomesAppendix 4 Subgroup analysesAppendix 5 Funnel plots Appendix 6 Summary of Peto odds ratios risk differ-ences and 95 confidence intervals for neuropsychiat-ric events
RESEARCH
1
open access
thethinspbmj | BMJ 2015350h1109 | doi 101136bmjh1109
School of Social and Community Medicine University of Bristol Bristol BS8 2PS UKCorrespondence to K H Thomas kylathomasbristolacukAdditional material is published online only To view please visit the journal online (httpdxdoiorg101136BMJh1109)Cite this as BMJ 2015350h1109doi 101136bmjh1109
Accepted 02 February 2015
Risk of neuropsychiatric adverse events associated with varenicline systematic review and meta-analysisKyla H Thomas Richard M Martin Duleeka W Knipe Julian P T Higgins David Gunnell
AbstrAct
ObjeCtiveTo determine the risk of neuropsychiatric adverse events associated with use of varenicline compared with placebo in randomised controlled trialsDesignSystematic review and meta-analysis comparing study effects using two summary estimates in fixed effects models risk differences and Peto odds ratiosData sOurCesMedline Embase PsycINFO the Cochrane Central Register of Controlled Trials (CENTRAL) and clinicaltrialsgoveligibility Criteria fOr seleCting stuDiesRandomised 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 excludedresultsIn the 39 randomised controlled trials (10 761 participants) there was no evidence of an increased risk of suicide or attempted suicide (odds ratio 167
95 confidence interval 033 to 857) suicidal ideation (058 028 to 120) depression (096 075 to 122) irritability (098 081 to 117) aggression (091 052 to 159) or death (105 047 to 238) in the varenicline users compared with placebo users Varenicline was associated with an increased risk of sleep disorders (163 129 to 207) insomnia (156 136 to 178) abnormal dreams (238 205 to 277) and fatigue (128 106 to 155) but a reduced risk of anxiety (075 061 to 093) 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)COnClusiOnsThis 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 recognisedsystematiC review registratiOnPROSPERO 2014CRD42014009224
IntroductionSmoking is the major avoidable cause of preventable morbidity and premature mortality in the United King-dom and internationally1 2 Researchers have estimated that smoking related illnesses cost the National Health Service (NHS) about pound5bn (euro7bn $8bn) annually3 Varenicline was first licensed in the UK in 2006 Ran-domised controlled trials have shown it to be the most clinically effective drug for short term abstinence in smoking cessation4 Concerns about its neuropsychiat-ric safety however led the Medicines and Healthcare Products Regulatory Agency (MHRA) to issue warnings about varenicline in the UK in 20085 Similarly since 2009 the United States Food and Drug Administration (FDA) has required the addition of a black box warning (the strongest safety warning that can be issued by the agency) to the labelling of varenicline6 These warnings were based on spontaneous reports of adverse drug reactions from the yellow card scheme and the FDA adverse events reporting system
Since the original safety warnings several studies have investigated the neuropsychiatric safety of vareni-cline7ndash10 Most of the studies were observational cohorts7ndash9 although one study examined the risk in a meta-analysis of 17 industry sponsored trials10 None of
WhAt Is AlreAdy knoWn on thIs topIcVarenicline is a commonly prescribed and effective drug for smoking cessation The Medicines and Healthcare Products Regulatory Agency (MHRA) and Food and Drug Administration (FDA) have issued safety warnings regarding suicidal thoughts and depression associated with the use of varenicline based on reports from spontaneous reporting systemsEvidence from previous observational cohort studies and a meta-analysis of 17 trials sponsored by Pfizer have found no evidence of an association with suicide non-fatal self harm or depressionConcerns have been raised about the validity of these findings as observational studies are prone to confounding and industry sponsored trials are more likely than other trials to report outcomes that are favourable to the study sponsor
WhAt thIs pAper AddsOur meta-analysis of all published randomised controlled trials is the most comprehensive meta-analysis of neuropsychiatric adverse events associated with varenicline use to date and reports effects using two summary statistics a relative measure (Peto odds ratio) and an absolute measure (risk difference)There was no evidence of an increased risk of suicide or attempted suicide suicidal ideation depression or death in varenicline users compared with placebo usersVarenicline was associated with an increased risk of sleep disorders insomnia and abnormal dreams side effects that are already well recognised and included in patient information leaflets for varenicline
RESEARCH
2 doi 101136bmjh1109 | BMJ 2015350h1109 | thethinspbmj
the studies found evidence of an increased risk of depression suicide or non-fatal self harm with vareni-cline Two major concerns however have been raised about the validity of these findings Firstly observa-tional studies are prone to confounding by indication11 For example the use of drugs for smoking cessation might seem to be associated with an increased risk of suicide because smokers themselves are at increased risk of mental illness and suicide12 13 Secondly there is evidence that industry sponsored trials are more likely than other trials to report outcomes that are favourable to the study sponsor14 Though the number of prescrip-tion items of varenicline dispensed in England increased from 499 in 2006 to a peak of almost a million in 2011 there was a 25 decrease from 2011 to 201315 This might reflect ongoing fears among prescribers and patients regarding vareniclinersquos safety
We conducted a systematic review and meta-analysis to determine the risk of neuropsychiatric adverse events and death in all published placebo controlled ran-domised controlled trials of varenicline This review deals with some of the limitations of the previous stud-ies and is the most comprehensive published review to date of the neuropsychiatric safety of varenicline
Methodseligibility and literature searchWe sought all placebo controlled randomised con-trolled trials of any duration in humans of varenicline at the maximum dose (1 mg twice daily) as described in the recommended standard titration regimen for varenicline (wwwchantixcom) We included studies in smokers and non-smokers We conducted searches of computer databases and online clinical trial registries (Medline Embase PsycINFO the Cochrane Central Register of Controlled Trials (CENTRAL) and clinicaltri-alsgov) The search strategy is shown in appendix 1 The searches were performed from the inception of each of the databases to 9 May 2014 There were no lan-guage restrictions We manually searched reference lists of relevant research articles and previous system-atic reviews10 16
Outcome measuresOur primary outcome measures were neuropsychiatric adverse events comprising suicide attempted suicide suicidal ideation and depression Secondary outcomes included other neuropsychiatric outcomes (abnormal dreams aggression anxiety fatigue insomnia irrita-bility sleep disorders somnolence) and death We included all deaths regardless of whether or not we believed they were related to drug treatment
Data extraction and managementTwo reviewers (KHT and DWK) independently screened the identified studies by title and abstract against the eligibility criteria We then obtained full reports of stud-ies for a second round of screening We identified dupli-cate publications for exclusion by examining the study name authors study population location and the dates of duration of the study A third reviewer (DG)
reviewed all excluded studies and studies when there was disagreement regarding inclusion or exclusion
KHT (all papers) and DG and RMM (papers equally shared) performed double data extraction to collect information on the study design (duration of treatment description of allocation concealment and blinding) study participants (inclusion and exclusion criteria country region population studied and baseline char-acteristics such as ethnicity sex smoking history) description of the intervention and placebo groups pri-mary and secondary outcomes measures of efficacy of treatment losses to follow-up and study sponsor KHT contacted authors of all studies to verify the accuracy of the extracted data
assessment of risk of biasThe Cochrane tool for assessing the risk of bias was used to assess whether there was high low or unclear risk of bias in the following domains random sequence generation allocation concealment blinding of partic-ipants and personnel blinding of outcome assess-ment incomplete outcome data selective outcome reporting and other sources of bias17 KHT (all papers) and DG and RMM (papers equally shared) assessed the risk of bias Discrepancies were resolved by referring to the original publications and discussion among all three reviewers KHT also contacted study authors to obtain study protocols and additional information that might not have been published to aid with assessment of the risk of bias
statistical analysisWe described study characteristics according to sample size characteristics of study participants study dura-tion duration of treatment and source of funding For trials with more than two intervention groups we extracted data for the maximum dose of varenicline (that is 1 mg twice daily) and the placebo group The ldquometanrdquo command in Stata (version 13 StataCorp USA) was used to conduct all of the meta-analyses18 Because our outcomes of interest are rare we followed recom-mendations of Bradburn and colleagues19 and used Peto odds ratios to compare the varenicline and placebo groups We also undertook meta-analyses using Man-tel-Haenszel risk differences We report results includ-ing 95 confidence intervals and forest plots for both measures so that findings can be compared Statistical heterogeneity was assessed with the I2 statistic20
For sensitivity analyses we used inverse variance methods under fixed and random effects models for the outcomes with the largest number of treatment events random effects models can be problematic for meta-analyses of rare events21 We report subgroup analyses for the primary outcomes by age (lt40 v ge40) sex (lt50 male v ge50 male) ethnicity (lt50 white v ge50 white) presence or absence of psychiatric ill-ness smoking status (smokers including smokeless tobacco users v majority non-smokers (gt60 non-smokers)) and whether or not the study was sponsored by a pharmaceutical company Studies were not categorised as sponsored by a pharmaceutical
RESEARCH
3thethinspbmj | BMJ 2015350h1109 | doi 101136bmjh1109
company if the drug was provided at no cost by the manufacturer andor if the research was investigator initiatedmdashthat is the drug and some funding was provided by the manufacturer although there was no other involvement in study conduct or publication and data were independently held by the researchers Tests for subgroup differences were performed Funnel plot asymmetry was assessed for two outcomemdashdepression and insomniamdashwith Harbordrsquos modified test for small study effects with the ldquometafunnelrdquo and ldquometabiasrdquo commands in Stata22 23
resultsstudy characteristicsFigure 1 summarises the selection of studies The search strategy identified 1089 studies from the com-puterised databases (476 from Medline 517 from Psy-cINFO and 96 from Embase) One additional trial was identified from CENTRAL and clinicaltrialsgov Out of the 1090 studies 130 were duplicates and 905 were excluded based on screening of titles and abstracts therefore 55 papers met the criteria for further screen-ing After the second round of screening 42 trials were identified for further data extraction24ndash65 Two addi-tional studies were identified when the search was repeated for the week beginning Monday 4 August 201466 67 Forty four studies were included in the sys-tematic review We received responses from study authors for 33 studies (75)
Table 1 and appendix 2 describe study characteris-tics The trials included 11 146 participants (6015 patients were randomised to receive a maximum of varenicline 1 mg twice daily and 5131 patients received a placebo) Of these randomised patients 10 998 were
evaluable for adverse events (5931 in the varenicline group and 5067 in the placebo group) The duration of treatment ranged from one week to 52 weeks while study duration ranged from eight days to 53 weeks Eighteen trials (613 of all participants) included cigarette smokers from the general population with no history of psychiatric illnesses (Table 2) In trials that included cigarette smokers (39 trials) participants smoked an average of 20 cigarettes a day for 266 years in the varenicline group and 20 cigarettes a day for 262 years in the placebo group Loss to follow-up ranged from 0 to 60 in both groups (appendix 2) In 12 trials losses to follow-up were higher in the varenicline group than the placebo group whereas in 17 trials losses to follow-up were higher in the placebo group than the varenicline group
Table 3 shows the assessment of risk of bias We excluded five trials from the meta-analysis as the risk of bias was unclear in four or more of the six domains47 52 60 or because no data were reported in the published papers and the study authors did not respond to our requests for data48 49 52 This resulted in exclusion of 114 patients (19) from the varenicline group and 123 patients (24) from the placebo group 10 761 patients were included in the meta-analyses (5817 in the varenicline group and 4944 in the placebo group) In three trials39 41 42 there were high losses to follow-up 537 60 and 452 respectively These studies were assessed as low risk of bias because of incomplete outcome data and were not excluded They were all small trials (combined total of n=92 in the varenicline group (16 of all people ran-domised to varenicline in our meta-analysis) and n=86 in the placebo group (17 of all people randomised to pla-cebo)) In addition only nine out of 178 patients (51) were lost to follow-up because of adverse events and these were mostly gastrointestinal in nature (such as nausea and vomiting)39 42 41
risk of neuropsychiatric adverse events and deathTwo people died by suicide (both in the varenicline arms) and four attempted to do so (two in the vareni-cline arm and two in the placebo arm) Table 4 sum-marises the Peto odds ratios risk differences and 95 confidence interval for the primary and secondary out-comes Because of the small numbers of events we combined suicide and attempted suicide into a single outcome Thirty one trials reported suicide and suicide attempt the Peto odds ratio for varenicline versus pla-cebo was 167 (95 confidence interval 033 to 857 P=054 I2=103) and the risk difference was 00003 (minus0002 to 0003 P=081 I2=00) Twenty trials reported suicidal ideation (figs 2 and 3) the Peto odds ratio was 058 (028 to 120 P=014 I2=00) and the risk difference was minus0003 (minus0009 to 0002 P=024 I2=00) Thirty one trials reported on depression (figs 4 and 5) the Peto odds ratio was 096 (075 to 122 P=074 I2=00) and the risk difference was minus0001 (minus001 to 001 P=074 I2=00) Death was reported in 36 trials (total 135760 in the varenicline group and 114887 in the placebo group) The Peto odds ratio for death was 105 (047 to 238 P=09 I2=387) and
Boxes (n=)Articles identied through literature search on 9 May 2014 (n=1090) Computerised databases (n=1089) Medline (n=476) Embase (n=96) PsycINFO (n=517) Additional trials identied from Cochrane database of randomised controlled trials or Clinicaltrialsgov (n=1)
Screening of titles and abstracts (n=1090)
Full text articles for second round of screening (n=55)
Eligible trials aer second round of screening (n=42)
Included in systematic review (n=44)
Additional trials published aer search (n=2)Drug manufacturer conrmed no furthertrials underway for publication in 2014
Duplicates (n=130)Excluded (n=905)
Excluded (n=13) Crossover trials (n=8) No monitoring of adverse eventssingle doseltmax dose varenicline (n=4) Second paper on same trial with no additional information (n=1)
fig 1 | flow chart showing selection of randomised controlled trials for inclusion in systematic review of varenicline
RESEARCH
4 doi 101136bmjh1109 | BMJ 2015350h1109 | thethinspbmj
there was no evidence of an increased risk of death in the varenicline group compared with the placebo group (risk difference 00001 minus0003 to 0003 P=094 I2=00) (Table 4) The forest plots for the secondary outcomes are shown in appendix 3
We found no evidence of an increased risk of irritabil-ity (odds ratio 098 05 confidence interval 081 to 117 P=079 I2=00) aggression (091 052 to 159 P=075 I2=208) or somnolence (123 094 to 162 P=013 I2=104) as the confidence intervals included the null value of 1 Varenicline was associated with an increased risk of sleep disorders (163 129 to 207 Plt0001 I2=00) insomnia (156 136 to 178 Plt0001 I2=00) abnormal dreams (238 205 to 277 Plt0001 I2=223)
and fatigue (128 106 to 155 P=001 I2=63) with some evidence of a reduced risk of anxiety (075 061 to 093 P=0008 I2=57) Consistent findings were observed for the risk differences (table 4)
sensitivity analysesThere were minimal differences in the effect measures and 95 confidence intervals with Peto fixed effects and random effects odds ratios (Table 5)
subgroup analysesThe subgroup analyses are shown in appendix 4 for the primary outcomes of depression and suicidal ideation Subgroup tests showed no evidence of a variation in the
table 1 | Characteristics of randomised controlled trials of varenicline 1mg twice daily included in systematic review
studyDuration (weeks) sample size mean age (years) men whitestudy treatment varenicline Placebo varenicline Placebo varenicline Placebo varenicline Placebo
Anthenelli 201324 52 12 256 269 454 471 379 368 NA NABolliger 201125 24 12 394 199 431 439 577 657 303 313Brandon 201126 22 22 56 58 458 412 609 611 541 648Burstein 200627 13 13 8 8 681 679 75 50 50 375Chengappa 201466 24 12 31 29 457 462 29 345 645 724Cinciripini 201328 24 12 86 106 438 452 616 632 581 717Ebbert 201129 24 12 38 38 407 41 100 100 100 100Evins 201430 64 40 40 47 514 457 60 66 75 72Faessel 200931 26 2 14 7 154 154 571 571 857 714Fagerstrom 201032 26 12 213 218 439 439 89 90 99 100Fatemi 201333 12 12 6 9 404 414 833 778 50 889Garza 201134 16 12 55 55 334 338 60 727 80 709Gonzales 200635 52 12 352 344 425 426 50 541 795 762Gonzales 201467 52 12 251 247 477 473 498 494 948 914Hughes 201136 24 8 107 111 44 412 605 572 914 919Jorenby 200637 52 12 344 341 446 423 552 581 855 85Litten 201338 16 13 97 101 46 45 732 683 619 703McClure 201339 5 5 54 50 45 43 40 59 32 36McKee 200940 11 1 10 10 342 353 80 80 40 90Meszaros 201341 12 8 5 5 42 44 80 60 40 60Mitchell 201242 16 12 33 31 29 25 55 65 73 64Nakamura 200743 52 12 156 154 401 399 792 76 NA NANiaura 200844 40 12 160 160 415 421 503 535 93 884Nides 200645 52 7 127 127 419 416 504 52 856 878Oncken 200646 52 12 259 129 422 43 485 519 808 721Plebani 201247 9 8 18 19 NA NA 696 75 11 33Plebani 201348 13 12 19 21 448 481 789 905 421 714Poling 201049 12 11 13 18 365 344 846 778 462 722Rennard 201250 24 12 493 166 439 432 60 596 68 681Rigotti 201051 52 12 355 359 57 559 752 822 803 808Shim 201252 8 8 60 60 399 399 38 45 0 0Stein 201353 24 24 137 45 392 406 46 622 825 756Steinberg 201154 24 12 40 39 NA NA 60 59 77 67Tashkin 201155 52 12 250 254 572 571 625 622 819 841Tonnesen 201356 52 12 70 69 536 556 429 493 NA NATonstad 200657 52 12 603 607 454 453 502 483 967 97Tsai 200758 24 12 126 124 397 409 849 927 0 0Wang 200959 24 12 165 168 39 385 964 97 0 0Weiner 201160 12 12 4 5 NA NA NA NA NA NAWilliams 200761 53 52 251 126 482 466 506 484 869 921Williams 201262 26 12 84 43 402 43 774 767 595 581Wong 201263 52 12 151 135 519 533 55 504 NA NAZesiewicz 201264 8 8 10 10 474 538 44 67 NA NAZhao 201165 37 3 14 10 71 73 429 50 100 90NA=not applicable
RESEARCH
5thethinspbmj | BMJ 2015350h1109 | doi 101136bmjh1109
side effects of depression and suicidal ideation by age group (P=0391 and P=0933 respectively for interac-tion) percentage of men in the study (P=0418 and P=0925) percentage of white people in the study (P=0685 and P=0254) presence or absence of psychi-atric illness (P=0126 and P=0304) smoking status (P=0906 for depression but not calculated for suicidal ideation as there were no reports of suicidal ideation in studies that included non-smokers) and whether the trial was industry sponsored or not (P=0386 and P=0380) The effect estimates (odds ratio) for the trials in which all participants had psychiatric illnesses com-pared with those where none of the participants had psychiatric illness were 149 (95 confidence interval 084 to 265) versus 091 (069 to 121) for depression and 079 (032 to 193) versus 034 (009 to 129) for suicidal ideation
table 2 | summary of characteristics of patients enrolled in 44 randomised controlled trials of vareniclineCharacteristics of trial participants no of trialsSmokers from general population 18Smokers with psychiatric illness 8Heavy drinking smokersalcohol dependence 4People dependent on cocaine or opioid dependent 3Smokeless tobacco users 2Smokers with mild to moderate COPD 1Smokers with cardiovascular disease 1Smokers about to undergo surgery 1Patients with spinocerebellar ataxia type 3 1Adolescent smokers 1Elderly non-smokers 1Smokers in hospital 1Smokers previously treated with varenicline 1Ex-smokers on long term NRT 1COPD=chronic obstructive pulmonary disease NRT=nicotine replacement therapy
table 3 | risk of bias assessment for each trial of varenicline using Cochrane risk of assessment of bias tool
studyrandom sequence generation
allocation concealment used
blindingincomplete outcome data
selective reporting Other bias
Participants and personnel
Outcome assessment
Anthenelli 201324 Low Low Low Low Low Low LowBolliger 201125 Low Low Low Low Low Low LowBrandon 201126 Low Low Low Low Low Low LowBurstein 200627 Low Low Low Low Low Low LowChengappa 201466 Low Low Low Low Low Low LowCinciripini 201328 Low Low Low Low Low Low LowEbbert 201129 Low Unclear Low Low Low Low LowEvins 201430 Low Low Low Low Low Low LowFaessel 200931 Low Low Low Low Low Low LowFagerstrom 201032 Low Low Low Low Low Low LowFatemi 201333 Unclear Low Low Low Low Low LowGarza 201134 Unclear Low Low Low Low Low LowGonzales 206635 Low Low Low Low Low Low LowGonzales 201467 Low Low Low Low Low Low LowHughes 201136 Low Low Low Low Low Unclear LowJorenby 200637 Low Low Low Low Low Low LowLitten 201338 Low Low Low Low Low Low LowMcClure 201339 Low Low Low Low Low Low LowMcKee 200940 Unclear Unclear Low Unclear Low Low LowMeszaros 201341 Low Low Low Low Low Low LowMitchell 201242 Low Low Low Low Low Low LowNakamura 200743 Low Low Low Low Low Low LowNiaura 200844 Low Low Low Low Low Low LowNides 200645 Low Low Low Low Low Low LowOncken 200646 Low Low Low Low Low Low LowPlebani 201247 Unclear Unclear Unclear Unclear Low Unclear LowPlebani 201348 Low Low Low Unclear Unclear Unclear LowPoling 201049 Low Unclear Low Unclear Low Low LowRennard 201250 Low Low Low Low Low Low LowRigotti 201051 Low Low Low Low Low Low LowShim 201252 Unclear Unclear Low Unclear Unclear Unclear UnclearStein 201353 Low Low Low Low Low Low LowSteinberg 201154 Low Low Low Low Low Low LowTashkin 201155 Low Low Low Low Low Low LowTonnesen 201356 Low Unclear Low Low Low Low LowTonstad 200657 Low Low Low Low Low Low LowTsai 200758 Low Low Low Low Low Low LowWang 200959 Low Low Low Low Low Low UnclearWeiner 201160 Unclear Unclear Unclear Unclear Low Unclear UnclearWilliams 200761 Low Low Low Low Low Low LowWilliams 201262 Low Low Low Low Low Low LowWong 201263 Low Low Low Low Low Low LowZesiewicz 201264 Low Low Low Low Low Low LowZhao 201165 Low Low Low Low Low Low Unclear
RESEARCH
6 doi 101136bmjh1109 | BMJ 2015350h1109 | thethinspbmj
small study effectsThe funnel plots for depression and insomnia are shown in appendix 5 The P values for funnel plot asym-metry were 053 for depression and 093 for insomnia (that is there was no evidence against the null hypoth-esis of no small study effects)
discussionThis meta-analysis of 39 randomised controlled trials involving 5817 patients prescribed varenicline 1 mg twice daily and 4944 patients prescribed placebo found no increased risk of suicide or attempted suicide
suicidal ideation depression or death in individuals treated with varenicline Almost half of the trial partici-pants were chronic heavy smokers (that is they had smoked on average 20 cigarettes a day for 26 years) Five separate trials (including 1281 participants randomised to varenicline and 1143 to placebo) reported a suicide andor suicide attempt (see appendix 3) one reported suicide only three reported attempted suicide only and one reported both suicide and attempted suicide Two suicides and two attempts occurred in the varenicline group of the trials (008) and two attempts occurred in the placebo group (005) Use of the maximum dose of varenicline (1 mg twice daily) was associated with a 28 increased risk of fatigue a 56 increased risk of insomnia a 63 increased risk of sleep disorders and more than twice the risk of abnormal dreams There was evidence of a 25 reduction in the risk of anxiety When we used risk differences for every 1000 patients there were an additional 10 cases of fatigue 40 cases of insomnia 20 cases of sleep disorders and 60 cases of abnormal dreams in those prescribed varenicline com-pared with placebo Similarly there were 10 fewer epi-sodes of anxiety per 1000 participants in the varenicline group compared with the placebo group (risk difference minus001 95 confidence interval minus002 to minus00003) There was no evidence of a variation in depression and sui-cidal ideation by age sex ethnicity presence or absence of psychiatric illness or type of study sponsor
Comparison with other studiesA recent study by Kishi and Iwata examined the effects of varenicline for smoking cessation in people with schizo-phrenia in a meta-analysis of seven randomised con-trolled trials68 With the exception of the study by Hong and colleagues69 we included all their randomised con-trolled trials in the current analysis Similar to our find-ings Kishi and Iwata found no significant differences in depression and suicidal ideation between the vareni-cline and placebo groups They reported however that varenicline use was associated with a lower risk of abnor-mal dreamsnightmares than placebo (relative risk 047 95 confidence interval 022 to 099 P=005)68
table 4 | summary of Peto odds ratios risk differences and 95 confidence intervals for neuropsychiatric events in people treated with varenicline
neuropsychiatric adverse eventno of eventsno treated
Odds ratio (95 Ci) P value risk difference (95 Ci) P valuevarenicline group Placebo groupPrimary outcomesDepression 1635356 1394487 096 (075 to 122) 074 minus0001 (minus001 to 001) 074Suicidal ideation 152799 182191 058 (028 to 120) 014 minus0003 (minus0009 to 0002) 024Attempted suicide 22184 21842 075 (010 to 565) 078 minus00003 (minus0005 to 0004) 091Suicide and attempted suicide 45352 24478 167 (033 to 857) 054 00003 (minus0002 to 0003) 081secondary outcomesAbnormal dreams 6035606 2244741 238 (205 to 277) lt0001 006 (005 to 007) lt0001Aggression 394276 243524 091 (052 to 159) 075 minus0001 (minus0005 to 0004) 079Anxiety 2094999 2264457 075 (061 to 093) 0008 minus001 (minus002 to minus00003) 001Death 135760 114887 105 (047 to 238) 09 00001 (minus0003 to 0003) 094Fatigue 2835502 2024701 128 (106 to 155) 001 001 (0002 to 002) 001Insomnia 6795621 3794762 156 (136 to 178) lt0001 004 (003 to 005) lt0001Irritability 2935406 2664615 098 (081 to 117) 079 minus0001 (minus001 to 0008) 079Sleep disorders 2115081 1234284 163 (129 to 207) lt0001 002 (001 to 002) lt0001Somnolence 1395360 914542 123 (094 to 162) 013 0005 (minus0001 to 001) 013
Jorenby 2006 Hughes 2011 Bolliger 2011 Tashkin 2011 Williams 2012 Rennard 2012 Mitchell 2012 Stein 2013 Cinciripini 2013 Meszaros 2013 Anthenelli 2013 Evins 2014 Chengappa 2014 Zhao 2011 Brandon 2011 Ebbert 2011 Steinberg 2011 Wong 2012 McClure 2013 Gonzales 2014Overall I2=0 P=0621
013 (000 to 676)014 (000 to 708)
453 (024 to 8523)014 (000 to 690)084 (019 to 380)011 (001 to 151)013 (000 to 641)
366 (003 to 38784)016 (000 to 842)
100 (009 to 1103)014 (001 to 136)118 (016 to 875)
186 (019 to 1864)ExcludedExcludedExcludedExcludedExcludedExcludedExcluded
058 (028 to 120)
3363
2383239
1013100000000
100
0001 001 01 1 10 100 1000
Study
Favourstreatment
Favoursplacebo
Odds ratio(95 CI)
Odds ratio(95 CI)
Weight()
0343010723900248584
1486033
111108625
0256240231014046038040
0151041
024915799
Treatment
1340111101981251343
2165131033
110625
3269247129110054038039
0135042
0245182191
ControlNo of eventstotal
fig 2 | forest plot of risk of suicidal ideation events (Peto odds ratio) associated with varenicline use in 20 placebo controlled randomised trials
RESEARCH
7thethinspbmj | BMJ 2015350h1109 | doi 101136bmjh1109
This discrepancy with our findings could be explained by the small sample size of their study (288 from four randomised controlled trials versus 10 347 from 35 ran-domised controlled trials in our analysis)
Gibbons and Mann used pooled data from 17 ran-domised controlled trials sponsored by Pfizer to exam-ine neuropsychiatric adverse events associated with varenicline10 Our study included industry and non- industry sponsored trials and more than twice the num-ber of trials that they included Their findings of no increased risk of suicidal events depression and agita-tion are consistent with our study Although the authors did not include references to the published literature for their included studies (which made cross referenc-ing difficult) it is likely that we included most of their studies in our analysis
Another meta-analysis examined the long term effi-cacy and safety of varenicline in trials with a minimum follow-up period of 12 months70 A meta-analysis of the main psychiatric related adverse effects (which com-bined depressed mood other mood disorders bipolar disorder delirium suicidal and self injurious behaviours adjustment disorders and abnormal think-ing into a single outcome) did not show a ldquosignificant increase of psychiatric side effects for varenicline com-pared with placebordquo70 This meta-analysis however included only three trials and the combined psychiat-ric outcome was non-specific The authors reported an increased risk of insomnia (relative risk 165 95 confi-dence interval 129 to 211) abnormal dreams (278 207 to 373) and sleep disturbance (209 162 to 269) but no
increased risk of irritability (114 075 to 173) which is consistent with our findings70
A previous Cochrane review examined the efficacy and tolerability of nicotine receptor partial agonists including varenicline16 Trials were excluded if partici-pants used smokeless tobacco or if there was less than six months of follow-up In addition to the efficacy out-comes meta-analyses were performed for the most commonly reported adverse events nausea insomnia abnormal dreams and headache Findings were consis-tent with our study for insomnia (relative risk 162 95 confidence interval 140 to 188) and abnormal dreams (291 234 to 362)16 The Cochrane review did not report any treatment emergent deaths Although we used a broader definition of deaths in our analysis by includ-ing all deaths irrespective of whether or not we thought they were related to treatment we did not find an increased risk of death in the varenicline group
strengths and limitationsTo the best of our knowledge this is the most compre-hensive published systematic review (and meta-analy-sis) of neuropsychiatric effects associated with use of varenicline Compared with the previous Cochrane review16 our analysis included 16 additional trials for the meta-analysis of the risk of insomnia events and 23 addi-tional trials for the pooled analysis of abnormal dreams
The choice of summary statistics for meta-analyses of rare events caused controversy (about whether the Peto odds ratio should be reported instead of risk differ-ences) when it led to conflicting findings from two sys-tematic reviews examining the risk of cardiovascular side effects associated with varenicline use71 72 We pres-ent results using both measures a relative measure (Peto odds ratio and sensitivity analyses with fixed and random effects odds ratios) as well as an absolute mea-sure (risk difference) Findings were consistent for all examined outcomes
Many study authors did not specify the actual dates that adverse events were reported so we included all reported events this decision would have increased the likelihood of obtaining reports of rare adverse events We contacted authors for all of our included trials to check the data extracted on adverse events and for study protocols and other information to adequately assess the risk of bias in the studies We had a high response rate (75)
There are some limitations Firstly in this analysis we used study level data instead of individual level data so we were unable to determine whether differences in the adverse events were because of greater quit rates in the varenicline group relative to placebo Secondly because of the small number of suicides and attempted suicide reported (n=6) we cannot rule out major beneficial or adverse effects of varenicline for this outcome (Peto odds ratio 167 95 confidence interval 033 to 857) Thirdly there was potential for heterogeneity in the reporting of adverse events Authors used a range of methods to record adverse events including self report open ended questions structured questionnaires side effect check-lists and case reports coded to the Medical Dictionary for
Jorenby 2006 Hughes 2011 Zhao 2011 Brandon 2011 Ebbert 2011 Steinberg 2011 Bolliger 2011 Tashkin 2011 Williams 2012 Rennard 2012 Mitchell 2012 Wong 2012 McClure 2013 Stein 2013 Cinciripini 2013 Meszaros 2013 Anthenelli 2013 Evins 2014 Chengappa 2014 Gonzales 2014Overall I2=0 P=0995
-000 (-001 to 001)-001 (-003 to 002)000 (-015 to 015)000 (-004 to 004)000 (-005 to 005)000 (-005 to 005)001 (-001 to 002)000 (-001 to 001)-001 (-010 to 008)-001 (-003 to 001)-003 (-012 to 005)000 (-001 to 001)000 (-005 to 005)001 (-004 to 005)-001 (-004 to 002)000 (-061 to 061)-001 (-003 to 000)001 (-008 to 010)003 (-008 to 014)000 (-001 to 001)-000 (-001 to 000)
1551222
11112
1016224lt11121
10100
-05 0 05
Study
Favourstreatment
Favoursplacebo
Odds ratio(95 CI)
Odds ratio(95 CI)
Weight()
03430107014046038040
23900248584
1486033
0151041
111108625
0256240231
0249152799
Treatment
13401111010054038039
01981251343
2165131
0135042033
110625
3269247129
0245182191
ControlNo of eventstotal
fig 3 | forest plot of risk of suicidal ideation events (mantel-Haenszel risk difference) associated with varenicline use in 20 placebo controlled randomised trials
RESEARCH
8 doi 101136bmjh1109 | BMJ 2015350h1109 | thethinspbmj
Regulatory Activities (MedDRA wwwmeddraorg) All of the industry sponsored trials coded adverse events using MedDRA Fourthly we excluded two studies69 73 from the review as the maximum dose of varenicline used in these studies was only 1 mg once a daymdashthat is half of the rec-ommended maximum dose Hong and colleagues exam-ined varenicline treatment in 20 smokers and 15 non-smokers with schizophrenia or schizoaffective disor-der and found no evidence that varenicline worsened psychiatric symptoms in these patients69 Mocking and colleagues studied the effects of varenicline on emotional and cognitive processing in 21 healthy adult non-smokers and concluded that it did not cause problems in emo-tional processing or impulsivity providing less support for a possible depressogenic effect of varenicline73 Fur-thermore a secondary analysis which included all doses of varenicline in the original trials and these two excluded randomised controlled trials produced similar findings to our main analysis (see appendix 6)
We tried to minimise reporting bias by including all events (such as deaths) reported regardless of whether or
not we considered them to be related to treatment It is still possible however that reporting bias could have occurred as for certain trials where the corresponding authors did not respond to our requests for additional information we could not determine whether a lack of reporting of deaths in the published paper was synonymous with no deaths It was difficult to interpret the funnel plots to assess whether publication bias might be present as most trials were efficacy trials and were not performed solely to deter-mine the incidence of psychiatric adverse events
Additionally smoking cessation has been shown to have a positive impact on mental health outcomes with a reduction in depression and anxiety compared with those who continue to smoke74 Patients prescribed varenicline were reported to have an approximately threefold increased chance of quitting smoking com-pared with those given placebo (odds ratio 288 95 confidence interval 240 to 347)4 this could explain the reduction in anxiety observed in this meta-analysis
Lastly half of the trials were sponsored by Pfizer the manufacturers of varenicline Although previous research with nicotine replacement therapy has shown that industry sponsored trials were more likely than other trials to report outcomes that were favourable to the study sponsor14 we did not find any evidence for differences in depression and suicidal ideation for industry versus non industry sponsored trials (P=0386 and P=0380 respectively for interaction) In addition all of the industry sponsored trials were assessed over-all as having a low risk of bias
Conclusions and clinical implicationsBased on this comprehensive systematic review of pub-lished randomised controlled trials there is no evi-dence of an increased risk of depression suicidal behaviour (that is suicide or attempted suicide sui-cidal ideation) and death from any cause associated with treatment with varenicline Varenicline users however have an increased risk of abnormal dreams insomnia and sleep disturbances which are consistent with findings from other studies and previously docu-mented commonly reported side effects of varenicline (wwwchantixcom) We reported our findings using two summary statistics (a relative measure and an abso-lute measure) and observed consistency with both methods This meta-analysis adds to previous research (observational and experimental) that found no evi-dence for increased suicidal behaviour or depression with varenicline the most effective drug for smoking cessation4 The dangers of smoking are well docu-mented and the health benefits of stopping smoking are well known Our analysis suggests that the benefits of varenicline for smoking cessation outweigh the as yet unproved risks of suicidal behaviour In the UK vareni-cline is recommended alongside bupropion and nico-tine replacement therapy as first line treatment for smoking cessation75 Therefore the reduction in vareni-cline prescribing in the UK should be as much a cause for concern to clinicians regulatory agencies and policy makers as the unfounded fears regarding vareni-clinersquos association with suicidal behaviour
Nides 2006 Tonstad 2006 Jorenby 2006 Onken 2006 Gonzales 2006 Williams 2007 Tsai 2007 Niaura 2008 Rigotti 2010 Fagerstrom 2010 Hughes 2011 Garza 2011 Ebbert 2011 Steinberg 2011 Bolliger 2011 Tashkin 2011 Williams 2012 Rennard 2012 Wong 2012 Zesiewicz 2012 McClure 2013 Stein 2013 Litten 2013 Cinciripini 2013 Meszaros 2013 Anthenelli 2013 Evins 2014 Chengappa 2014 Gonzales 2014 Faessel 2009 Brandon 2011Overall I2=0 P=0631
193 (020 to 1870)088 (044 to 178)
419 (095 to 1855)070 (018 to 267)057 (017 to 186)148 (051 to 428)050 (005 to 488)148 (025 to 864)164 (041 to 661)043 (010 to 191)053 (005 to 514)
100 (006 to 1619)014 (000 to 682)097 (013 to 719)102 (030 to 340)122 (037 to 402)066 (013 to 326)020 (004 to 090)089 (089 to 642)012 (012 to 208)078 (078 to 185)066 (066 to 185)123 (123 to 378)051 (020 to 130)
100 (005 to 1991)140 (067 to 292)
118 (007 to 1932)381 (099 to 1467)234 (053 to 1040)
ExcludedExcluded
096 (075 to 122)
1123345123311lt1144232186571
1113300
100
0001 001 01 1 10 100 1000
Study
Favourstreatment
Favoursplacebo
Odds ratio(95 CI)
Odds ratio(95 CI)
Weight()
212515602634362534349
1225111263157535322131107155038240
83906248484
44862151
091741
1711179768615
17256140831
5249014046
1635356
Treatment
112317604134041217344412621242155335052182111155138239
41985251343
51652135
292042733
610114106
1513269
147229
224507
0541394487
ControlNo of eventstotal
fig 4 | forest plot of risk of depression events (Peto odds ratio) associated with varenicline use in 31 placebo controlled randomised trials
RESEARCH
9thethinspbmj | BMJ 2015350h1109 | doi 101136bmjh1109
We are grateful to the corresponding authors of the trials and Cristina Russ of Pfizer (for the Pfizer sponsored trials) for their support with providing access to the data on psychiatric adverse events and death used in this studyContributors KHT DG and RMM conceived the study KHT conducted the literature search KHT and DWK screened the abstracts with assistance from DG KHT DG and RMM were responsible for data extraction and the risk of bias assessment KHT did the statistical analysis with support from JPH KHT wrote the paper with contributions from all authors All authors have approved the final draft of the manuscript KHT is study guarantor had full access to all of the data (including statistical reports and tables) and can take responsibility for the integrity of the data and the accuracy of the data analysisFunding KHT is currently funded by a clinical lectureship from the National Institute for Health Research Part of this work was undertaken while KHT was on a National Institute for Health Research doctoral research fellowship (DRF-2010-03-138) DWK is funded by a Wellcome Trust four year studentship (WT099874MA) DG is an NIHR senior investigator The views expressed in this publication are those of the authors and not necessarily those of the NHS the National Institute for Health Research or the Department of HealthCompeting interests All authors have completed the Unified Competing Interest form at wwwicmjeorgcoi_disclosurepdf (available on request from the corresponding author) and declare RMM had specified relationship with the MHRA in the past (was a member of the MHRArsquos Independent Scientific Advisory Committee for CPRD research and received expenses and a small fee for meeting attendance and preparation for meetings) DG had specified relationship with the MHRA in the past (was a member of the MHRArsquos Pharmacovigilance Expert Advisory Group and received travel expenses and a small fee for meeting attendance and preparation for meetings)Ethics approval Not requiredData sharing No additional data are availableTransparency declaration KHT affirms that this manuscript is an honest accurate and transparent account of the study being reported that no important aspects of the study have been omitted and that any discrepancies from the study as planned (and if relevant registered) have been explainedThis is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 40) license which permits others to distribute remix adapt build upon this work non-commercially and license their derivative works on different terms provided the original work is properly cited and the use is non-commercial See httpcreativecommonsorglicensesby-nc401 Peto R Darby S Deo H Silcocks P Whitley E Doll R Smoking
smoking cessation and lung cancer in the UK since 1950 combination of national statistics with two case-control studies BMJ 2000321323ndash9
2 Jha P Peto R Global effects of smoking of quitting and of taxing tobacco N Engl J Med 201437060ndash8
3 Allender S Balakrishnan R Scarborough P Webster P Rayner M The burden of smoking-related ill health in the UK Tob Control 200918262ndash67
4 Cahill K Stevens S Perera R Lancaster T Pharmacological interventions for smoking cessation an overview and network meta-analysis Cochrane Database Syst Rev 20135CD009329
5 Medicines and Healthcare Products Regulatory Agency Varenicline adverse psychiatric reactions including depression Drug Safety Update 200822ndash3
6 US Food and Drug Administration Information for healthcare professionals varenicline (marketed as Chantix) and bupropion (marketed as Zyban Wellbutrin and generics) FDA Drug Safety Newsletter 2009
7 Gunnell D Irvine D Wise L Davies C Martin RM Varenicline and suicidal behaviour a cohort study based on data from the General Practice Research Database BMJ 2009339b3805
8 Meyer TE Taylor LG Xie S Graham DJ Mosholder AD Williams JR et al Neuropsychiatric events in varenicline and nicotine replacement patch users in the Military Health System Addiction 2013108203ndash10
9 Thomas KH Martin RM Davies N Metcalfe C Windmeijer F Gunnell D Smoking cessation treatment and the risk of depression suicide and self-harm in the Clinical Practice Research Datalink prospective cohort study BMJ 2013347f5704
10 Gibbons RD Mann JJ Varenicline smoking cessation and neuropsychiatric adverse events Am J Psychiatry 20131701460ndash7
11 Walker AM Confounding by indication Epidemiology 19967335ndash612 Miller M Hemenway D Bell NS Yore MM Amoroso PJ Cigarette
smoking and suicide a prospective study of 300000 male active-duty Army soldiers Am J Epidemiol 20001511060ndash3
Nides 2006 Tonstad 2006 Jorenby 2006 Onken 2006 Gonzales 2006 Williams 2007 Tsai 2007 Niaura 2008 Faessel 2009 Rigotti 2010 Fagerstrom 2010 Hughes 2011 Garza 2011 Brandon 2011 Ebbert 2011 Steinberg 2011 Bolliger 2011 Tashkin 2011 Williams 2012 Rennard 2012 Wong 2012 Zesiewicz 2012 McClure 2013 Stein 2013 Litten 2013 Cinciripini 2013 Meszaros 2013 Anthenelli 2013 Evins 2014 Chengappa 2014 Gonzales 2014Overall I2=0 P=0783
001 (-002 to 003)-000 (-002 to 001)001 (-000 to 003)-001 (-005 to 003)-001 (-003 to 001)-002 (-002 to 006)001 (-004 to 002)001 (-002 to 003)000 (-019 to 019)001 (-001 to 002)-001 (-004 to 001)-001 (-004 to 002)000 (-005 to 005)000 (-004 to 004)-003 (-010 to 004)-000 (-010 to 010)000 (-002 to 002)000 (-002 to 003)-002 (-011 to 007)-002 (-005 to 001)-000 (-003 to 003)-022 (-052 to 008)-006 (-027 to 015)-006 (-021 to 010)001 (-006 to 008)-006 (-015 to 002)000 (-050 to 050)002 (-002 to 006)000 (-006 to 007)019 (001 to 037)001 (-001 to 003)-000 (-001 to 001)
313737433lt1752111165153lt11122lt16115
100
-05 0 05
Study
Favourstreatment
Favoursplacebo
Odds ratio(95 CI)
Odds ratio(95 CI)
Weight()
212515602634362534349
1225111263157014
535322131107155046038240
83906248484
44862151
091741
1711179768615
17256140831
52491635356
Treatment
112317604134041217344412621242155
07335052182111155054138239
41985251343
51652135
292042733
610114106
1513269
147229
22451394487
ControlNo of eventstotal
fig 5 | forest plot of risk of depression events (mantel-Haenszel risk difference) associated with varenicline use in 31 placebo controlled randomised trials
table 5 | Comparison of Peto fixed effects and random effects odds ratios (Or) for insomnia sleep disorders and abnormal dreams in people treated with varenicline
neuropsychiatric adverse event
no of eventsno treatedOdds ratio (95 Ci)
test for heterogeneity ()varenicline group Placebo group
insomniaPeto OR 6795621 3794762 156 (136 to 178) 0Fixed effects OR 6795621 3794762 156 (135 to 179) 0Random effects OR 6795621 3794762 156 (135 to 179) 0sleep disordersPeto OR 2115081 1234284 163 (129 to 207) 0Fixed effects OR 2115081 1234284 157 (122 to 203) 0Random effects OR 2115081 1234284 157 (122 to 203) 0abnormal dreams Peto OR 6035606 2244741 238 (205 to 277) 223Fixed effects OR 6035606 2244741 237 (199 to 282) 316Random effects OR 6035606 2244741 236 (187 to 298) 316All Plt0001
RESEARCH
10 doi 101136bmjh1109 | BMJ 2015350h1109 | thethinspbmj
13 Miller M Hemenway D Rimm E Cigarettes and suicide a prospective study of 50000 men Am J Public Health 200090768ndash73
14 Etter JF Burri M Stapleton J The impact of pharmaceutical company funding on results of randomized trials of nicotine replacement therapy for smoking cessation a meta-analysis Addiction 2007102815ndash22
15 Prescribing and Primary Care team Health and Social Care Information Centre Prescription cost analysis England 2013 Health and Social Care Information Centre 2014
16 Cahill K Stead LF Lancaster T Nicotine receptor partial agonists for smoking cessation Cochrane Database Syst Rev 20124CD006103
17 Higgins JPT Altman DG Assessing risk of bias in included studies Cochrane handbook for systematic reviews of interventions John Wiley 2008187ndash241
18 Harris R Bradburn M Deeks J Harbord R Altman D Sterne J metan fixed- and random-effects meta-analysis Stata J 200883ndash28
19 Bradburn MJ Deeks JJ Berlin JA Russell Localio A Much ado about nothing a comparison of the performance of meta-analytical methods with rare events Stat Med 20072653ndash77
20 Higgins JP Thompson SG Deeks JJ Altman DG Measuring inconsistency in meta-analyses BMJ 2003327557ndash60
21 Higgins JPT Deeks JJ Altman DG Special topics in statistics Cochrane handbook for systematic reviews of interventions John Wiley 2008481ndash529
22 Sterne JAC Harbord RM Funnel plots in meta-analysis Stata J 20044127ndash41
23 Harbord RM Harris RJ Sterne JAC Updated tests for small-study effects in meta-analyses Stata J 20099197ndash210
24 Anthenelli RM Morris C Ramey TS Dubrava SJ Tsilkos K Russ C et al Effects of varenicline on smoking cessation in adults with stably treated current or past major depression a randomized trial Ann Intern Med 2013159390ndash400
25 Bolliger CT Issa JS Posadas-Valay R Safwat T Abreu P Correia EA et al Effects of varenicline in adult smokers a multinational 24-week randomized double-blind placebo-controlled study Clin Ther 201133465ndash77
26 Brandon TH Drobes DJ Unrod M Heckman BW Oliver JA Roetzheim RC et al Varenicline effects on craving cue reactivity and smoking reward Psychopharmacology (Berl) 2011218391ndash403
27 Burstein AH Fullerton T Clark DJ Faessel HM Pharmacokinetics safety and tolerability after single and multiple oral doses of varenicline in elderly smokers J Clin Pharmacol 2006461234ndash40
28 Cinciripini PM Robinson JD Karam-Hage M Minnix JA Lam C Versace F et al Effects of varenicline and bupropion sustained-release use plus intensive smoking cessation counseling on prolonged abstinence from smoking and on depression negative affect and other symptoms of nicotine withdrawal JAMA Psychiatry 201370522ndash33
29 Ebbert JO Croghan IT Severson HH Schroeder DR Hays JT A pilot study of the efficacy of varenicline for the treatment of smokeless tobacco users in Midwestern United States Nicotine Tob Res 201113820ndash6
30 Evins AE Cather C Pratt SA Pachas GN Hoeppner SS Goff DC et al Maintenance treatment with varenicline for smoking cessation in patients with schizophrenia and bipolar disorder a randomized clinical trial JAMA 2014311145ndash54
31 Faessel H Ravva P Williams K Pharmacokinetics safety and tolerability of varenicline in healthy adolescent smokers a multicenter randomized double-blind placebo-controlled parallel-group study Clin Ther 200931177ndash89
32 Fagerstrom K Gilljam H Metcalfe M Tonstad S Messig M Stopping smokeless tobacco with varenicline randomised double blind placebo controlled trial BMJ 2010341c6549
33 Fatemi SH Yousefi MK Kneeland RE Liesch SB Folsom TD Thuras PD Antismoking and potential antipsychotic effects of varenicline in subjects with schizophrenia or schizoaffective disorder a double-blind placebo and bupropion-controlled study Schizophr Res 2013146376ndash8
34 Garza D Murphy M Tseng LJ Riordan HJ Chatterjee A A double-blind randomized placebo-controlled pilot study of neuropsychiatric adverse events in abstinent smokers treated with varenicline or placebo Biol Psychiatry 2011691075ndash82
35 Gonzales D Rennard SI Nides M Oncken C Azoulay S Billing CB et al Varenicline an alpha4beta2 nicotinic acetylcholine receptor partial agonist vs sustained-release bupropion and placebo for smoking cessation a randomized controlled trial JAMA 200629647ndash55
36 Hughes JR Rennard SI Fingar JR Talbot SK Callas PW Fagerstrom KO Efficacy of varenicline to prompt quit attempts in smokers not currently trying to quit a randomized placebo-controlled trial Nicotine Tob Res 201113955ndash64
37 Jorenby DE Hays JT Rigotti NA Azoulay S Watsky EJ Williams KE et al Efficacy of varenicline an alpha4beta2 nicotinic acetylcholine receptor partial agonist vs placebo or sustained-release bupropion for smoking cessation a randomized controlled trial JAMA 200629656ndash63
38 Litten RZ Ryan ML Fertig JB Falk DE Johnson B Dunn KE et al A double-blind placebo-controlled trial assessing the efficacy of varenicline tartrate for alcohol dependence J Addict Med 20137277ndash86
39 McClure EA Vandrey RG Johnson MW Stitzer ML Effects of varenicline on abstinence and smoking reward following a programmed lapse Nicotine Tob Res 201315139ndash48
40 McKee SA Harrison EL OrsquoMalley SS Krishnan-Sarin S Shi J Tetrault JM et al Varenicline reduces alcohol self-administration in heavy-drinking smokers Biol Psychiatry 200966185ndash90
41 Meszaros ZS Abdul-Malak Y Dimmock JA Wang D Ajagbe TO Batki SL Varenicline treatment of concurrent alcohol and nicotine dependence in schizophrenia a randomized placebo-controlled pilot trial J Clin Psychopharmacol 201333243ndash7
42 Mitchell JM Teague CH Kayser AS Bartlett SE Fields HL Varenicline decreases alcohol consumption in heavy-drinking smokers Psychopharmacology (Berl) 2012223299ndash306
43 Nakamura M Oshima A Fujimoto Y Maruyama N Ishibashi T Reeves KR Efficacy and tolerability of varenicline an alpha4beta2 nicotinic acetylcholine receptor partial agonist in a 12-week randomized placebo-controlled dose-response study with 40-week follow-up for smoking cessation in Japanese smokers Clin Ther 2007291040ndash56
44 Niaura R Hays JT Jorenby DE Leone FT Pappas JE Reeves KR et al The efficacy and safety of varenicline for smoking cessation using a flexible dosing strategy in adult smokers a randomized controlled trial Curr Med Res Opin 2008241931ndash41
45 Nides M Oncken C Gonzales D Rennard S Watsky EJ Anziano R et al Smoking cessation with varenicline a selective alpha4beta2 nicotinic receptor partial agonist results from a 7-week randomized placebo- and bupropion-controlled trial with 1-year follow-up Arch Intern Med 20061661561ndash8
46 Oncken C Gonzales D Nides M Rennard S Watsky E Billing CB et al Efficacy and safety of the novel selective nicotinic acetylcholine receptor partial agonist varenicline for smoking cessation Arch Intern Med 20061661571ndash7
47 Plebani JG Lynch KG Yu Q Pettinati HM OrsquoBrien CP Kampman KM Results of an initial clinical trial of varenicline for the treatment of cocaine dependence Drug Alcohol Depend 2012121163ndash6
48 Plebani JG Lynch KG Rennert L Pettinati HM OrsquoBrien CP Kampman KM Results from a pilot clinical trial of varenicline for the treatment of alcohol dependence Drug Alcohol Depend 2013133754ndash8
49 Poling J Rounsaville B Gonsai K Severino K Sofuoglu M The safety and efficacy of varenicline in cocaine using smokers maintained on methadone a pilot study Am J Addict 201019401ndash8
50 Rennard S Hughes J Cinciripini PM Kralikova E Raupach T Arteaga C et al A randomized placebo-controlled trial of varenicline for smoking cessation allowing flexible quit dates Nicotine Tob Res 201214343ndash50
51 Rigotti NA Pipe AL Benowitz NL Arteaga C Garza D Tonstad S Efficacy and safety of varenicline for smoking cessation in patients with cardiovascular disease a randomized trial Circulation 2010121221ndash9
52 Shim JC Jung DU Jung SS Seo YS Cho DM Lee JH et al Adjunctive varenicline treatment with antipsychotic medications for cognitive impairments in people with schizophrenia a randomized double-blind placebo-controlled trial Neuropsychopharmacology 201237660ndash8
53 Stein MD Caviness CM Kurth ME Audet D Olson J Anderson BJ Varenicline for smoking cessation among methadone-maintained smokers a randomized clinical trial Drug Alcohol Depend 2013133486ndash93
54 Steinberg MB Randall J Greenhaus S Schmelzer AC Richardson DL Carson JL Tobacco dependence treatment for hospitalized smokers a randomized controlled pilot trial using varenicline Addic Behav 2011361127ndash32
55 Tashkin DP Rennard S Hays JT Ma W Lawrence D Lee TC Effects of varenicline on smoking cessation in patients with mild to moderate COPD a randomized controlled trial Chest 2011139591ndash9
56 Tonnesen P Mikkelsen K Varenicline to stop long-term nicotine replacement use a double-blind randomized placebo-controlled trial Nicotine Tob Res 201315419ndash27
57 Tonstad S Tonnesen P Hajek P Williams KE Billing CB Reeves KR et al Effect of maintenance therapy with varenicline on smoking cessation a randomized controlled trial JAMA 200629664ndash71
58 Tsai ST Cho HJ Cheng HS Kim CH Hsueh KC Billing CB Jr et al A randomized placebo-controlled trial of varenicline a selective alpha4beta2 nicotinic acetylcholine receptor partial agonist as a new therapy for smoking cessation in Asian smokers Clin Ther 2007291027ndash39
59 Wang C Xiao D Chan KPW Pothirat C Garza D Davies S Varenicline for smoking cessation A placebo-controlled randomized study Respirology 200914384ndash92
60 Weiner E Buchholz A Coffay A Liu F McMahon RP Buchanan RW et al Varenicline for smoking cessation in people with schizophrenia a double blind randomized pilot study Schizophr Res 201112994ndash5
RESEARCH
11thethinspbmj | BMJ 2015350h1109 | doi 101136bmjh1109
61 Williams K Reeves K Billing C Pennington A Gong J A double-blind study evaluating the long-term safety of varenicline for smoking cessation Curr Med Res Opin 200723793ndash801
62 Williams JM Anthenelli RM Morris CD Treadow J Thompson JR Yunis C et al A randomized double-blind placebo-controlled study evaluating the safety and efficacy of varenicline for smoking cessation in patients with schizophrenia or schizoaffective disorder J Clin Psychiatry 201273654ndash60
63 Wong J Abrishami A Yang Y Zaki A Friedman Z Selby P et al A perioperative smoking cessation intervention with varenicline a double-blind randomized placebo-controlled trial Anesthesiology 2012117755ndash64
64 Zesiewicz TA Greenstein PE Sullivan KL Wecker L Miller A Jahan I et al A randomized trial of varenicline (Chantix) for the treatment of spinocerebellar ataxia type 3 Neurology 201278545ndash50
65 Zhao Q Schwam E Fullerton T OrsquoGorman M Burstein AH Pharmacokinetics safety and tolerability following multiple oral doses of varenicline under various titration schedules in elderly nonsmokers J Clin Pharmacol 201151492ndash501
66 Chengappa KN Perkins KA Brar JS Schlicht PJ Turkin SR Hetrick ML et al Varenicline for smoking cessation in bipolar disorder a randomized double-blind placebo-controlled study J Clin Psychiatry 201475765ndash72
67 Gonzales D Hajek P Pliamm L Nackaerts K Tseng LJ McRae TD et al Retreatment with varenicline for smoking cessation in smokers who have previously taken varenicline a randomized placebo-controlled trial Clin Pharmacol Ther 201496390ndash6
68 Kishi T Iwata N Varenicline for smoking cessation in people with schizophrenia systematic review and meta-analysis Eur Arch Psychiatry Clin Neurosci 2014 Oct 5 [Epub ahead of print]
69 Hong LE Thaker GK McMahon RP Summerfelt A Rachbeisel J Fuller RL et al Effects of moderate-dose treatment with varenicline on neurobiological and cognitive biomarkers in smokers and nonsmokers with schizophrenia or schizoaffective disorder Arch Gen Psychiatry 2011681195ndash206
70 Huang Y Li W Yang L Jiang Y Wu Y Long-term efficacy and safety of varenicline for smoking cessation a systematic review and
meta-analysis of randomized controlled trials J Public Health 201220355ndash65
71 Singh S Loke YK Spangler JG Furberg CD Risk of serious adverse cardiovascular events associated with varenicline a systematic review and meta-analysis CMAJ 20111831359ndash66
72 Prochaska JJ Hilton JF Risk of cardiovascular serious adverse events associated with varenicline use for tobacco cessation systematic review and meta-analysis BMJ 2012344e2856
73 Mocking RJ Patrick Pflanz C Pringle A Parsons E McTavish SF Cowen PJ et al Effects of short-term varenicline administration on emotional and cognitive processing in healthy non-smoking adults a randomized double-blind study Neuropsychopharmacology 201338476ndash84
74 Taylor G McNeill A Girling A Farley A Lindson-Hawley N Aveyard P Change in mental health after smoking cessation systematic review and meta-analysis BMJ 2014348g1151
75 Smoking cessation services in primary care pharmacies local authorities and workplaces particularly for manual working groups pregnant women and hard to reach communities NICE public health guidance 10 National Institute for Health and Care Excellence 2008
copy BMJ Publishing Group Ltd 2015
Appendix 1 Search strategy to identify relevant articles in MedlineAppendix 2 Further characteristics of included ran-domised controlled trialsAppendix 3 Forest plots for secondary outcomesAppendix 4 Subgroup analysesAppendix 5 Funnel plots Appendix 6 Summary of Peto odds ratios risk differ-ences and 95 confidence intervals for neuropsychiat-ric events
RESEARCH
2 doi 101136bmjh1109 | BMJ 2015350h1109 | thethinspbmj
the studies found evidence of an increased risk of depression suicide or non-fatal self harm with vareni-cline Two major concerns however have been raised about the validity of these findings Firstly observa-tional studies are prone to confounding by indication11 For example the use of drugs for smoking cessation might seem to be associated with an increased risk of suicide because smokers themselves are at increased risk of mental illness and suicide12 13 Secondly there is evidence that industry sponsored trials are more likely than other trials to report outcomes that are favourable to the study sponsor14 Though the number of prescrip-tion items of varenicline dispensed in England increased from 499 in 2006 to a peak of almost a million in 2011 there was a 25 decrease from 2011 to 201315 This might reflect ongoing fears among prescribers and patients regarding vareniclinersquos safety
We conducted a systematic review and meta-analysis to determine the risk of neuropsychiatric adverse events and death in all published placebo controlled ran-domised controlled trials of varenicline This review deals with some of the limitations of the previous stud-ies and is the most comprehensive published review to date of the neuropsychiatric safety of varenicline
Methodseligibility and literature searchWe sought all placebo controlled randomised con-trolled trials of any duration in humans of varenicline at the maximum dose (1 mg twice daily) as described in the recommended standard titration regimen for varenicline (wwwchantixcom) We included studies in smokers and non-smokers We conducted searches of computer databases and online clinical trial registries (Medline Embase PsycINFO the Cochrane Central Register of Controlled Trials (CENTRAL) and clinicaltri-alsgov) The search strategy is shown in appendix 1 The searches were performed from the inception of each of the databases to 9 May 2014 There were no lan-guage restrictions We manually searched reference lists of relevant research articles and previous system-atic reviews10 16
Outcome measuresOur primary outcome measures were neuropsychiatric adverse events comprising suicide attempted suicide suicidal ideation and depression Secondary outcomes included other neuropsychiatric outcomes (abnormal dreams aggression anxiety fatigue insomnia irrita-bility sleep disorders somnolence) and death We included all deaths regardless of whether or not we believed they were related to drug treatment
Data extraction and managementTwo reviewers (KHT and DWK) independently screened the identified studies by title and abstract against the eligibility criteria We then obtained full reports of stud-ies for a second round of screening We identified dupli-cate publications for exclusion by examining the study name authors study population location and the dates of duration of the study A third reviewer (DG)
reviewed all excluded studies and studies when there was disagreement regarding inclusion or exclusion
KHT (all papers) and DG and RMM (papers equally shared) performed double data extraction to collect information on the study design (duration of treatment description of allocation concealment and blinding) study participants (inclusion and exclusion criteria country region population studied and baseline char-acteristics such as ethnicity sex smoking history) description of the intervention and placebo groups pri-mary and secondary outcomes measures of efficacy of treatment losses to follow-up and study sponsor KHT contacted authors of all studies to verify the accuracy of the extracted data
assessment of risk of biasThe Cochrane tool for assessing the risk of bias was used to assess whether there was high low or unclear risk of bias in the following domains random sequence generation allocation concealment blinding of partic-ipants and personnel blinding of outcome assess-ment incomplete outcome data selective outcome reporting and other sources of bias17 KHT (all papers) and DG and RMM (papers equally shared) assessed the risk of bias Discrepancies were resolved by referring to the original publications and discussion among all three reviewers KHT also contacted study authors to obtain study protocols and additional information that might not have been published to aid with assessment of the risk of bias
statistical analysisWe described study characteristics according to sample size characteristics of study participants study dura-tion duration of treatment and source of funding For trials with more than two intervention groups we extracted data for the maximum dose of varenicline (that is 1 mg twice daily) and the placebo group The ldquometanrdquo command in Stata (version 13 StataCorp USA) was used to conduct all of the meta-analyses18 Because our outcomes of interest are rare we followed recom-mendations of Bradburn and colleagues19 and used Peto odds ratios to compare the varenicline and placebo groups We also undertook meta-analyses using Man-tel-Haenszel risk differences We report results includ-ing 95 confidence intervals and forest plots for both measures so that findings can be compared Statistical heterogeneity was assessed with the I2 statistic20
For sensitivity analyses we used inverse variance methods under fixed and random effects models for the outcomes with the largest number of treatment events random effects models can be problematic for meta-analyses of rare events21 We report subgroup analyses for the primary outcomes by age (lt40 v ge40) sex (lt50 male v ge50 male) ethnicity (lt50 white v ge50 white) presence or absence of psychiatric ill-ness smoking status (smokers including smokeless tobacco users v majority non-smokers (gt60 non-smokers)) and whether or not the study was sponsored by a pharmaceutical company Studies were not categorised as sponsored by a pharmaceutical
RESEARCH
3thethinspbmj | BMJ 2015350h1109 | doi 101136bmjh1109
company if the drug was provided at no cost by the manufacturer andor if the research was investigator initiatedmdashthat is the drug and some funding was provided by the manufacturer although there was no other involvement in study conduct or publication and data were independently held by the researchers Tests for subgroup differences were performed Funnel plot asymmetry was assessed for two outcomemdashdepression and insomniamdashwith Harbordrsquos modified test for small study effects with the ldquometafunnelrdquo and ldquometabiasrdquo commands in Stata22 23
resultsstudy characteristicsFigure 1 summarises the selection of studies The search strategy identified 1089 studies from the com-puterised databases (476 from Medline 517 from Psy-cINFO and 96 from Embase) One additional trial was identified from CENTRAL and clinicaltrialsgov Out of the 1090 studies 130 were duplicates and 905 were excluded based on screening of titles and abstracts therefore 55 papers met the criteria for further screen-ing After the second round of screening 42 trials were identified for further data extraction24ndash65 Two addi-tional studies were identified when the search was repeated for the week beginning Monday 4 August 201466 67 Forty four studies were included in the sys-tematic review We received responses from study authors for 33 studies (75)
Table 1 and appendix 2 describe study characteris-tics The trials included 11 146 participants (6015 patients were randomised to receive a maximum of varenicline 1 mg twice daily and 5131 patients received a placebo) Of these randomised patients 10 998 were
evaluable for adverse events (5931 in the varenicline group and 5067 in the placebo group) The duration of treatment ranged from one week to 52 weeks while study duration ranged from eight days to 53 weeks Eighteen trials (613 of all participants) included cigarette smokers from the general population with no history of psychiatric illnesses (Table 2) In trials that included cigarette smokers (39 trials) participants smoked an average of 20 cigarettes a day for 266 years in the varenicline group and 20 cigarettes a day for 262 years in the placebo group Loss to follow-up ranged from 0 to 60 in both groups (appendix 2) In 12 trials losses to follow-up were higher in the varenicline group than the placebo group whereas in 17 trials losses to follow-up were higher in the placebo group than the varenicline group
Table 3 shows the assessment of risk of bias We excluded five trials from the meta-analysis as the risk of bias was unclear in four or more of the six domains47 52 60 or because no data were reported in the published papers and the study authors did not respond to our requests for data48 49 52 This resulted in exclusion of 114 patients (19) from the varenicline group and 123 patients (24) from the placebo group 10 761 patients were included in the meta-analyses (5817 in the varenicline group and 4944 in the placebo group) In three trials39 41 42 there were high losses to follow-up 537 60 and 452 respectively These studies were assessed as low risk of bias because of incomplete outcome data and were not excluded They were all small trials (combined total of n=92 in the varenicline group (16 of all people ran-domised to varenicline in our meta-analysis) and n=86 in the placebo group (17 of all people randomised to pla-cebo)) In addition only nine out of 178 patients (51) were lost to follow-up because of adverse events and these were mostly gastrointestinal in nature (such as nausea and vomiting)39 42 41
risk of neuropsychiatric adverse events and deathTwo people died by suicide (both in the varenicline arms) and four attempted to do so (two in the vareni-cline arm and two in the placebo arm) Table 4 sum-marises the Peto odds ratios risk differences and 95 confidence interval for the primary and secondary out-comes Because of the small numbers of events we combined suicide and attempted suicide into a single outcome Thirty one trials reported suicide and suicide attempt the Peto odds ratio for varenicline versus pla-cebo was 167 (95 confidence interval 033 to 857 P=054 I2=103) and the risk difference was 00003 (minus0002 to 0003 P=081 I2=00) Twenty trials reported suicidal ideation (figs 2 and 3) the Peto odds ratio was 058 (028 to 120 P=014 I2=00) and the risk difference was minus0003 (minus0009 to 0002 P=024 I2=00) Thirty one trials reported on depression (figs 4 and 5) the Peto odds ratio was 096 (075 to 122 P=074 I2=00) and the risk difference was minus0001 (minus001 to 001 P=074 I2=00) Death was reported in 36 trials (total 135760 in the varenicline group and 114887 in the placebo group) The Peto odds ratio for death was 105 (047 to 238 P=09 I2=387) and
Boxes (n=)Articles identied through literature search on 9 May 2014 (n=1090) Computerised databases (n=1089) Medline (n=476) Embase (n=96) PsycINFO (n=517) Additional trials identied from Cochrane database of randomised controlled trials or Clinicaltrialsgov (n=1)
Screening of titles and abstracts (n=1090)
Full text articles for second round of screening (n=55)
Eligible trials aer second round of screening (n=42)
Included in systematic review (n=44)
Additional trials published aer search (n=2)Drug manufacturer conrmed no furthertrials underway for publication in 2014
Duplicates (n=130)Excluded (n=905)
Excluded (n=13) Crossover trials (n=8) No monitoring of adverse eventssingle doseltmax dose varenicline (n=4) Second paper on same trial with no additional information (n=1)
fig 1 | flow chart showing selection of randomised controlled trials for inclusion in systematic review of varenicline
RESEARCH
4 doi 101136bmjh1109 | BMJ 2015350h1109 | thethinspbmj
there was no evidence of an increased risk of death in the varenicline group compared with the placebo group (risk difference 00001 minus0003 to 0003 P=094 I2=00) (Table 4) The forest plots for the secondary outcomes are shown in appendix 3
We found no evidence of an increased risk of irritabil-ity (odds ratio 098 05 confidence interval 081 to 117 P=079 I2=00) aggression (091 052 to 159 P=075 I2=208) or somnolence (123 094 to 162 P=013 I2=104) as the confidence intervals included the null value of 1 Varenicline was associated with an increased risk of sleep disorders (163 129 to 207 Plt0001 I2=00) insomnia (156 136 to 178 Plt0001 I2=00) abnormal dreams (238 205 to 277 Plt0001 I2=223)
and fatigue (128 106 to 155 P=001 I2=63) with some evidence of a reduced risk of anxiety (075 061 to 093 P=0008 I2=57) Consistent findings were observed for the risk differences (table 4)
sensitivity analysesThere were minimal differences in the effect measures and 95 confidence intervals with Peto fixed effects and random effects odds ratios (Table 5)
subgroup analysesThe subgroup analyses are shown in appendix 4 for the primary outcomes of depression and suicidal ideation Subgroup tests showed no evidence of a variation in the
table 1 | Characteristics of randomised controlled trials of varenicline 1mg twice daily included in systematic review
studyDuration (weeks) sample size mean age (years) men whitestudy treatment varenicline Placebo varenicline Placebo varenicline Placebo varenicline Placebo
Anthenelli 201324 52 12 256 269 454 471 379 368 NA NABolliger 201125 24 12 394 199 431 439 577 657 303 313Brandon 201126 22 22 56 58 458 412 609 611 541 648Burstein 200627 13 13 8 8 681 679 75 50 50 375Chengappa 201466 24 12 31 29 457 462 29 345 645 724Cinciripini 201328 24 12 86 106 438 452 616 632 581 717Ebbert 201129 24 12 38 38 407 41 100 100 100 100Evins 201430 64 40 40 47 514 457 60 66 75 72Faessel 200931 26 2 14 7 154 154 571 571 857 714Fagerstrom 201032 26 12 213 218 439 439 89 90 99 100Fatemi 201333 12 12 6 9 404 414 833 778 50 889Garza 201134 16 12 55 55 334 338 60 727 80 709Gonzales 200635 52 12 352 344 425 426 50 541 795 762Gonzales 201467 52 12 251 247 477 473 498 494 948 914Hughes 201136 24 8 107 111 44 412 605 572 914 919Jorenby 200637 52 12 344 341 446 423 552 581 855 85Litten 201338 16 13 97 101 46 45 732 683 619 703McClure 201339 5 5 54 50 45 43 40 59 32 36McKee 200940 11 1 10 10 342 353 80 80 40 90Meszaros 201341 12 8 5 5 42 44 80 60 40 60Mitchell 201242 16 12 33 31 29 25 55 65 73 64Nakamura 200743 52 12 156 154 401 399 792 76 NA NANiaura 200844 40 12 160 160 415 421 503 535 93 884Nides 200645 52 7 127 127 419 416 504 52 856 878Oncken 200646 52 12 259 129 422 43 485 519 808 721Plebani 201247 9 8 18 19 NA NA 696 75 11 33Plebani 201348 13 12 19 21 448 481 789 905 421 714Poling 201049 12 11 13 18 365 344 846 778 462 722Rennard 201250 24 12 493 166 439 432 60 596 68 681Rigotti 201051 52 12 355 359 57 559 752 822 803 808Shim 201252 8 8 60 60 399 399 38 45 0 0Stein 201353 24 24 137 45 392 406 46 622 825 756Steinberg 201154 24 12 40 39 NA NA 60 59 77 67Tashkin 201155 52 12 250 254 572 571 625 622 819 841Tonnesen 201356 52 12 70 69 536 556 429 493 NA NATonstad 200657 52 12 603 607 454 453 502 483 967 97Tsai 200758 24 12 126 124 397 409 849 927 0 0Wang 200959 24 12 165 168 39 385 964 97 0 0Weiner 201160 12 12 4 5 NA NA NA NA NA NAWilliams 200761 53 52 251 126 482 466 506 484 869 921Williams 201262 26 12 84 43 402 43 774 767 595 581Wong 201263 52 12 151 135 519 533 55 504 NA NAZesiewicz 201264 8 8 10 10 474 538 44 67 NA NAZhao 201165 37 3 14 10 71 73 429 50 100 90NA=not applicable
RESEARCH
5thethinspbmj | BMJ 2015350h1109 | doi 101136bmjh1109
side effects of depression and suicidal ideation by age group (P=0391 and P=0933 respectively for interac-tion) percentage of men in the study (P=0418 and P=0925) percentage of white people in the study (P=0685 and P=0254) presence or absence of psychi-atric illness (P=0126 and P=0304) smoking status (P=0906 for depression but not calculated for suicidal ideation as there were no reports of suicidal ideation in studies that included non-smokers) and whether the trial was industry sponsored or not (P=0386 and P=0380) The effect estimates (odds ratio) for the trials in which all participants had psychiatric illnesses com-pared with those where none of the participants had psychiatric illness were 149 (95 confidence interval 084 to 265) versus 091 (069 to 121) for depression and 079 (032 to 193) versus 034 (009 to 129) for suicidal ideation
table 2 | summary of characteristics of patients enrolled in 44 randomised controlled trials of vareniclineCharacteristics of trial participants no of trialsSmokers from general population 18Smokers with psychiatric illness 8Heavy drinking smokersalcohol dependence 4People dependent on cocaine or opioid dependent 3Smokeless tobacco users 2Smokers with mild to moderate COPD 1Smokers with cardiovascular disease 1Smokers about to undergo surgery 1Patients with spinocerebellar ataxia type 3 1Adolescent smokers 1Elderly non-smokers 1Smokers in hospital 1Smokers previously treated with varenicline 1Ex-smokers on long term NRT 1COPD=chronic obstructive pulmonary disease NRT=nicotine replacement therapy
table 3 | risk of bias assessment for each trial of varenicline using Cochrane risk of assessment of bias tool
studyrandom sequence generation
allocation concealment used
blindingincomplete outcome data
selective reporting Other bias
Participants and personnel
Outcome assessment
Anthenelli 201324 Low Low Low Low Low Low LowBolliger 201125 Low Low Low Low Low Low LowBrandon 201126 Low Low Low Low Low Low LowBurstein 200627 Low Low Low Low Low Low LowChengappa 201466 Low Low Low Low Low Low LowCinciripini 201328 Low Low Low Low Low Low LowEbbert 201129 Low Unclear Low Low Low Low LowEvins 201430 Low Low Low Low Low Low LowFaessel 200931 Low Low Low Low Low Low LowFagerstrom 201032 Low Low Low Low Low Low LowFatemi 201333 Unclear Low Low Low Low Low LowGarza 201134 Unclear Low Low Low Low Low LowGonzales 206635 Low Low Low Low Low Low LowGonzales 201467 Low Low Low Low Low Low LowHughes 201136 Low Low Low Low Low Unclear LowJorenby 200637 Low Low Low Low Low Low LowLitten 201338 Low Low Low Low Low Low LowMcClure 201339 Low Low Low Low Low Low LowMcKee 200940 Unclear Unclear Low Unclear Low Low LowMeszaros 201341 Low Low Low Low Low Low LowMitchell 201242 Low Low Low Low Low Low LowNakamura 200743 Low Low Low Low Low Low LowNiaura 200844 Low Low Low Low Low Low LowNides 200645 Low Low Low Low Low Low LowOncken 200646 Low Low Low Low Low Low LowPlebani 201247 Unclear Unclear Unclear Unclear Low Unclear LowPlebani 201348 Low Low Low Unclear Unclear Unclear LowPoling 201049 Low Unclear Low Unclear Low Low LowRennard 201250 Low Low Low Low Low Low LowRigotti 201051 Low Low Low Low Low Low LowShim 201252 Unclear Unclear Low Unclear Unclear Unclear UnclearStein 201353 Low Low Low Low Low Low LowSteinberg 201154 Low Low Low Low Low Low LowTashkin 201155 Low Low Low Low Low Low LowTonnesen 201356 Low Unclear Low Low Low Low LowTonstad 200657 Low Low Low Low Low Low LowTsai 200758 Low Low Low Low Low Low LowWang 200959 Low Low Low Low Low Low UnclearWeiner 201160 Unclear Unclear Unclear Unclear Low Unclear UnclearWilliams 200761 Low Low Low Low Low Low LowWilliams 201262 Low Low Low Low Low Low LowWong 201263 Low Low Low Low Low Low LowZesiewicz 201264 Low Low Low Low Low Low LowZhao 201165 Low Low Low Low Low Low Unclear
RESEARCH
6 doi 101136bmjh1109 | BMJ 2015350h1109 | thethinspbmj
small study effectsThe funnel plots for depression and insomnia are shown in appendix 5 The P values for funnel plot asym-metry were 053 for depression and 093 for insomnia (that is there was no evidence against the null hypoth-esis of no small study effects)
discussionThis meta-analysis of 39 randomised controlled trials involving 5817 patients prescribed varenicline 1 mg twice daily and 4944 patients prescribed placebo found no increased risk of suicide or attempted suicide
suicidal ideation depression or death in individuals treated with varenicline Almost half of the trial partici-pants were chronic heavy smokers (that is they had smoked on average 20 cigarettes a day for 26 years) Five separate trials (including 1281 participants randomised to varenicline and 1143 to placebo) reported a suicide andor suicide attempt (see appendix 3) one reported suicide only three reported attempted suicide only and one reported both suicide and attempted suicide Two suicides and two attempts occurred in the varenicline group of the trials (008) and two attempts occurred in the placebo group (005) Use of the maximum dose of varenicline (1 mg twice daily) was associated with a 28 increased risk of fatigue a 56 increased risk of insomnia a 63 increased risk of sleep disorders and more than twice the risk of abnormal dreams There was evidence of a 25 reduction in the risk of anxiety When we used risk differences for every 1000 patients there were an additional 10 cases of fatigue 40 cases of insomnia 20 cases of sleep disorders and 60 cases of abnormal dreams in those prescribed varenicline com-pared with placebo Similarly there were 10 fewer epi-sodes of anxiety per 1000 participants in the varenicline group compared with the placebo group (risk difference minus001 95 confidence interval minus002 to minus00003) There was no evidence of a variation in depression and sui-cidal ideation by age sex ethnicity presence or absence of psychiatric illness or type of study sponsor
Comparison with other studiesA recent study by Kishi and Iwata examined the effects of varenicline for smoking cessation in people with schizo-phrenia in a meta-analysis of seven randomised con-trolled trials68 With the exception of the study by Hong and colleagues69 we included all their randomised con-trolled trials in the current analysis Similar to our find-ings Kishi and Iwata found no significant differences in depression and suicidal ideation between the vareni-cline and placebo groups They reported however that varenicline use was associated with a lower risk of abnor-mal dreamsnightmares than placebo (relative risk 047 95 confidence interval 022 to 099 P=005)68
table 4 | summary of Peto odds ratios risk differences and 95 confidence intervals for neuropsychiatric events in people treated with varenicline
neuropsychiatric adverse eventno of eventsno treated
Odds ratio (95 Ci) P value risk difference (95 Ci) P valuevarenicline group Placebo groupPrimary outcomesDepression 1635356 1394487 096 (075 to 122) 074 minus0001 (minus001 to 001) 074Suicidal ideation 152799 182191 058 (028 to 120) 014 minus0003 (minus0009 to 0002) 024Attempted suicide 22184 21842 075 (010 to 565) 078 minus00003 (minus0005 to 0004) 091Suicide and attempted suicide 45352 24478 167 (033 to 857) 054 00003 (minus0002 to 0003) 081secondary outcomesAbnormal dreams 6035606 2244741 238 (205 to 277) lt0001 006 (005 to 007) lt0001Aggression 394276 243524 091 (052 to 159) 075 minus0001 (minus0005 to 0004) 079Anxiety 2094999 2264457 075 (061 to 093) 0008 minus001 (minus002 to minus00003) 001Death 135760 114887 105 (047 to 238) 09 00001 (minus0003 to 0003) 094Fatigue 2835502 2024701 128 (106 to 155) 001 001 (0002 to 002) 001Insomnia 6795621 3794762 156 (136 to 178) lt0001 004 (003 to 005) lt0001Irritability 2935406 2664615 098 (081 to 117) 079 minus0001 (minus001 to 0008) 079Sleep disorders 2115081 1234284 163 (129 to 207) lt0001 002 (001 to 002) lt0001Somnolence 1395360 914542 123 (094 to 162) 013 0005 (minus0001 to 001) 013
Jorenby 2006 Hughes 2011 Bolliger 2011 Tashkin 2011 Williams 2012 Rennard 2012 Mitchell 2012 Stein 2013 Cinciripini 2013 Meszaros 2013 Anthenelli 2013 Evins 2014 Chengappa 2014 Zhao 2011 Brandon 2011 Ebbert 2011 Steinberg 2011 Wong 2012 McClure 2013 Gonzales 2014Overall I2=0 P=0621
013 (000 to 676)014 (000 to 708)
453 (024 to 8523)014 (000 to 690)084 (019 to 380)011 (001 to 151)013 (000 to 641)
366 (003 to 38784)016 (000 to 842)
100 (009 to 1103)014 (001 to 136)118 (016 to 875)
186 (019 to 1864)ExcludedExcludedExcludedExcludedExcludedExcludedExcluded
058 (028 to 120)
3363
2383239
1013100000000
100
0001 001 01 1 10 100 1000
Study
Favourstreatment
Favoursplacebo
Odds ratio(95 CI)
Odds ratio(95 CI)
Weight()
0343010723900248584
1486033
111108625
0256240231014046038040
0151041
024915799
Treatment
1340111101981251343
2165131033
110625
3269247129110054038039
0135042
0245182191
ControlNo of eventstotal
fig 2 | forest plot of risk of suicidal ideation events (Peto odds ratio) associated with varenicline use in 20 placebo controlled randomised trials
RESEARCH
7thethinspbmj | BMJ 2015350h1109 | doi 101136bmjh1109
This discrepancy with our findings could be explained by the small sample size of their study (288 from four randomised controlled trials versus 10 347 from 35 ran-domised controlled trials in our analysis)
Gibbons and Mann used pooled data from 17 ran-domised controlled trials sponsored by Pfizer to exam-ine neuropsychiatric adverse events associated with varenicline10 Our study included industry and non- industry sponsored trials and more than twice the num-ber of trials that they included Their findings of no increased risk of suicidal events depression and agita-tion are consistent with our study Although the authors did not include references to the published literature for their included studies (which made cross referenc-ing difficult) it is likely that we included most of their studies in our analysis
Another meta-analysis examined the long term effi-cacy and safety of varenicline in trials with a minimum follow-up period of 12 months70 A meta-analysis of the main psychiatric related adverse effects (which com-bined depressed mood other mood disorders bipolar disorder delirium suicidal and self injurious behaviours adjustment disorders and abnormal think-ing into a single outcome) did not show a ldquosignificant increase of psychiatric side effects for varenicline com-pared with placebordquo70 This meta-analysis however included only three trials and the combined psychiat-ric outcome was non-specific The authors reported an increased risk of insomnia (relative risk 165 95 confi-dence interval 129 to 211) abnormal dreams (278 207 to 373) and sleep disturbance (209 162 to 269) but no
increased risk of irritability (114 075 to 173) which is consistent with our findings70
A previous Cochrane review examined the efficacy and tolerability of nicotine receptor partial agonists including varenicline16 Trials were excluded if partici-pants used smokeless tobacco or if there was less than six months of follow-up In addition to the efficacy out-comes meta-analyses were performed for the most commonly reported adverse events nausea insomnia abnormal dreams and headache Findings were consis-tent with our study for insomnia (relative risk 162 95 confidence interval 140 to 188) and abnormal dreams (291 234 to 362)16 The Cochrane review did not report any treatment emergent deaths Although we used a broader definition of deaths in our analysis by includ-ing all deaths irrespective of whether or not we thought they were related to treatment we did not find an increased risk of death in the varenicline group
strengths and limitationsTo the best of our knowledge this is the most compre-hensive published systematic review (and meta-analy-sis) of neuropsychiatric effects associated with use of varenicline Compared with the previous Cochrane review16 our analysis included 16 additional trials for the meta-analysis of the risk of insomnia events and 23 addi-tional trials for the pooled analysis of abnormal dreams
The choice of summary statistics for meta-analyses of rare events caused controversy (about whether the Peto odds ratio should be reported instead of risk differ-ences) when it led to conflicting findings from two sys-tematic reviews examining the risk of cardiovascular side effects associated with varenicline use71 72 We pres-ent results using both measures a relative measure (Peto odds ratio and sensitivity analyses with fixed and random effects odds ratios) as well as an absolute mea-sure (risk difference) Findings were consistent for all examined outcomes
Many study authors did not specify the actual dates that adverse events were reported so we included all reported events this decision would have increased the likelihood of obtaining reports of rare adverse events We contacted authors for all of our included trials to check the data extracted on adverse events and for study protocols and other information to adequately assess the risk of bias in the studies We had a high response rate (75)
There are some limitations Firstly in this analysis we used study level data instead of individual level data so we were unable to determine whether differences in the adverse events were because of greater quit rates in the varenicline group relative to placebo Secondly because of the small number of suicides and attempted suicide reported (n=6) we cannot rule out major beneficial or adverse effects of varenicline for this outcome (Peto odds ratio 167 95 confidence interval 033 to 857) Thirdly there was potential for heterogeneity in the reporting of adverse events Authors used a range of methods to record adverse events including self report open ended questions structured questionnaires side effect check-lists and case reports coded to the Medical Dictionary for
Jorenby 2006 Hughes 2011 Zhao 2011 Brandon 2011 Ebbert 2011 Steinberg 2011 Bolliger 2011 Tashkin 2011 Williams 2012 Rennard 2012 Mitchell 2012 Wong 2012 McClure 2013 Stein 2013 Cinciripini 2013 Meszaros 2013 Anthenelli 2013 Evins 2014 Chengappa 2014 Gonzales 2014Overall I2=0 P=0995
-000 (-001 to 001)-001 (-003 to 002)000 (-015 to 015)000 (-004 to 004)000 (-005 to 005)000 (-005 to 005)001 (-001 to 002)000 (-001 to 001)-001 (-010 to 008)-001 (-003 to 001)-003 (-012 to 005)000 (-001 to 001)000 (-005 to 005)001 (-004 to 005)-001 (-004 to 002)000 (-061 to 061)-001 (-003 to 000)001 (-008 to 010)003 (-008 to 014)000 (-001 to 001)-000 (-001 to 000)
1551222
11112
1016224lt11121
10100
-05 0 05
Study
Favourstreatment
Favoursplacebo
Odds ratio(95 CI)
Odds ratio(95 CI)
Weight()
03430107014046038040
23900248584
1486033
0151041
111108625
0256240231
0249152799
Treatment
13401111010054038039
01981251343
2165131
0135042033
110625
3269247129
0245182191
ControlNo of eventstotal
fig 3 | forest plot of risk of suicidal ideation events (mantel-Haenszel risk difference) associated with varenicline use in 20 placebo controlled randomised trials
RESEARCH
8 doi 101136bmjh1109 | BMJ 2015350h1109 | thethinspbmj
Regulatory Activities (MedDRA wwwmeddraorg) All of the industry sponsored trials coded adverse events using MedDRA Fourthly we excluded two studies69 73 from the review as the maximum dose of varenicline used in these studies was only 1 mg once a daymdashthat is half of the rec-ommended maximum dose Hong and colleagues exam-ined varenicline treatment in 20 smokers and 15 non-smokers with schizophrenia or schizoaffective disor-der and found no evidence that varenicline worsened psychiatric symptoms in these patients69 Mocking and colleagues studied the effects of varenicline on emotional and cognitive processing in 21 healthy adult non-smokers and concluded that it did not cause problems in emo-tional processing or impulsivity providing less support for a possible depressogenic effect of varenicline73 Fur-thermore a secondary analysis which included all doses of varenicline in the original trials and these two excluded randomised controlled trials produced similar findings to our main analysis (see appendix 6)
We tried to minimise reporting bias by including all events (such as deaths) reported regardless of whether or
not we considered them to be related to treatment It is still possible however that reporting bias could have occurred as for certain trials where the corresponding authors did not respond to our requests for additional information we could not determine whether a lack of reporting of deaths in the published paper was synonymous with no deaths It was difficult to interpret the funnel plots to assess whether publication bias might be present as most trials were efficacy trials and were not performed solely to deter-mine the incidence of psychiatric adverse events
Additionally smoking cessation has been shown to have a positive impact on mental health outcomes with a reduction in depression and anxiety compared with those who continue to smoke74 Patients prescribed varenicline were reported to have an approximately threefold increased chance of quitting smoking com-pared with those given placebo (odds ratio 288 95 confidence interval 240 to 347)4 this could explain the reduction in anxiety observed in this meta-analysis
Lastly half of the trials were sponsored by Pfizer the manufacturers of varenicline Although previous research with nicotine replacement therapy has shown that industry sponsored trials were more likely than other trials to report outcomes that were favourable to the study sponsor14 we did not find any evidence for differences in depression and suicidal ideation for industry versus non industry sponsored trials (P=0386 and P=0380 respectively for interaction) In addition all of the industry sponsored trials were assessed over-all as having a low risk of bias
Conclusions and clinical implicationsBased on this comprehensive systematic review of pub-lished randomised controlled trials there is no evi-dence of an increased risk of depression suicidal behaviour (that is suicide or attempted suicide sui-cidal ideation) and death from any cause associated with treatment with varenicline Varenicline users however have an increased risk of abnormal dreams insomnia and sleep disturbances which are consistent with findings from other studies and previously docu-mented commonly reported side effects of varenicline (wwwchantixcom) We reported our findings using two summary statistics (a relative measure and an abso-lute measure) and observed consistency with both methods This meta-analysis adds to previous research (observational and experimental) that found no evi-dence for increased suicidal behaviour or depression with varenicline the most effective drug for smoking cessation4 The dangers of smoking are well docu-mented and the health benefits of stopping smoking are well known Our analysis suggests that the benefits of varenicline for smoking cessation outweigh the as yet unproved risks of suicidal behaviour In the UK vareni-cline is recommended alongside bupropion and nico-tine replacement therapy as first line treatment for smoking cessation75 Therefore the reduction in vareni-cline prescribing in the UK should be as much a cause for concern to clinicians regulatory agencies and policy makers as the unfounded fears regarding vareni-clinersquos association with suicidal behaviour
Nides 2006 Tonstad 2006 Jorenby 2006 Onken 2006 Gonzales 2006 Williams 2007 Tsai 2007 Niaura 2008 Rigotti 2010 Fagerstrom 2010 Hughes 2011 Garza 2011 Ebbert 2011 Steinberg 2011 Bolliger 2011 Tashkin 2011 Williams 2012 Rennard 2012 Wong 2012 Zesiewicz 2012 McClure 2013 Stein 2013 Litten 2013 Cinciripini 2013 Meszaros 2013 Anthenelli 2013 Evins 2014 Chengappa 2014 Gonzales 2014 Faessel 2009 Brandon 2011Overall I2=0 P=0631
193 (020 to 1870)088 (044 to 178)
419 (095 to 1855)070 (018 to 267)057 (017 to 186)148 (051 to 428)050 (005 to 488)148 (025 to 864)164 (041 to 661)043 (010 to 191)053 (005 to 514)
100 (006 to 1619)014 (000 to 682)097 (013 to 719)102 (030 to 340)122 (037 to 402)066 (013 to 326)020 (004 to 090)089 (089 to 642)012 (012 to 208)078 (078 to 185)066 (066 to 185)123 (123 to 378)051 (020 to 130)
100 (005 to 1991)140 (067 to 292)
118 (007 to 1932)381 (099 to 1467)234 (053 to 1040)
ExcludedExcluded
096 (075 to 122)
1123345123311lt1144232186571
1113300
100
0001 001 01 1 10 100 1000
Study
Favourstreatment
Favoursplacebo
Odds ratio(95 CI)
Odds ratio(95 CI)
Weight()
212515602634362534349
1225111263157535322131107155038240
83906248484
44862151
091741
1711179768615
17256140831
5249014046
1635356
Treatment
112317604134041217344412621242155335052182111155138239
41985251343
51652135
292042733
610114106
1513269
147229
224507
0541394487
ControlNo of eventstotal
fig 4 | forest plot of risk of depression events (Peto odds ratio) associated with varenicline use in 31 placebo controlled randomised trials
RESEARCH
9thethinspbmj | BMJ 2015350h1109 | doi 101136bmjh1109
We are grateful to the corresponding authors of the trials and Cristina Russ of Pfizer (for the Pfizer sponsored trials) for their support with providing access to the data on psychiatric adverse events and death used in this studyContributors KHT DG and RMM conceived the study KHT conducted the literature search KHT and DWK screened the abstracts with assistance from DG KHT DG and RMM were responsible for data extraction and the risk of bias assessment KHT did the statistical analysis with support from JPH KHT wrote the paper with contributions from all authors All authors have approved the final draft of the manuscript KHT is study guarantor had full access to all of the data (including statistical reports and tables) and can take responsibility for the integrity of the data and the accuracy of the data analysisFunding KHT is currently funded by a clinical lectureship from the National Institute for Health Research Part of this work was undertaken while KHT was on a National Institute for Health Research doctoral research fellowship (DRF-2010-03-138) DWK is funded by a Wellcome Trust four year studentship (WT099874MA) DG is an NIHR senior investigator The views expressed in this publication are those of the authors and not necessarily those of the NHS the National Institute for Health Research or the Department of HealthCompeting interests All authors have completed the Unified Competing Interest form at wwwicmjeorgcoi_disclosurepdf (available on request from the corresponding author) and declare RMM had specified relationship with the MHRA in the past (was a member of the MHRArsquos Independent Scientific Advisory Committee for CPRD research and received expenses and a small fee for meeting attendance and preparation for meetings) DG had specified relationship with the MHRA in the past (was a member of the MHRArsquos Pharmacovigilance Expert Advisory Group and received travel expenses and a small fee for meeting attendance and preparation for meetings)Ethics approval Not requiredData sharing No additional data are availableTransparency declaration KHT affirms that this manuscript is an honest accurate and transparent account of the study being reported that no important aspects of the study have been omitted and that any discrepancies from the study as planned (and if relevant registered) have been explainedThis is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 40) license which permits others to distribute remix adapt build upon this work non-commercially and license their derivative works on different terms provided the original work is properly cited and the use is non-commercial See httpcreativecommonsorglicensesby-nc401 Peto R Darby S Deo H Silcocks P Whitley E Doll R Smoking
smoking cessation and lung cancer in the UK since 1950 combination of national statistics with two case-control studies BMJ 2000321323ndash9
2 Jha P Peto R Global effects of smoking of quitting and of taxing tobacco N Engl J Med 201437060ndash8
3 Allender S Balakrishnan R Scarborough P Webster P Rayner M The burden of smoking-related ill health in the UK Tob Control 200918262ndash67
4 Cahill K Stevens S Perera R Lancaster T Pharmacological interventions for smoking cessation an overview and network meta-analysis Cochrane Database Syst Rev 20135CD009329
5 Medicines and Healthcare Products Regulatory Agency Varenicline adverse psychiatric reactions including depression Drug Safety Update 200822ndash3
6 US Food and Drug Administration Information for healthcare professionals varenicline (marketed as Chantix) and bupropion (marketed as Zyban Wellbutrin and generics) FDA Drug Safety Newsletter 2009
7 Gunnell D Irvine D Wise L Davies C Martin RM Varenicline and suicidal behaviour a cohort study based on data from the General Practice Research Database BMJ 2009339b3805
8 Meyer TE Taylor LG Xie S Graham DJ Mosholder AD Williams JR et al Neuropsychiatric events in varenicline and nicotine replacement patch users in the Military Health System Addiction 2013108203ndash10
9 Thomas KH Martin RM Davies N Metcalfe C Windmeijer F Gunnell D Smoking cessation treatment and the risk of depression suicide and self-harm in the Clinical Practice Research Datalink prospective cohort study BMJ 2013347f5704
10 Gibbons RD Mann JJ Varenicline smoking cessation and neuropsychiatric adverse events Am J Psychiatry 20131701460ndash7
11 Walker AM Confounding by indication Epidemiology 19967335ndash612 Miller M Hemenway D Bell NS Yore MM Amoroso PJ Cigarette
smoking and suicide a prospective study of 300000 male active-duty Army soldiers Am J Epidemiol 20001511060ndash3
Nides 2006 Tonstad 2006 Jorenby 2006 Onken 2006 Gonzales 2006 Williams 2007 Tsai 2007 Niaura 2008 Faessel 2009 Rigotti 2010 Fagerstrom 2010 Hughes 2011 Garza 2011 Brandon 2011 Ebbert 2011 Steinberg 2011 Bolliger 2011 Tashkin 2011 Williams 2012 Rennard 2012 Wong 2012 Zesiewicz 2012 McClure 2013 Stein 2013 Litten 2013 Cinciripini 2013 Meszaros 2013 Anthenelli 2013 Evins 2014 Chengappa 2014 Gonzales 2014Overall I2=0 P=0783
001 (-002 to 003)-000 (-002 to 001)001 (-000 to 003)-001 (-005 to 003)-001 (-003 to 001)-002 (-002 to 006)001 (-004 to 002)001 (-002 to 003)000 (-019 to 019)001 (-001 to 002)-001 (-004 to 001)-001 (-004 to 002)000 (-005 to 005)000 (-004 to 004)-003 (-010 to 004)-000 (-010 to 010)000 (-002 to 002)000 (-002 to 003)-002 (-011 to 007)-002 (-005 to 001)-000 (-003 to 003)-022 (-052 to 008)-006 (-027 to 015)-006 (-021 to 010)001 (-006 to 008)-006 (-015 to 002)000 (-050 to 050)002 (-002 to 006)000 (-006 to 007)019 (001 to 037)001 (-001 to 003)-000 (-001 to 001)
313737433lt1752111165153lt11122lt16115
100
-05 0 05
Study
Favourstreatment
Favoursplacebo
Odds ratio(95 CI)
Odds ratio(95 CI)
Weight()
212515602634362534349
1225111263157014
535322131107155046038240
83906248484
44862151
091741
1711179768615
17256140831
52491635356
Treatment
112317604134041217344412621242155
07335052182111155054138239
41985251343
51652135
292042733
610114106
1513269
147229
22451394487
ControlNo of eventstotal
fig 5 | forest plot of risk of depression events (mantel-Haenszel risk difference) associated with varenicline use in 31 placebo controlled randomised trials
table 5 | Comparison of Peto fixed effects and random effects odds ratios (Or) for insomnia sleep disorders and abnormal dreams in people treated with varenicline
neuropsychiatric adverse event
no of eventsno treatedOdds ratio (95 Ci)
test for heterogeneity ()varenicline group Placebo group
insomniaPeto OR 6795621 3794762 156 (136 to 178) 0Fixed effects OR 6795621 3794762 156 (135 to 179) 0Random effects OR 6795621 3794762 156 (135 to 179) 0sleep disordersPeto OR 2115081 1234284 163 (129 to 207) 0Fixed effects OR 2115081 1234284 157 (122 to 203) 0Random effects OR 2115081 1234284 157 (122 to 203) 0abnormal dreams Peto OR 6035606 2244741 238 (205 to 277) 223Fixed effects OR 6035606 2244741 237 (199 to 282) 316Random effects OR 6035606 2244741 236 (187 to 298) 316All Plt0001
RESEARCH
10 doi 101136bmjh1109 | BMJ 2015350h1109 | thethinspbmj
13 Miller M Hemenway D Rimm E Cigarettes and suicide a prospective study of 50000 men Am J Public Health 200090768ndash73
14 Etter JF Burri M Stapleton J The impact of pharmaceutical company funding on results of randomized trials of nicotine replacement therapy for smoking cessation a meta-analysis Addiction 2007102815ndash22
15 Prescribing and Primary Care team Health and Social Care Information Centre Prescription cost analysis England 2013 Health and Social Care Information Centre 2014
16 Cahill K Stead LF Lancaster T Nicotine receptor partial agonists for smoking cessation Cochrane Database Syst Rev 20124CD006103
17 Higgins JPT Altman DG Assessing risk of bias in included studies Cochrane handbook for systematic reviews of interventions John Wiley 2008187ndash241
18 Harris R Bradburn M Deeks J Harbord R Altman D Sterne J metan fixed- and random-effects meta-analysis Stata J 200883ndash28
19 Bradburn MJ Deeks JJ Berlin JA Russell Localio A Much ado about nothing a comparison of the performance of meta-analytical methods with rare events Stat Med 20072653ndash77
20 Higgins JP Thompson SG Deeks JJ Altman DG Measuring inconsistency in meta-analyses BMJ 2003327557ndash60
21 Higgins JPT Deeks JJ Altman DG Special topics in statistics Cochrane handbook for systematic reviews of interventions John Wiley 2008481ndash529
22 Sterne JAC Harbord RM Funnel plots in meta-analysis Stata J 20044127ndash41
23 Harbord RM Harris RJ Sterne JAC Updated tests for small-study effects in meta-analyses Stata J 20099197ndash210
24 Anthenelli RM Morris C Ramey TS Dubrava SJ Tsilkos K Russ C et al Effects of varenicline on smoking cessation in adults with stably treated current or past major depression a randomized trial Ann Intern Med 2013159390ndash400
25 Bolliger CT Issa JS Posadas-Valay R Safwat T Abreu P Correia EA et al Effects of varenicline in adult smokers a multinational 24-week randomized double-blind placebo-controlled study Clin Ther 201133465ndash77
26 Brandon TH Drobes DJ Unrod M Heckman BW Oliver JA Roetzheim RC et al Varenicline effects on craving cue reactivity and smoking reward Psychopharmacology (Berl) 2011218391ndash403
27 Burstein AH Fullerton T Clark DJ Faessel HM Pharmacokinetics safety and tolerability after single and multiple oral doses of varenicline in elderly smokers J Clin Pharmacol 2006461234ndash40
28 Cinciripini PM Robinson JD Karam-Hage M Minnix JA Lam C Versace F et al Effects of varenicline and bupropion sustained-release use plus intensive smoking cessation counseling on prolonged abstinence from smoking and on depression negative affect and other symptoms of nicotine withdrawal JAMA Psychiatry 201370522ndash33
29 Ebbert JO Croghan IT Severson HH Schroeder DR Hays JT A pilot study of the efficacy of varenicline for the treatment of smokeless tobacco users in Midwestern United States Nicotine Tob Res 201113820ndash6
30 Evins AE Cather C Pratt SA Pachas GN Hoeppner SS Goff DC et al Maintenance treatment with varenicline for smoking cessation in patients with schizophrenia and bipolar disorder a randomized clinical trial JAMA 2014311145ndash54
31 Faessel H Ravva P Williams K Pharmacokinetics safety and tolerability of varenicline in healthy adolescent smokers a multicenter randomized double-blind placebo-controlled parallel-group study Clin Ther 200931177ndash89
32 Fagerstrom K Gilljam H Metcalfe M Tonstad S Messig M Stopping smokeless tobacco with varenicline randomised double blind placebo controlled trial BMJ 2010341c6549
33 Fatemi SH Yousefi MK Kneeland RE Liesch SB Folsom TD Thuras PD Antismoking and potential antipsychotic effects of varenicline in subjects with schizophrenia or schizoaffective disorder a double-blind placebo and bupropion-controlled study Schizophr Res 2013146376ndash8
34 Garza D Murphy M Tseng LJ Riordan HJ Chatterjee A A double-blind randomized placebo-controlled pilot study of neuropsychiatric adverse events in abstinent smokers treated with varenicline or placebo Biol Psychiatry 2011691075ndash82
35 Gonzales D Rennard SI Nides M Oncken C Azoulay S Billing CB et al Varenicline an alpha4beta2 nicotinic acetylcholine receptor partial agonist vs sustained-release bupropion and placebo for smoking cessation a randomized controlled trial JAMA 200629647ndash55
36 Hughes JR Rennard SI Fingar JR Talbot SK Callas PW Fagerstrom KO Efficacy of varenicline to prompt quit attempts in smokers not currently trying to quit a randomized placebo-controlled trial Nicotine Tob Res 201113955ndash64
37 Jorenby DE Hays JT Rigotti NA Azoulay S Watsky EJ Williams KE et al Efficacy of varenicline an alpha4beta2 nicotinic acetylcholine receptor partial agonist vs placebo or sustained-release bupropion for smoking cessation a randomized controlled trial JAMA 200629656ndash63
38 Litten RZ Ryan ML Fertig JB Falk DE Johnson B Dunn KE et al A double-blind placebo-controlled trial assessing the efficacy of varenicline tartrate for alcohol dependence J Addict Med 20137277ndash86
39 McClure EA Vandrey RG Johnson MW Stitzer ML Effects of varenicline on abstinence and smoking reward following a programmed lapse Nicotine Tob Res 201315139ndash48
40 McKee SA Harrison EL OrsquoMalley SS Krishnan-Sarin S Shi J Tetrault JM et al Varenicline reduces alcohol self-administration in heavy-drinking smokers Biol Psychiatry 200966185ndash90
41 Meszaros ZS Abdul-Malak Y Dimmock JA Wang D Ajagbe TO Batki SL Varenicline treatment of concurrent alcohol and nicotine dependence in schizophrenia a randomized placebo-controlled pilot trial J Clin Psychopharmacol 201333243ndash7
42 Mitchell JM Teague CH Kayser AS Bartlett SE Fields HL Varenicline decreases alcohol consumption in heavy-drinking smokers Psychopharmacology (Berl) 2012223299ndash306
43 Nakamura M Oshima A Fujimoto Y Maruyama N Ishibashi T Reeves KR Efficacy and tolerability of varenicline an alpha4beta2 nicotinic acetylcholine receptor partial agonist in a 12-week randomized placebo-controlled dose-response study with 40-week follow-up for smoking cessation in Japanese smokers Clin Ther 2007291040ndash56
44 Niaura R Hays JT Jorenby DE Leone FT Pappas JE Reeves KR et al The efficacy and safety of varenicline for smoking cessation using a flexible dosing strategy in adult smokers a randomized controlled trial Curr Med Res Opin 2008241931ndash41
45 Nides M Oncken C Gonzales D Rennard S Watsky EJ Anziano R et al Smoking cessation with varenicline a selective alpha4beta2 nicotinic receptor partial agonist results from a 7-week randomized placebo- and bupropion-controlled trial with 1-year follow-up Arch Intern Med 20061661561ndash8
46 Oncken C Gonzales D Nides M Rennard S Watsky E Billing CB et al Efficacy and safety of the novel selective nicotinic acetylcholine receptor partial agonist varenicline for smoking cessation Arch Intern Med 20061661571ndash7
47 Plebani JG Lynch KG Yu Q Pettinati HM OrsquoBrien CP Kampman KM Results of an initial clinical trial of varenicline for the treatment of cocaine dependence Drug Alcohol Depend 2012121163ndash6
48 Plebani JG Lynch KG Rennert L Pettinati HM OrsquoBrien CP Kampman KM Results from a pilot clinical trial of varenicline for the treatment of alcohol dependence Drug Alcohol Depend 2013133754ndash8
49 Poling J Rounsaville B Gonsai K Severino K Sofuoglu M The safety and efficacy of varenicline in cocaine using smokers maintained on methadone a pilot study Am J Addict 201019401ndash8
50 Rennard S Hughes J Cinciripini PM Kralikova E Raupach T Arteaga C et al A randomized placebo-controlled trial of varenicline for smoking cessation allowing flexible quit dates Nicotine Tob Res 201214343ndash50
51 Rigotti NA Pipe AL Benowitz NL Arteaga C Garza D Tonstad S Efficacy and safety of varenicline for smoking cessation in patients with cardiovascular disease a randomized trial Circulation 2010121221ndash9
52 Shim JC Jung DU Jung SS Seo YS Cho DM Lee JH et al Adjunctive varenicline treatment with antipsychotic medications for cognitive impairments in people with schizophrenia a randomized double-blind placebo-controlled trial Neuropsychopharmacology 201237660ndash8
53 Stein MD Caviness CM Kurth ME Audet D Olson J Anderson BJ Varenicline for smoking cessation among methadone-maintained smokers a randomized clinical trial Drug Alcohol Depend 2013133486ndash93
54 Steinberg MB Randall J Greenhaus S Schmelzer AC Richardson DL Carson JL Tobacco dependence treatment for hospitalized smokers a randomized controlled pilot trial using varenicline Addic Behav 2011361127ndash32
55 Tashkin DP Rennard S Hays JT Ma W Lawrence D Lee TC Effects of varenicline on smoking cessation in patients with mild to moderate COPD a randomized controlled trial Chest 2011139591ndash9
56 Tonnesen P Mikkelsen K Varenicline to stop long-term nicotine replacement use a double-blind randomized placebo-controlled trial Nicotine Tob Res 201315419ndash27
57 Tonstad S Tonnesen P Hajek P Williams KE Billing CB Reeves KR et al Effect of maintenance therapy with varenicline on smoking cessation a randomized controlled trial JAMA 200629664ndash71
58 Tsai ST Cho HJ Cheng HS Kim CH Hsueh KC Billing CB Jr et al A randomized placebo-controlled trial of varenicline a selective alpha4beta2 nicotinic acetylcholine receptor partial agonist as a new therapy for smoking cessation in Asian smokers Clin Ther 2007291027ndash39
59 Wang C Xiao D Chan KPW Pothirat C Garza D Davies S Varenicline for smoking cessation A placebo-controlled randomized study Respirology 200914384ndash92
60 Weiner E Buchholz A Coffay A Liu F McMahon RP Buchanan RW et al Varenicline for smoking cessation in people with schizophrenia a double blind randomized pilot study Schizophr Res 201112994ndash5
RESEARCH
11thethinspbmj | BMJ 2015350h1109 | doi 101136bmjh1109
61 Williams K Reeves K Billing C Pennington A Gong J A double-blind study evaluating the long-term safety of varenicline for smoking cessation Curr Med Res Opin 200723793ndash801
62 Williams JM Anthenelli RM Morris CD Treadow J Thompson JR Yunis C et al A randomized double-blind placebo-controlled study evaluating the safety and efficacy of varenicline for smoking cessation in patients with schizophrenia or schizoaffective disorder J Clin Psychiatry 201273654ndash60
63 Wong J Abrishami A Yang Y Zaki A Friedman Z Selby P et al A perioperative smoking cessation intervention with varenicline a double-blind randomized placebo-controlled trial Anesthesiology 2012117755ndash64
64 Zesiewicz TA Greenstein PE Sullivan KL Wecker L Miller A Jahan I et al A randomized trial of varenicline (Chantix) for the treatment of spinocerebellar ataxia type 3 Neurology 201278545ndash50
65 Zhao Q Schwam E Fullerton T OrsquoGorman M Burstein AH Pharmacokinetics safety and tolerability following multiple oral doses of varenicline under various titration schedules in elderly nonsmokers J Clin Pharmacol 201151492ndash501
66 Chengappa KN Perkins KA Brar JS Schlicht PJ Turkin SR Hetrick ML et al Varenicline for smoking cessation in bipolar disorder a randomized double-blind placebo-controlled study J Clin Psychiatry 201475765ndash72
67 Gonzales D Hajek P Pliamm L Nackaerts K Tseng LJ McRae TD et al Retreatment with varenicline for smoking cessation in smokers who have previously taken varenicline a randomized placebo-controlled trial Clin Pharmacol Ther 201496390ndash6
68 Kishi T Iwata N Varenicline for smoking cessation in people with schizophrenia systematic review and meta-analysis Eur Arch Psychiatry Clin Neurosci 2014 Oct 5 [Epub ahead of print]
69 Hong LE Thaker GK McMahon RP Summerfelt A Rachbeisel J Fuller RL et al Effects of moderate-dose treatment with varenicline on neurobiological and cognitive biomarkers in smokers and nonsmokers with schizophrenia or schizoaffective disorder Arch Gen Psychiatry 2011681195ndash206
70 Huang Y Li W Yang L Jiang Y Wu Y Long-term efficacy and safety of varenicline for smoking cessation a systematic review and
meta-analysis of randomized controlled trials J Public Health 201220355ndash65
71 Singh S Loke YK Spangler JG Furberg CD Risk of serious adverse cardiovascular events associated with varenicline a systematic review and meta-analysis CMAJ 20111831359ndash66
72 Prochaska JJ Hilton JF Risk of cardiovascular serious adverse events associated with varenicline use for tobacco cessation systematic review and meta-analysis BMJ 2012344e2856
73 Mocking RJ Patrick Pflanz C Pringle A Parsons E McTavish SF Cowen PJ et al Effects of short-term varenicline administration on emotional and cognitive processing in healthy non-smoking adults a randomized double-blind study Neuropsychopharmacology 201338476ndash84
74 Taylor G McNeill A Girling A Farley A Lindson-Hawley N Aveyard P Change in mental health after smoking cessation systematic review and meta-analysis BMJ 2014348g1151
75 Smoking cessation services in primary care pharmacies local authorities and workplaces particularly for manual working groups pregnant women and hard to reach communities NICE public health guidance 10 National Institute for Health and Care Excellence 2008
copy BMJ Publishing Group Ltd 2015
Appendix 1 Search strategy to identify relevant articles in MedlineAppendix 2 Further characteristics of included ran-domised controlled trialsAppendix 3 Forest plots for secondary outcomesAppendix 4 Subgroup analysesAppendix 5 Funnel plots Appendix 6 Summary of Peto odds ratios risk differ-ences and 95 confidence intervals for neuropsychiat-ric events
RESEARCH
3thethinspbmj | BMJ 2015350h1109 | doi 101136bmjh1109
company if the drug was provided at no cost by the manufacturer andor if the research was investigator initiatedmdashthat is the drug and some funding was provided by the manufacturer although there was no other involvement in study conduct or publication and data were independently held by the researchers Tests for subgroup differences were performed Funnel plot asymmetry was assessed for two outcomemdashdepression and insomniamdashwith Harbordrsquos modified test for small study effects with the ldquometafunnelrdquo and ldquometabiasrdquo commands in Stata22 23
resultsstudy characteristicsFigure 1 summarises the selection of studies The search strategy identified 1089 studies from the com-puterised databases (476 from Medline 517 from Psy-cINFO and 96 from Embase) One additional trial was identified from CENTRAL and clinicaltrialsgov Out of the 1090 studies 130 were duplicates and 905 were excluded based on screening of titles and abstracts therefore 55 papers met the criteria for further screen-ing After the second round of screening 42 trials were identified for further data extraction24ndash65 Two addi-tional studies were identified when the search was repeated for the week beginning Monday 4 August 201466 67 Forty four studies were included in the sys-tematic review We received responses from study authors for 33 studies (75)
Table 1 and appendix 2 describe study characteris-tics The trials included 11 146 participants (6015 patients were randomised to receive a maximum of varenicline 1 mg twice daily and 5131 patients received a placebo) Of these randomised patients 10 998 were
evaluable for adverse events (5931 in the varenicline group and 5067 in the placebo group) The duration of treatment ranged from one week to 52 weeks while study duration ranged from eight days to 53 weeks Eighteen trials (613 of all participants) included cigarette smokers from the general population with no history of psychiatric illnesses (Table 2) In trials that included cigarette smokers (39 trials) participants smoked an average of 20 cigarettes a day for 266 years in the varenicline group and 20 cigarettes a day for 262 years in the placebo group Loss to follow-up ranged from 0 to 60 in both groups (appendix 2) In 12 trials losses to follow-up were higher in the varenicline group than the placebo group whereas in 17 trials losses to follow-up were higher in the placebo group than the varenicline group
Table 3 shows the assessment of risk of bias We excluded five trials from the meta-analysis as the risk of bias was unclear in four or more of the six domains47 52 60 or because no data were reported in the published papers and the study authors did not respond to our requests for data48 49 52 This resulted in exclusion of 114 patients (19) from the varenicline group and 123 patients (24) from the placebo group 10 761 patients were included in the meta-analyses (5817 in the varenicline group and 4944 in the placebo group) In three trials39 41 42 there were high losses to follow-up 537 60 and 452 respectively These studies were assessed as low risk of bias because of incomplete outcome data and were not excluded They were all small trials (combined total of n=92 in the varenicline group (16 of all people ran-domised to varenicline in our meta-analysis) and n=86 in the placebo group (17 of all people randomised to pla-cebo)) In addition only nine out of 178 patients (51) were lost to follow-up because of adverse events and these were mostly gastrointestinal in nature (such as nausea and vomiting)39 42 41
risk of neuropsychiatric adverse events and deathTwo people died by suicide (both in the varenicline arms) and four attempted to do so (two in the vareni-cline arm and two in the placebo arm) Table 4 sum-marises the Peto odds ratios risk differences and 95 confidence interval for the primary and secondary out-comes Because of the small numbers of events we combined suicide and attempted suicide into a single outcome Thirty one trials reported suicide and suicide attempt the Peto odds ratio for varenicline versus pla-cebo was 167 (95 confidence interval 033 to 857 P=054 I2=103) and the risk difference was 00003 (minus0002 to 0003 P=081 I2=00) Twenty trials reported suicidal ideation (figs 2 and 3) the Peto odds ratio was 058 (028 to 120 P=014 I2=00) and the risk difference was minus0003 (minus0009 to 0002 P=024 I2=00) Thirty one trials reported on depression (figs 4 and 5) the Peto odds ratio was 096 (075 to 122 P=074 I2=00) and the risk difference was minus0001 (minus001 to 001 P=074 I2=00) Death was reported in 36 trials (total 135760 in the varenicline group and 114887 in the placebo group) The Peto odds ratio for death was 105 (047 to 238 P=09 I2=387) and
Boxes (n=)Articles identied through literature search on 9 May 2014 (n=1090) Computerised databases (n=1089) Medline (n=476) Embase (n=96) PsycINFO (n=517) Additional trials identied from Cochrane database of randomised controlled trials or Clinicaltrialsgov (n=1)
Screening of titles and abstracts (n=1090)
Full text articles for second round of screening (n=55)
Eligible trials aer second round of screening (n=42)
Included in systematic review (n=44)
Additional trials published aer search (n=2)Drug manufacturer conrmed no furthertrials underway for publication in 2014
Duplicates (n=130)Excluded (n=905)
Excluded (n=13) Crossover trials (n=8) No monitoring of adverse eventssingle doseltmax dose varenicline (n=4) Second paper on same trial with no additional information (n=1)
fig 1 | flow chart showing selection of randomised controlled trials for inclusion in systematic review of varenicline
RESEARCH
4 doi 101136bmjh1109 | BMJ 2015350h1109 | thethinspbmj
there was no evidence of an increased risk of death in the varenicline group compared with the placebo group (risk difference 00001 minus0003 to 0003 P=094 I2=00) (Table 4) The forest plots for the secondary outcomes are shown in appendix 3
We found no evidence of an increased risk of irritabil-ity (odds ratio 098 05 confidence interval 081 to 117 P=079 I2=00) aggression (091 052 to 159 P=075 I2=208) or somnolence (123 094 to 162 P=013 I2=104) as the confidence intervals included the null value of 1 Varenicline was associated with an increased risk of sleep disorders (163 129 to 207 Plt0001 I2=00) insomnia (156 136 to 178 Plt0001 I2=00) abnormal dreams (238 205 to 277 Plt0001 I2=223)
and fatigue (128 106 to 155 P=001 I2=63) with some evidence of a reduced risk of anxiety (075 061 to 093 P=0008 I2=57) Consistent findings were observed for the risk differences (table 4)
sensitivity analysesThere were minimal differences in the effect measures and 95 confidence intervals with Peto fixed effects and random effects odds ratios (Table 5)
subgroup analysesThe subgroup analyses are shown in appendix 4 for the primary outcomes of depression and suicidal ideation Subgroup tests showed no evidence of a variation in the
table 1 | Characteristics of randomised controlled trials of varenicline 1mg twice daily included in systematic review
studyDuration (weeks) sample size mean age (years) men whitestudy treatment varenicline Placebo varenicline Placebo varenicline Placebo varenicline Placebo
Anthenelli 201324 52 12 256 269 454 471 379 368 NA NABolliger 201125 24 12 394 199 431 439 577 657 303 313Brandon 201126 22 22 56 58 458 412 609 611 541 648Burstein 200627 13 13 8 8 681 679 75 50 50 375Chengappa 201466 24 12 31 29 457 462 29 345 645 724Cinciripini 201328 24 12 86 106 438 452 616 632 581 717Ebbert 201129 24 12 38 38 407 41 100 100 100 100Evins 201430 64 40 40 47 514 457 60 66 75 72Faessel 200931 26 2 14 7 154 154 571 571 857 714Fagerstrom 201032 26 12 213 218 439 439 89 90 99 100Fatemi 201333 12 12 6 9 404 414 833 778 50 889Garza 201134 16 12 55 55 334 338 60 727 80 709Gonzales 200635 52 12 352 344 425 426 50 541 795 762Gonzales 201467 52 12 251 247 477 473 498 494 948 914Hughes 201136 24 8 107 111 44 412 605 572 914 919Jorenby 200637 52 12 344 341 446 423 552 581 855 85Litten 201338 16 13 97 101 46 45 732 683 619 703McClure 201339 5 5 54 50 45 43 40 59 32 36McKee 200940 11 1 10 10 342 353 80 80 40 90Meszaros 201341 12 8 5 5 42 44 80 60 40 60Mitchell 201242 16 12 33 31 29 25 55 65 73 64Nakamura 200743 52 12 156 154 401 399 792 76 NA NANiaura 200844 40 12 160 160 415 421 503 535 93 884Nides 200645 52 7 127 127 419 416 504 52 856 878Oncken 200646 52 12 259 129 422 43 485 519 808 721Plebani 201247 9 8 18 19 NA NA 696 75 11 33Plebani 201348 13 12 19 21 448 481 789 905 421 714Poling 201049 12 11 13 18 365 344 846 778 462 722Rennard 201250 24 12 493 166 439 432 60 596 68 681Rigotti 201051 52 12 355 359 57 559 752 822 803 808Shim 201252 8 8 60 60 399 399 38 45 0 0Stein 201353 24 24 137 45 392 406 46 622 825 756Steinberg 201154 24 12 40 39 NA NA 60 59 77 67Tashkin 201155 52 12 250 254 572 571 625 622 819 841Tonnesen 201356 52 12 70 69 536 556 429 493 NA NATonstad 200657 52 12 603 607 454 453 502 483 967 97Tsai 200758 24 12 126 124 397 409 849 927 0 0Wang 200959 24 12 165 168 39 385 964 97 0 0Weiner 201160 12 12 4 5 NA NA NA NA NA NAWilliams 200761 53 52 251 126 482 466 506 484 869 921Williams 201262 26 12 84 43 402 43 774 767 595 581Wong 201263 52 12 151 135 519 533 55 504 NA NAZesiewicz 201264 8 8 10 10 474 538 44 67 NA NAZhao 201165 37 3 14 10 71 73 429 50 100 90NA=not applicable
RESEARCH
5thethinspbmj | BMJ 2015350h1109 | doi 101136bmjh1109
side effects of depression and suicidal ideation by age group (P=0391 and P=0933 respectively for interac-tion) percentage of men in the study (P=0418 and P=0925) percentage of white people in the study (P=0685 and P=0254) presence or absence of psychi-atric illness (P=0126 and P=0304) smoking status (P=0906 for depression but not calculated for suicidal ideation as there were no reports of suicidal ideation in studies that included non-smokers) and whether the trial was industry sponsored or not (P=0386 and P=0380) The effect estimates (odds ratio) for the trials in which all participants had psychiatric illnesses com-pared with those where none of the participants had psychiatric illness were 149 (95 confidence interval 084 to 265) versus 091 (069 to 121) for depression and 079 (032 to 193) versus 034 (009 to 129) for suicidal ideation
table 2 | summary of characteristics of patients enrolled in 44 randomised controlled trials of vareniclineCharacteristics of trial participants no of trialsSmokers from general population 18Smokers with psychiatric illness 8Heavy drinking smokersalcohol dependence 4People dependent on cocaine or opioid dependent 3Smokeless tobacco users 2Smokers with mild to moderate COPD 1Smokers with cardiovascular disease 1Smokers about to undergo surgery 1Patients with spinocerebellar ataxia type 3 1Adolescent smokers 1Elderly non-smokers 1Smokers in hospital 1Smokers previously treated with varenicline 1Ex-smokers on long term NRT 1COPD=chronic obstructive pulmonary disease NRT=nicotine replacement therapy
table 3 | risk of bias assessment for each trial of varenicline using Cochrane risk of assessment of bias tool
studyrandom sequence generation
allocation concealment used
blindingincomplete outcome data
selective reporting Other bias
Participants and personnel
Outcome assessment
Anthenelli 201324 Low Low Low Low Low Low LowBolliger 201125 Low Low Low Low Low Low LowBrandon 201126 Low Low Low Low Low Low LowBurstein 200627 Low Low Low Low Low Low LowChengappa 201466 Low Low Low Low Low Low LowCinciripini 201328 Low Low Low Low Low Low LowEbbert 201129 Low Unclear Low Low Low Low LowEvins 201430 Low Low Low Low Low Low LowFaessel 200931 Low Low Low Low Low Low LowFagerstrom 201032 Low Low Low Low Low Low LowFatemi 201333 Unclear Low Low Low Low Low LowGarza 201134 Unclear Low Low Low Low Low LowGonzales 206635 Low Low Low Low Low Low LowGonzales 201467 Low Low Low Low Low Low LowHughes 201136 Low Low Low Low Low Unclear LowJorenby 200637 Low Low Low Low Low Low LowLitten 201338 Low Low Low Low Low Low LowMcClure 201339 Low Low Low Low Low Low LowMcKee 200940 Unclear Unclear Low Unclear Low Low LowMeszaros 201341 Low Low Low Low Low Low LowMitchell 201242 Low Low Low Low Low Low LowNakamura 200743 Low Low Low Low Low Low LowNiaura 200844 Low Low Low Low Low Low LowNides 200645 Low Low Low Low Low Low LowOncken 200646 Low Low Low Low Low Low LowPlebani 201247 Unclear Unclear Unclear Unclear Low Unclear LowPlebani 201348 Low Low Low Unclear Unclear Unclear LowPoling 201049 Low Unclear Low Unclear Low Low LowRennard 201250 Low Low Low Low Low Low LowRigotti 201051 Low Low Low Low Low Low LowShim 201252 Unclear Unclear Low Unclear Unclear Unclear UnclearStein 201353 Low Low Low Low Low Low LowSteinberg 201154 Low Low Low Low Low Low LowTashkin 201155 Low Low Low Low Low Low LowTonnesen 201356 Low Unclear Low Low Low Low LowTonstad 200657 Low Low Low Low Low Low LowTsai 200758 Low Low Low Low Low Low LowWang 200959 Low Low Low Low Low Low UnclearWeiner 201160 Unclear Unclear Unclear Unclear Low Unclear UnclearWilliams 200761 Low Low Low Low Low Low LowWilliams 201262 Low Low Low Low Low Low LowWong 201263 Low Low Low Low Low Low LowZesiewicz 201264 Low Low Low Low Low Low LowZhao 201165 Low Low Low Low Low Low Unclear
RESEARCH
6 doi 101136bmjh1109 | BMJ 2015350h1109 | thethinspbmj
small study effectsThe funnel plots for depression and insomnia are shown in appendix 5 The P values for funnel plot asym-metry were 053 for depression and 093 for insomnia (that is there was no evidence against the null hypoth-esis of no small study effects)
discussionThis meta-analysis of 39 randomised controlled trials involving 5817 patients prescribed varenicline 1 mg twice daily and 4944 patients prescribed placebo found no increased risk of suicide or attempted suicide
suicidal ideation depression or death in individuals treated with varenicline Almost half of the trial partici-pants were chronic heavy smokers (that is they had smoked on average 20 cigarettes a day for 26 years) Five separate trials (including 1281 participants randomised to varenicline and 1143 to placebo) reported a suicide andor suicide attempt (see appendix 3) one reported suicide only three reported attempted suicide only and one reported both suicide and attempted suicide Two suicides and two attempts occurred in the varenicline group of the trials (008) and two attempts occurred in the placebo group (005) Use of the maximum dose of varenicline (1 mg twice daily) was associated with a 28 increased risk of fatigue a 56 increased risk of insomnia a 63 increased risk of sleep disorders and more than twice the risk of abnormal dreams There was evidence of a 25 reduction in the risk of anxiety When we used risk differences for every 1000 patients there were an additional 10 cases of fatigue 40 cases of insomnia 20 cases of sleep disorders and 60 cases of abnormal dreams in those prescribed varenicline com-pared with placebo Similarly there were 10 fewer epi-sodes of anxiety per 1000 participants in the varenicline group compared with the placebo group (risk difference minus001 95 confidence interval minus002 to minus00003) There was no evidence of a variation in depression and sui-cidal ideation by age sex ethnicity presence or absence of psychiatric illness or type of study sponsor
Comparison with other studiesA recent study by Kishi and Iwata examined the effects of varenicline for smoking cessation in people with schizo-phrenia in a meta-analysis of seven randomised con-trolled trials68 With the exception of the study by Hong and colleagues69 we included all their randomised con-trolled trials in the current analysis Similar to our find-ings Kishi and Iwata found no significant differences in depression and suicidal ideation between the vareni-cline and placebo groups They reported however that varenicline use was associated with a lower risk of abnor-mal dreamsnightmares than placebo (relative risk 047 95 confidence interval 022 to 099 P=005)68
table 4 | summary of Peto odds ratios risk differences and 95 confidence intervals for neuropsychiatric events in people treated with varenicline
neuropsychiatric adverse eventno of eventsno treated
Odds ratio (95 Ci) P value risk difference (95 Ci) P valuevarenicline group Placebo groupPrimary outcomesDepression 1635356 1394487 096 (075 to 122) 074 minus0001 (minus001 to 001) 074Suicidal ideation 152799 182191 058 (028 to 120) 014 minus0003 (minus0009 to 0002) 024Attempted suicide 22184 21842 075 (010 to 565) 078 minus00003 (minus0005 to 0004) 091Suicide and attempted suicide 45352 24478 167 (033 to 857) 054 00003 (minus0002 to 0003) 081secondary outcomesAbnormal dreams 6035606 2244741 238 (205 to 277) lt0001 006 (005 to 007) lt0001Aggression 394276 243524 091 (052 to 159) 075 minus0001 (minus0005 to 0004) 079Anxiety 2094999 2264457 075 (061 to 093) 0008 minus001 (minus002 to minus00003) 001Death 135760 114887 105 (047 to 238) 09 00001 (minus0003 to 0003) 094Fatigue 2835502 2024701 128 (106 to 155) 001 001 (0002 to 002) 001Insomnia 6795621 3794762 156 (136 to 178) lt0001 004 (003 to 005) lt0001Irritability 2935406 2664615 098 (081 to 117) 079 minus0001 (minus001 to 0008) 079Sleep disorders 2115081 1234284 163 (129 to 207) lt0001 002 (001 to 002) lt0001Somnolence 1395360 914542 123 (094 to 162) 013 0005 (minus0001 to 001) 013
Jorenby 2006 Hughes 2011 Bolliger 2011 Tashkin 2011 Williams 2012 Rennard 2012 Mitchell 2012 Stein 2013 Cinciripini 2013 Meszaros 2013 Anthenelli 2013 Evins 2014 Chengappa 2014 Zhao 2011 Brandon 2011 Ebbert 2011 Steinberg 2011 Wong 2012 McClure 2013 Gonzales 2014Overall I2=0 P=0621
013 (000 to 676)014 (000 to 708)
453 (024 to 8523)014 (000 to 690)084 (019 to 380)011 (001 to 151)013 (000 to 641)
366 (003 to 38784)016 (000 to 842)
100 (009 to 1103)014 (001 to 136)118 (016 to 875)
186 (019 to 1864)ExcludedExcludedExcludedExcludedExcludedExcludedExcluded
058 (028 to 120)
3363
2383239
1013100000000
100
0001 001 01 1 10 100 1000
Study
Favourstreatment
Favoursplacebo
Odds ratio(95 CI)
Odds ratio(95 CI)
Weight()
0343010723900248584
1486033
111108625
0256240231014046038040
0151041
024915799
Treatment
1340111101981251343
2165131033
110625
3269247129110054038039
0135042
0245182191
ControlNo of eventstotal
fig 2 | forest plot of risk of suicidal ideation events (Peto odds ratio) associated with varenicline use in 20 placebo controlled randomised trials
RESEARCH
7thethinspbmj | BMJ 2015350h1109 | doi 101136bmjh1109
This discrepancy with our findings could be explained by the small sample size of their study (288 from four randomised controlled trials versus 10 347 from 35 ran-domised controlled trials in our analysis)
Gibbons and Mann used pooled data from 17 ran-domised controlled trials sponsored by Pfizer to exam-ine neuropsychiatric adverse events associated with varenicline10 Our study included industry and non- industry sponsored trials and more than twice the num-ber of trials that they included Their findings of no increased risk of suicidal events depression and agita-tion are consistent with our study Although the authors did not include references to the published literature for their included studies (which made cross referenc-ing difficult) it is likely that we included most of their studies in our analysis
Another meta-analysis examined the long term effi-cacy and safety of varenicline in trials with a minimum follow-up period of 12 months70 A meta-analysis of the main psychiatric related adverse effects (which com-bined depressed mood other mood disorders bipolar disorder delirium suicidal and self injurious behaviours adjustment disorders and abnormal think-ing into a single outcome) did not show a ldquosignificant increase of psychiatric side effects for varenicline com-pared with placebordquo70 This meta-analysis however included only three trials and the combined psychiat-ric outcome was non-specific The authors reported an increased risk of insomnia (relative risk 165 95 confi-dence interval 129 to 211) abnormal dreams (278 207 to 373) and sleep disturbance (209 162 to 269) but no
increased risk of irritability (114 075 to 173) which is consistent with our findings70
A previous Cochrane review examined the efficacy and tolerability of nicotine receptor partial agonists including varenicline16 Trials were excluded if partici-pants used smokeless tobacco or if there was less than six months of follow-up In addition to the efficacy out-comes meta-analyses were performed for the most commonly reported adverse events nausea insomnia abnormal dreams and headache Findings were consis-tent with our study for insomnia (relative risk 162 95 confidence interval 140 to 188) and abnormal dreams (291 234 to 362)16 The Cochrane review did not report any treatment emergent deaths Although we used a broader definition of deaths in our analysis by includ-ing all deaths irrespective of whether or not we thought they were related to treatment we did not find an increased risk of death in the varenicline group
strengths and limitationsTo the best of our knowledge this is the most compre-hensive published systematic review (and meta-analy-sis) of neuropsychiatric effects associated with use of varenicline Compared with the previous Cochrane review16 our analysis included 16 additional trials for the meta-analysis of the risk of insomnia events and 23 addi-tional trials for the pooled analysis of abnormal dreams
The choice of summary statistics for meta-analyses of rare events caused controversy (about whether the Peto odds ratio should be reported instead of risk differ-ences) when it led to conflicting findings from two sys-tematic reviews examining the risk of cardiovascular side effects associated with varenicline use71 72 We pres-ent results using both measures a relative measure (Peto odds ratio and sensitivity analyses with fixed and random effects odds ratios) as well as an absolute mea-sure (risk difference) Findings were consistent for all examined outcomes
Many study authors did not specify the actual dates that adverse events were reported so we included all reported events this decision would have increased the likelihood of obtaining reports of rare adverse events We contacted authors for all of our included trials to check the data extracted on adverse events and for study protocols and other information to adequately assess the risk of bias in the studies We had a high response rate (75)
There are some limitations Firstly in this analysis we used study level data instead of individual level data so we were unable to determine whether differences in the adverse events were because of greater quit rates in the varenicline group relative to placebo Secondly because of the small number of suicides and attempted suicide reported (n=6) we cannot rule out major beneficial or adverse effects of varenicline for this outcome (Peto odds ratio 167 95 confidence interval 033 to 857) Thirdly there was potential for heterogeneity in the reporting of adverse events Authors used a range of methods to record adverse events including self report open ended questions structured questionnaires side effect check-lists and case reports coded to the Medical Dictionary for
Jorenby 2006 Hughes 2011 Zhao 2011 Brandon 2011 Ebbert 2011 Steinberg 2011 Bolliger 2011 Tashkin 2011 Williams 2012 Rennard 2012 Mitchell 2012 Wong 2012 McClure 2013 Stein 2013 Cinciripini 2013 Meszaros 2013 Anthenelli 2013 Evins 2014 Chengappa 2014 Gonzales 2014Overall I2=0 P=0995
-000 (-001 to 001)-001 (-003 to 002)000 (-015 to 015)000 (-004 to 004)000 (-005 to 005)000 (-005 to 005)001 (-001 to 002)000 (-001 to 001)-001 (-010 to 008)-001 (-003 to 001)-003 (-012 to 005)000 (-001 to 001)000 (-005 to 005)001 (-004 to 005)-001 (-004 to 002)000 (-061 to 061)-001 (-003 to 000)001 (-008 to 010)003 (-008 to 014)000 (-001 to 001)-000 (-001 to 000)
1551222
11112
1016224lt11121
10100
-05 0 05
Study
Favourstreatment
Favoursplacebo
Odds ratio(95 CI)
Odds ratio(95 CI)
Weight()
03430107014046038040
23900248584
1486033
0151041
111108625
0256240231
0249152799
Treatment
13401111010054038039
01981251343
2165131
0135042033
110625
3269247129
0245182191
ControlNo of eventstotal
fig 3 | forest plot of risk of suicidal ideation events (mantel-Haenszel risk difference) associated with varenicline use in 20 placebo controlled randomised trials
RESEARCH
8 doi 101136bmjh1109 | BMJ 2015350h1109 | thethinspbmj
Regulatory Activities (MedDRA wwwmeddraorg) All of the industry sponsored trials coded adverse events using MedDRA Fourthly we excluded two studies69 73 from the review as the maximum dose of varenicline used in these studies was only 1 mg once a daymdashthat is half of the rec-ommended maximum dose Hong and colleagues exam-ined varenicline treatment in 20 smokers and 15 non-smokers with schizophrenia or schizoaffective disor-der and found no evidence that varenicline worsened psychiatric symptoms in these patients69 Mocking and colleagues studied the effects of varenicline on emotional and cognitive processing in 21 healthy adult non-smokers and concluded that it did not cause problems in emo-tional processing or impulsivity providing less support for a possible depressogenic effect of varenicline73 Fur-thermore a secondary analysis which included all doses of varenicline in the original trials and these two excluded randomised controlled trials produced similar findings to our main analysis (see appendix 6)
We tried to minimise reporting bias by including all events (such as deaths) reported regardless of whether or
not we considered them to be related to treatment It is still possible however that reporting bias could have occurred as for certain trials where the corresponding authors did not respond to our requests for additional information we could not determine whether a lack of reporting of deaths in the published paper was synonymous with no deaths It was difficult to interpret the funnel plots to assess whether publication bias might be present as most trials were efficacy trials and were not performed solely to deter-mine the incidence of psychiatric adverse events
Additionally smoking cessation has been shown to have a positive impact on mental health outcomes with a reduction in depression and anxiety compared with those who continue to smoke74 Patients prescribed varenicline were reported to have an approximately threefold increased chance of quitting smoking com-pared with those given placebo (odds ratio 288 95 confidence interval 240 to 347)4 this could explain the reduction in anxiety observed in this meta-analysis
Lastly half of the trials were sponsored by Pfizer the manufacturers of varenicline Although previous research with nicotine replacement therapy has shown that industry sponsored trials were more likely than other trials to report outcomes that were favourable to the study sponsor14 we did not find any evidence for differences in depression and suicidal ideation for industry versus non industry sponsored trials (P=0386 and P=0380 respectively for interaction) In addition all of the industry sponsored trials were assessed over-all as having a low risk of bias
Conclusions and clinical implicationsBased on this comprehensive systematic review of pub-lished randomised controlled trials there is no evi-dence of an increased risk of depression suicidal behaviour (that is suicide or attempted suicide sui-cidal ideation) and death from any cause associated with treatment with varenicline Varenicline users however have an increased risk of abnormal dreams insomnia and sleep disturbances which are consistent with findings from other studies and previously docu-mented commonly reported side effects of varenicline (wwwchantixcom) We reported our findings using two summary statistics (a relative measure and an abso-lute measure) and observed consistency with both methods This meta-analysis adds to previous research (observational and experimental) that found no evi-dence for increased suicidal behaviour or depression with varenicline the most effective drug for smoking cessation4 The dangers of smoking are well docu-mented and the health benefits of stopping smoking are well known Our analysis suggests that the benefits of varenicline for smoking cessation outweigh the as yet unproved risks of suicidal behaviour In the UK vareni-cline is recommended alongside bupropion and nico-tine replacement therapy as first line treatment for smoking cessation75 Therefore the reduction in vareni-cline prescribing in the UK should be as much a cause for concern to clinicians regulatory agencies and policy makers as the unfounded fears regarding vareni-clinersquos association with suicidal behaviour
Nides 2006 Tonstad 2006 Jorenby 2006 Onken 2006 Gonzales 2006 Williams 2007 Tsai 2007 Niaura 2008 Rigotti 2010 Fagerstrom 2010 Hughes 2011 Garza 2011 Ebbert 2011 Steinberg 2011 Bolliger 2011 Tashkin 2011 Williams 2012 Rennard 2012 Wong 2012 Zesiewicz 2012 McClure 2013 Stein 2013 Litten 2013 Cinciripini 2013 Meszaros 2013 Anthenelli 2013 Evins 2014 Chengappa 2014 Gonzales 2014 Faessel 2009 Brandon 2011Overall I2=0 P=0631
193 (020 to 1870)088 (044 to 178)
419 (095 to 1855)070 (018 to 267)057 (017 to 186)148 (051 to 428)050 (005 to 488)148 (025 to 864)164 (041 to 661)043 (010 to 191)053 (005 to 514)
100 (006 to 1619)014 (000 to 682)097 (013 to 719)102 (030 to 340)122 (037 to 402)066 (013 to 326)020 (004 to 090)089 (089 to 642)012 (012 to 208)078 (078 to 185)066 (066 to 185)123 (123 to 378)051 (020 to 130)
100 (005 to 1991)140 (067 to 292)
118 (007 to 1932)381 (099 to 1467)234 (053 to 1040)
ExcludedExcluded
096 (075 to 122)
1123345123311lt1144232186571
1113300
100
0001 001 01 1 10 100 1000
Study
Favourstreatment
Favoursplacebo
Odds ratio(95 CI)
Odds ratio(95 CI)
Weight()
212515602634362534349
1225111263157535322131107155038240
83906248484
44862151
091741
1711179768615
17256140831
5249014046
1635356
Treatment
112317604134041217344412621242155335052182111155138239
41985251343
51652135
292042733
610114106
1513269
147229
224507
0541394487
ControlNo of eventstotal
fig 4 | forest plot of risk of depression events (Peto odds ratio) associated with varenicline use in 31 placebo controlled randomised trials
RESEARCH
9thethinspbmj | BMJ 2015350h1109 | doi 101136bmjh1109
We are grateful to the corresponding authors of the trials and Cristina Russ of Pfizer (for the Pfizer sponsored trials) for their support with providing access to the data on psychiatric adverse events and death used in this studyContributors KHT DG and RMM conceived the study KHT conducted the literature search KHT and DWK screened the abstracts with assistance from DG KHT DG and RMM were responsible for data extraction and the risk of bias assessment KHT did the statistical analysis with support from JPH KHT wrote the paper with contributions from all authors All authors have approved the final draft of the manuscript KHT is study guarantor had full access to all of the data (including statistical reports and tables) and can take responsibility for the integrity of the data and the accuracy of the data analysisFunding KHT is currently funded by a clinical lectureship from the National Institute for Health Research Part of this work was undertaken while KHT was on a National Institute for Health Research doctoral research fellowship (DRF-2010-03-138) DWK is funded by a Wellcome Trust four year studentship (WT099874MA) DG is an NIHR senior investigator The views expressed in this publication are those of the authors and not necessarily those of the NHS the National Institute for Health Research or the Department of HealthCompeting interests All authors have completed the Unified Competing Interest form at wwwicmjeorgcoi_disclosurepdf (available on request from the corresponding author) and declare RMM had specified relationship with the MHRA in the past (was a member of the MHRArsquos Independent Scientific Advisory Committee for CPRD research and received expenses and a small fee for meeting attendance and preparation for meetings) DG had specified relationship with the MHRA in the past (was a member of the MHRArsquos Pharmacovigilance Expert Advisory Group and received travel expenses and a small fee for meeting attendance and preparation for meetings)Ethics approval Not requiredData sharing No additional data are availableTransparency declaration KHT affirms that this manuscript is an honest accurate and transparent account of the study being reported that no important aspects of the study have been omitted and that any discrepancies from the study as planned (and if relevant registered) have been explainedThis is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 40) license which permits others to distribute remix adapt build upon this work non-commercially and license their derivative works on different terms provided the original work is properly cited and the use is non-commercial See httpcreativecommonsorglicensesby-nc401 Peto R Darby S Deo H Silcocks P Whitley E Doll R Smoking
smoking cessation and lung cancer in the UK since 1950 combination of national statistics with two case-control studies BMJ 2000321323ndash9
2 Jha P Peto R Global effects of smoking of quitting and of taxing tobacco N Engl J Med 201437060ndash8
3 Allender S Balakrishnan R Scarborough P Webster P Rayner M The burden of smoking-related ill health in the UK Tob Control 200918262ndash67
4 Cahill K Stevens S Perera R Lancaster T Pharmacological interventions for smoking cessation an overview and network meta-analysis Cochrane Database Syst Rev 20135CD009329
5 Medicines and Healthcare Products Regulatory Agency Varenicline adverse psychiatric reactions including depression Drug Safety Update 200822ndash3
6 US Food and Drug Administration Information for healthcare professionals varenicline (marketed as Chantix) and bupropion (marketed as Zyban Wellbutrin and generics) FDA Drug Safety Newsletter 2009
7 Gunnell D Irvine D Wise L Davies C Martin RM Varenicline and suicidal behaviour a cohort study based on data from the General Practice Research Database BMJ 2009339b3805
8 Meyer TE Taylor LG Xie S Graham DJ Mosholder AD Williams JR et al Neuropsychiatric events in varenicline and nicotine replacement patch users in the Military Health System Addiction 2013108203ndash10
9 Thomas KH Martin RM Davies N Metcalfe C Windmeijer F Gunnell D Smoking cessation treatment and the risk of depression suicide and self-harm in the Clinical Practice Research Datalink prospective cohort study BMJ 2013347f5704
10 Gibbons RD Mann JJ Varenicline smoking cessation and neuropsychiatric adverse events Am J Psychiatry 20131701460ndash7
11 Walker AM Confounding by indication Epidemiology 19967335ndash612 Miller M Hemenway D Bell NS Yore MM Amoroso PJ Cigarette
smoking and suicide a prospective study of 300000 male active-duty Army soldiers Am J Epidemiol 20001511060ndash3
Nides 2006 Tonstad 2006 Jorenby 2006 Onken 2006 Gonzales 2006 Williams 2007 Tsai 2007 Niaura 2008 Faessel 2009 Rigotti 2010 Fagerstrom 2010 Hughes 2011 Garza 2011 Brandon 2011 Ebbert 2011 Steinberg 2011 Bolliger 2011 Tashkin 2011 Williams 2012 Rennard 2012 Wong 2012 Zesiewicz 2012 McClure 2013 Stein 2013 Litten 2013 Cinciripini 2013 Meszaros 2013 Anthenelli 2013 Evins 2014 Chengappa 2014 Gonzales 2014Overall I2=0 P=0783
001 (-002 to 003)-000 (-002 to 001)001 (-000 to 003)-001 (-005 to 003)-001 (-003 to 001)-002 (-002 to 006)001 (-004 to 002)001 (-002 to 003)000 (-019 to 019)001 (-001 to 002)-001 (-004 to 001)-001 (-004 to 002)000 (-005 to 005)000 (-004 to 004)-003 (-010 to 004)-000 (-010 to 010)000 (-002 to 002)000 (-002 to 003)-002 (-011 to 007)-002 (-005 to 001)-000 (-003 to 003)-022 (-052 to 008)-006 (-027 to 015)-006 (-021 to 010)001 (-006 to 008)-006 (-015 to 002)000 (-050 to 050)002 (-002 to 006)000 (-006 to 007)019 (001 to 037)001 (-001 to 003)-000 (-001 to 001)
313737433lt1752111165153lt11122lt16115
100
-05 0 05
Study
Favourstreatment
Favoursplacebo
Odds ratio(95 CI)
Odds ratio(95 CI)
Weight()
212515602634362534349
1225111263157014
535322131107155046038240
83906248484
44862151
091741
1711179768615
17256140831
52491635356
Treatment
112317604134041217344412621242155
07335052182111155054138239
41985251343
51652135
292042733
610114106
1513269
147229
22451394487
ControlNo of eventstotal
fig 5 | forest plot of risk of depression events (mantel-Haenszel risk difference) associated with varenicline use in 31 placebo controlled randomised trials
table 5 | Comparison of Peto fixed effects and random effects odds ratios (Or) for insomnia sleep disorders and abnormal dreams in people treated with varenicline
neuropsychiatric adverse event
no of eventsno treatedOdds ratio (95 Ci)
test for heterogeneity ()varenicline group Placebo group
insomniaPeto OR 6795621 3794762 156 (136 to 178) 0Fixed effects OR 6795621 3794762 156 (135 to 179) 0Random effects OR 6795621 3794762 156 (135 to 179) 0sleep disordersPeto OR 2115081 1234284 163 (129 to 207) 0Fixed effects OR 2115081 1234284 157 (122 to 203) 0Random effects OR 2115081 1234284 157 (122 to 203) 0abnormal dreams Peto OR 6035606 2244741 238 (205 to 277) 223Fixed effects OR 6035606 2244741 237 (199 to 282) 316Random effects OR 6035606 2244741 236 (187 to 298) 316All Plt0001
RESEARCH
10 doi 101136bmjh1109 | BMJ 2015350h1109 | thethinspbmj
13 Miller M Hemenway D Rimm E Cigarettes and suicide a prospective study of 50000 men Am J Public Health 200090768ndash73
14 Etter JF Burri M Stapleton J The impact of pharmaceutical company funding on results of randomized trials of nicotine replacement therapy for smoking cessation a meta-analysis Addiction 2007102815ndash22
15 Prescribing and Primary Care team Health and Social Care Information Centre Prescription cost analysis England 2013 Health and Social Care Information Centre 2014
16 Cahill K Stead LF Lancaster T Nicotine receptor partial agonists for smoking cessation Cochrane Database Syst Rev 20124CD006103
17 Higgins JPT Altman DG Assessing risk of bias in included studies Cochrane handbook for systematic reviews of interventions John Wiley 2008187ndash241
18 Harris R Bradburn M Deeks J Harbord R Altman D Sterne J metan fixed- and random-effects meta-analysis Stata J 200883ndash28
19 Bradburn MJ Deeks JJ Berlin JA Russell Localio A Much ado about nothing a comparison of the performance of meta-analytical methods with rare events Stat Med 20072653ndash77
20 Higgins JP Thompson SG Deeks JJ Altman DG Measuring inconsistency in meta-analyses BMJ 2003327557ndash60
21 Higgins JPT Deeks JJ Altman DG Special topics in statistics Cochrane handbook for systematic reviews of interventions John Wiley 2008481ndash529
22 Sterne JAC Harbord RM Funnel plots in meta-analysis Stata J 20044127ndash41
23 Harbord RM Harris RJ Sterne JAC Updated tests for small-study effects in meta-analyses Stata J 20099197ndash210
24 Anthenelli RM Morris C Ramey TS Dubrava SJ Tsilkos K Russ C et al Effects of varenicline on smoking cessation in adults with stably treated current or past major depression a randomized trial Ann Intern Med 2013159390ndash400
25 Bolliger CT Issa JS Posadas-Valay R Safwat T Abreu P Correia EA et al Effects of varenicline in adult smokers a multinational 24-week randomized double-blind placebo-controlled study Clin Ther 201133465ndash77
26 Brandon TH Drobes DJ Unrod M Heckman BW Oliver JA Roetzheim RC et al Varenicline effects on craving cue reactivity and smoking reward Psychopharmacology (Berl) 2011218391ndash403
27 Burstein AH Fullerton T Clark DJ Faessel HM Pharmacokinetics safety and tolerability after single and multiple oral doses of varenicline in elderly smokers J Clin Pharmacol 2006461234ndash40
28 Cinciripini PM Robinson JD Karam-Hage M Minnix JA Lam C Versace F et al Effects of varenicline and bupropion sustained-release use plus intensive smoking cessation counseling on prolonged abstinence from smoking and on depression negative affect and other symptoms of nicotine withdrawal JAMA Psychiatry 201370522ndash33
29 Ebbert JO Croghan IT Severson HH Schroeder DR Hays JT A pilot study of the efficacy of varenicline for the treatment of smokeless tobacco users in Midwestern United States Nicotine Tob Res 201113820ndash6
30 Evins AE Cather C Pratt SA Pachas GN Hoeppner SS Goff DC et al Maintenance treatment with varenicline for smoking cessation in patients with schizophrenia and bipolar disorder a randomized clinical trial JAMA 2014311145ndash54
31 Faessel H Ravva P Williams K Pharmacokinetics safety and tolerability of varenicline in healthy adolescent smokers a multicenter randomized double-blind placebo-controlled parallel-group study Clin Ther 200931177ndash89
32 Fagerstrom K Gilljam H Metcalfe M Tonstad S Messig M Stopping smokeless tobacco with varenicline randomised double blind placebo controlled trial BMJ 2010341c6549
33 Fatemi SH Yousefi MK Kneeland RE Liesch SB Folsom TD Thuras PD Antismoking and potential antipsychotic effects of varenicline in subjects with schizophrenia or schizoaffective disorder a double-blind placebo and bupropion-controlled study Schizophr Res 2013146376ndash8
34 Garza D Murphy M Tseng LJ Riordan HJ Chatterjee A A double-blind randomized placebo-controlled pilot study of neuropsychiatric adverse events in abstinent smokers treated with varenicline or placebo Biol Psychiatry 2011691075ndash82
35 Gonzales D Rennard SI Nides M Oncken C Azoulay S Billing CB et al Varenicline an alpha4beta2 nicotinic acetylcholine receptor partial agonist vs sustained-release bupropion and placebo for smoking cessation a randomized controlled trial JAMA 200629647ndash55
36 Hughes JR Rennard SI Fingar JR Talbot SK Callas PW Fagerstrom KO Efficacy of varenicline to prompt quit attempts in smokers not currently trying to quit a randomized placebo-controlled trial Nicotine Tob Res 201113955ndash64
37 Jorenby DE Hays JT Rigotti NA Azoulay S Watsky EJ Williams KE et al Efficacy of varenicline an alpha4beta2 nicotinic acetylcholine receptor partial agonist vs placebo or sustained-release bupropion for smoking cessation a randomized controlled trial JAMA 200629656ndash63
38 Litten RZ Ryan ML Fertig JB Falk DE Johnson B Dunn KE et al A double-blind placebo-controlled trial assessing the efficacy of varenicline tartrate for alcohol dependence J Addict Med 20137277ndash86
39 McClure EA Vandrey RG Johnson MW Stitzer ML Effects of varenicline on abstinence and smoking reward following a programmed lapse Nicotine Tob Res 201315139ndash48
40 McKee SA Harrison EL OrsquoMalley SS Krishnan-Sarin S Shi J Tetrault JM et al Varenicline reduces alcohol self-administration in heavy-drinking smokers Biol Psychiatry 200966185ndash90
41 Meszaros ZS Abdul-Malak Y Dimmock JA Wang D Ajagbe TO Batki SL Varenicline treatment of concurrent alcohol and nicotine dependence in schizophrenia a randomized placebo-controlled pilot trial J Clin Psychopharmacol 201333243ndash7
42 Mitchell JM Teague CH Kayser AS Bartlett SE Fields HL Varenicline decreases alcohol consumption in heavy-drinking smokers Psychopharmacology (Berl) 2012223299ndash306
43 Nakamura M Oshima A Fujimoto Y Maruyama N Ishibashi T Reeves KR Efficacy and tolerability of varenicline an alpha4beta2 nicotinic acetylcholine receptor partial agonist in a 12-week randomized placebo-controlled dose-response study with 40-week follow-up for smoking cessation in Japanese smokers Clin Ther 2007291040ndash56
44 Niaura R Hays JT Jorenby DE Leone FT Pappas JE Reeves KR et al The efficacy and safety of varenicline for smoking cessation using a flexible dosing strategy in adult smokers a randomized controlled trial Curr Med Res Opin 2008241931ndash41
45 Nides M Oncken C Gonzales D Rennard S Watsky EJ Anziano R et al Smoking cessation with varenicline a selective alpha4beta2 nicotinic receptor partial agonist results from a 7-week randomized placebo- and bupropion-controlled trial with 1-year follow-up Arch Intern Med 20061661561ndash8
46 Oncken C Gonzales D Nides M Rennard S Watsky E Billing CB et al Efficacy and safety of the novel selective nicotinic acetylcholine receptor partial agonist varenicline for smoking cessation Arch Intern Med 20061661571ndash7
47 Plebani JG Lynch KG Yu Q Pettinati HM OrsquoBrien CP Kampman KM Results of an initial clinical trial of varenicline for the treatment of cocaine dependence Drug Alcohol Depend 2012121163ndash6
48 Plebani JG Lynch KG Rennert L Pettinati HM OrsquoBrien CP Kampman KM Results from a pilot clinical trial of varenicline for the treatment of alcohol dependence Drug Alcohol Depend 2013133754ndash8
49 Poling J Rounsaville B Gonsai K Severino K Sofuoglu M The safety and efficacy of varenicline in cocaine using smokers maintained on methadone a pilot study Am J Addict 201019401ndash8
50 Rennard S Hughes J Cinciripini PM Kralikova E Raupach T Arteaga C et al A randomized placebo-controlled trial of varenicline for smoking cessation allowing flexible quit dates Nicotine Tob Res 201214343ndash50
51 Rigotti NA Pipe AL Benowitz NL Arteaga C Garza D Tonstad S Efficacy and safety of varenicline for smoking cessation in patients with cardiovascular disease a randomized trial Circulation 2010121221ndash9
52 Shim JC Jung DU Jung SS Seo YS Cho DM Lee JH et al Adjunctive varenicline treatment with antipsychotic medications for cognitive impairments in people with schizophrenia a randomized double-blind placebo-controlled trial Neuropsychopharmacology 201237660ndash8
53 Stein MD Caviness CM Kurth ME Audet D Olson J Anderson BJ Varenicline for smoking cessation among methadone-maintained smokers a randomized clinical trial Drug Alcohol Depend 2013133486ndash93
54 Steinberg MB Randall J Greenhaus S Schmelzer AC Richardson DL Carson JL Tobacco dependence treatment for hospitalized smokers a randomized controlled pilot trial using varenicline Addic Behav 2011361127ndash32
55 Tashkin DP Rennard S Hays JT Ma W Lawrence D Lee TC Effects of varenicline on smoking cessation in patients with mild to moderate COPD a randomized controlled trial Chest 2011139591ndash9
56 Tonnesen P Mikkelsen K Varenicline to stop long-term nicotine replacement use a double-blind randomized placebo-controlled trial Nicotine Tob Res 201315419ndash27
57 Tonstad S Tonnesen P Hajek P Williams KE Billing CB Reeves KR et al Effect of maintenance therapy with varenicline on smoking cessation a randomized controlled trial JAMA 200629664ndash71
58 Tsai ST Cho HJ Cheng HS Kim CH Hsueh KC Billing CB Jr et al A randomized placebo-controlled trial of varenicline a selective alpha4beta2 nicotinic acetylcholine receptor partial agonist as a new therapy for smoking cessation in Asian smokers Clin Ther 2007291027ndash39
59 Wang C Xiao D Chan KPW Pothirat C Garza D Davies S Varenicline for smoking cessation A placebo-controlled randomized study Respirology 200914384ndash92
60 Weiner E Buchholz A Coffay A Liu F McMahon RP Buchanan RW et al Varenicline for smoking cessation in people with schizophrenia a double blind randomized pilot study Schizophr Res 201112994ndash5
RESEARCH
11thethinspbmj | BMJ 2015350h1109 | doi 101136bmjh1109
61 Williams K Reeves K Billing C Pennington A Gong J A double-blind study evaluating the long-term safety of varenicline for smoking cessation Curr Med Res Opin 200723793ndash801
62 Williams JM Anthenelli RM Morris CD Treadow J Thompson JR Yunis C et al A randomized double-blind placebo-controlled study evaluating the safety and efficacy of varenicline for smoking cessation in patients with schizophrenia or schizoaffective disorder J Clin Psychiatry 201273654ndash60
63 Wong J Abrishami A Yang Y Zaki A Friedman Z Selby P et al A perioperative smoking cessation intervention with varenicline a double-blind randomized placebo-controlled trial Anesthesiology 2012117755ndash64
64 Zesiewicz TA Greenstein PE Sullivan KL Wecker L Miller A Jahan I et al A randomized trial of varenicline (Chantix) for the treatment of spinocerebellar ataxia type 3 Neurology 201278545ndash50
65 Zhao Q Schwam E Fullerton T OrsquoGorman M Burstein AH Pharmacokinetics safety and tolerability following multiple oral doses of varenicline under various titration schedules in elderly nonsmokers J Clin Pharmacol 201151492ndash501
66 Chengappa KN Perkins KA Brar JS Schlicht PJ Turkin SR Hetrick ML et al Varenicline for smoking cessation in bipolar disorder a randomized double-blind placebo-controlled study J Clin Psychiatry 201475765ndash72
67 Gonzales D Hajek P Pliamm L Nackaerts K Tseng LJ McRae TD et al Retreatment with varenicline for smoking cessation in smokers who have previously taken varenicline a randomized placebo-controlled trial Clin Pharmacol Ther 201496390ndash6
68 Kishi T Iwata N Varenicline for smoking cessation in people with schizophrenia systematic review and meta-analysis Eur Arch Psychiatry Clin Neurosci 2014 Oct 5 [Epub ahead of print]
69 Hong LE Thaker GK McMahon RP Summerfelt A Rachbeisel J Fuller RL et al Effects of moderate-dose treatment with varenicline on neurobiological and cognitive biomarkers in smokers and nonsmokers with schizophrenia or schizoaffective disorder Arch Gen Psychiatry 2011681195ndash206
70 Huang Y Li W Yang L Jiang Y Wu Y Long-term efficacy and safety of varenicline for smoking cessation a systematic review and
meta-analysis of randomized controlled trials J Public Health 201220355ndash65
71 Singh S Loke YK Spangler JG Furberg CD Risk of serious adverse cardiovascular events associated with varenicline a systematic review and meta-analysis CMAJ 20111831359ndash66
72 Prochaska JJ Hilton JF Risk of cardiovascular serious adverse events associated with varenicline use for tobacco cessation systematic review and meta-analysis BMJ 2012344e2856
73 Mocking RJ Patrick Pflanz C Pringle A Parsons E McTavish SF Cowen PJ et al Effects of short-term varenicline administration on emotional and cognitive processing in healthy non-smoking adults a randomized double-blind study Neuropsychopharmacology 201338476ndash84
74 Taylor G McNeill A Girling A Farley A Lindson-Hawley N Aveyard P Change in mental health after smoking cessation systematic review and meta-analysis BMJ 2014348g1151
75 Smoking cessation services in primary care pharmacies local authorities and workplaces particularly for manual working groups pregnant women and hard to reach communities NICE public health guidance 10 National Institute for Health and Care Excellence 2008
copy BMJ Publishing Group Ltd 2015
Appendix 1 Search strategy to identify relevant articles in MedlineAppendix 2 Further characteristics of included ran-domised controlled trialsAppendix 3 Forest plots for secondary outcomesAppendix 4 Subgroup analysesAppendix 5 Funnel plots Appendix 6 Summary of Peto odds ratios risk differ-ences and 95 confidence intervals for neuropsychiat-ric events
RESEARCH
4 doi 101136bmjh1109 | BMJ 2015350h1109 | thethinspbmj
there was no evidence of an increased risk of death in the varenicline group compared with the placebo group (risk difference 00001 minus0003 to 0003 P=094 I2=00) (Table 4) The forest plots for the secondary outcomes are shown in appendix 3
We found no evidence of an increased risk of irritabil-ity (odds ratio 098 05 confidence interval 081 to 117 P=079 I2=00) aggression (091 052 to 159 P=075 I2=208) or somnolence (123 094 to 162 P=013 I2=104) as the confidence intervals included the null value of 1 Varenicline was associated with an increased risk of sleep disorders (163 129 to 207 Plt0001 I2=00) insomnia (156 136 to 178 Plt0001 I2=00) abnormal dreams (238 205 to 277 Plt0001 I2=223)
and fatigue (128 106 to 155 P=001 I2=63) with some evidence of a reduced risk of anxiety (075 061 to 093 P=0008 I2=57) Consistent findings were observed for the risk differences (table 4)
sensitivity analysesThere were minimal differences in the effect measures and 95 confidence intervals with Peto fixed effects and random effects odds ratios (Table 5)
subgroup analysesThe subgroup analyses are shown in appendix 4 for the primary outcomes of depression and suicidal ideation Subgroup tests showed no evidence of a variation in the
table 1 | Characteristics of randomised controlled trials of varenicline 1mg twice daily included in systematic review
studyDuration (weeks) sample size mean age (years) men whitestudy treatment varenicline Placebo varenicline Placebo varenicline Placebo varenicline Placebo
Anthenelli 201324 52 12 256 269 454 471 379 368 NA NABolliger 201125 24 12 394 199 431 439 577 657 303 313Brandon 201126 22 22 56 58 458 412 609 611 541 648Burstein 200627 13 13 8 8 681 679 75 50 50 375Chengappa 201466 24 12 31 29 457 462 29 345 645 724Cinciripini 201328 24 12 86 106 438 452 616 632 581 717Ebbert 201129 24 12 38 38 407 41 100 100 100 100Evins 201430 64 40 40 47 514 457 60 66 75 72Faessel 200931 26 2 14 7 154 154 571 571 857 714Fagerstrom 201032 26 12 213 218 439 439 89 90 99 100Fatemi 201333 12 12 6 9 404 414 833 778 50 889Garza 201134 16 12 55 55 334 338 60 727 80 709Gonzales 200635 52 12 352 344 425 426 50 541 795 762Gonzales 201467 52 12 251 247 477 473 498 494 948 914Hughes 201136 24 8 107 111 44 412 605 572 914 919Jorenby 200637 52 12 344 341 446 423 552 581 855 85Litten 201338 16 13 97 101 46 45 732 683 619 703McClure 201339 5 5 54 50 45 43 40 59 32 36McKee 200940 11 1 10 10 342 353 80 80 40 90Meszaros 201341 12 8 5 5 42 44 80 60 40 60Mitchell 201242 16 12 33 31 29 25 55 65 73 64Nakamura 200743 52 12 156 154 401 399 792 76 NA NANiaura 200844 40 12 160 160 415 421 503 535 93 884Nides 200645 52 7 127 127 419 416 504 52 856 878Oncken 200646 52 12 259 129 422 43 485 519 808 721Plebani 201247 9 8 18 19 NA NA 696 75 11 33Plebani 201348 13 12 19 21 448 481 789 905 421 714Poling 201049 12 11 13 18 365 344 846 778 462 722Rennard 201250 24 12 493 166 439 432 60 596 68 681Rigotti 201051 52 12 355 359 57 559 752 822 803 808Shim 201252 8 8 60 60 399 399 38 45 0 0Stein 201353 24 24 137 45 392 406 46 622 825 756Steinberg 201154 24 12 40 39 NA NA 60 59 77 67Tashkin 201155 52 12 250 254 572 571 625 622 819 841Tonnesen 201356 52 12 70 69 536 556 429 493 NA NATonstad 200657 52 12 603 607 454 453 502 483 967 97Tsai 200758 24 12 126 124 397 409 849 927 0 0Wang 200959 24 12 165 168 39 385 964 97 0 0Weiner 201160 12 12 4 5 NA NA NA NA NA NAWilliams 200761 53 52 251 126 482 466 506 484 869 921Williams 201262 26 12 84 43 402 43 774 767 595 581Wong 201263 52 12 151 135 519 533 55 504 NA NAZesiewicz 201264 8 8 10 10 474 538 44 67 NA NAZhao 201165 37 3 14 10 71 73 429 50 100 90NA=not applicable
RESEARCH
5thethinspbmj | BMJ 2015350h1109 | doi 101136bmjh1109
side effects of depression and suicidal ideation by age group (P=0391 and P=0933 respectively for interac-tion) percentage of men in the study (P=0418 and P=0925) percentage of white people in the study (P=0685 and P=0254) presence or absence of psychi-atric illness (P=0126 and P=0304) smoking status (P=0906 for depression but not calculated for suicidal ideation as there were no reports of suicidal ideation in studies that included non-smokers) and whether the trial was industry sponsored or not (P=0386 and P=0380) The effect estimates (odds ratio) for the trials in which all participants had psychiatric illnesses com-pared with those where none of the participants had psychiatric illness were 149 (95 confidence interval 084 to 265) versus 091 (069 to 121) for depression and 079 (032 to 193) versus 034 (009 to 129) for suicidal ideation
table 2 | summary of characteristics of patients enrolled in 44 randomised controlled trials of vareniclineCharacteristics of trial participants no of trialsSmokers from general population 18Smokers with psychiatric illness 8Heavy drinking smokersalcohol dependence 4People dependent on cocaine or opioid dependent 3Smokeless tobacco users 2Smokers with mild to moderate COPD 1Smokers with cardiovascular disease 1Smokers about to undergo surgery 1Patients with spinocerebellar ataxia type 3 1Adolescent smokers 1Elderly non-smokers 1Smokers in hospital 1Smokers previously treated with varenicline 1Ex-smokers on long term NRT 1COPD=chronic obstructive pulmonary disease NRT=nicotine replacement therapy
table 3 | risk of bias assessment for each trial of varenicline using Cochrane risk of assessment of bias tool
studyrandom sequence generation
allocation concealment used
blindingincomplete outcome data
selective reporting Other bias
Participants and personnel
Outcome assessment
Anthenelli 201324 Low Low Low Low Low Low LowBolliger 201125 Low Low Low Low Low Low LowBrandon 201126 Low Low Low Low Low Low LowBurstein 200627 Low Low Low Low Low Low LowChengappa 201466 Low Low Low Low Low Low LowCinciripini 201328 Low Low Low Low Low Low LowEbbert 201129 Low Unclear Low Low Low Low LowEvins 201430 Low Low Low Low Low Low LowFaessel 200931 Low Low Low Low Low Low LowFagerstrom 201032 Low Low Low Low Low Low LowFatemi 201333 Unclear Low Low Low Low Low LowGarza 201134 Unclear Low Low Low Low Low LowGonzales 206635 Low Low Low Low Low Low LowGonzales 201467 Low Low Low Low Low Low LowHughes 201136 Low Low Low Low Low Unclear LowJorenby 200637 Low Low Low Low Low Low LowLitten 201338 Low Low Low Low Low Low LowMcClure 201339 Low Low Low Low Low Low LowMcKee 200940 Unclear Unclear Low Unclear Low Low LowMeszaros 201341 Low Low Low Low Low Low LowMitchell 201242 Low Low Low Low Low Low LowNakamura 200743 Low Low Low Low Low Low LowNiaura 200844 Low Low Low Low Low Low LowNides 200645 Low Low Low Low Low Low LowOncken 200646 Low Low Low Low Low Low LowPlebani 201247 Unclear Unclear Unclear Unclear Low Unclear LowPlebani 201348 Low Low Low Unclear Unclear Unclear LowPoling 201049 Low Unclear Low Unclear Low Low LowRennard 201250 Low Low Low Low Low Low LowRigotti 201051 Low Low Low Low Low Low LowShim 201252 Unclear Unclear Low Unclear Unclear Unclear UnclearStein 201353 Low Low Low Low Low Low LowSteinberg 201154 Low Low Low Low Low Low LowTashkin 201155 Low Low Low Low Low Low LowTonnesen 201356 Low Unclear Low Low Low Low LowTonstad 200657 Low Low Low Low Low Low LowTsai 200758 Low Low Low Low Low Low LowWang 200959 Low Low Low Low Low Low UnclearWeiner 201160 Unclear Unclear Unclear Unclear Low Unclear UnclearWilliams 200761 Low Low Low Low Low Low LowWilliams 201262 Low Low Low Low Low Low LowWong 201263 Low Low Low Low Low Low LowZesiewicz 201264 Low Low Low Low Low Low LowZhao 201165 Low Low Low Low Low Low Unclear
RESEARCH
6 doi 101136bmjh1109 | BMJ 2015350h1109 | thethinspbmj
small study effectsThe funnel plots for depression and insomnia are shown in appendix 5 The P values for funnel plot asym-metry were 053 for depression and 093 for insomnia (that is there was no evidence against the null hypoth-esis of no small study effects)
discussionThis meta-analysis of 39 randomised controlled trials involving 5817 patients prescribed varenicline 1 mg twice daily and 4944 patients prescribed placebo found no increased risk of suicide or attempted suicide
suicidal ideation depression or death in individuals treated with varenicline Almost half of the trial partici-pants were chronic heavy smokers (that is they had smoked on average 20 cigarettes a day for 26 years) Five separate trials (including 1281 participants randomised to varenicline and 1143 to placebo) reported a suicide andor suicide attempt (see appendix 3) one reported suicide only three reported attempted suicide only and one reported both suicide and attempted suicide Two suicides and two attempts occurred in the varenicline group of the trials (008) and two attempts occurred in the placebo group (005) Use of the maximum dose of varenicline (1 mg twice daily) was associated with a 28 increased risk of fatigue a 56 increased risk of insomnia a 63 increased risk of sleep disorders and more than twice the risk of abnormal dreams There was evidence of a 25 reduction in the risk of anxiety When we used risk differences for every 1000 patients there were an additional 10 cases of fatigue 40 cases of insomnia 20 cases of sleep disorders and 60 cases of abnormal dreams in those prescribed varenicline com-pared with placebo Similarly there were 10 fewer epi-sodes of anxiety per 1000 participants in the varenicline group compared with the placebo group (risk difference minus001 95 confidence interval minus002 to minus00003) There was no evidence of a variation in depression and sui-cidal ideation by age sex ethnicity presence or absence of psychiatric illness or type of study sponsor
Comparison with other studiesA recent study by Kishi and Iwata examined the effects of varenicline for smoking cessation in people with schizo-phrenia in a meta-analysis of seven randomised con-trolled trials68 With the exception of the study by Hong and colleagues69 we included all their randomised con-trolled trials in the current analysis Similar to our find-ings Kishi and Iwata found no significant differences in depression and suicidal ideation between the vareni-cline and placebo groups They reported however that varenicline use was associated with a lower risk of abnor-mal dreamsnightmares than placebo (relative risk 047 95 confidence interval 022 to 099 P=005)68
table 4 | summary of Peto odds ratios risk differences and 95 confidence intervals for neuropsychiatric events in people treated with varenicline
neuropsychiatric adverse eventno of eventsno treated
Odds ratio (95 Ci) P value risk difference (95 Ci) P valuevarenicline group Placebo groupPrimary outcomesDepression 1635356 1394487 096 (075 to 122) 074 minus0001 (minus001 to 001) 074Suicidal ideation 152799 182191 058 (028 to 120) 014 minus0003 (minus0009 to 0002) 024Attempted suicide 22184 21842 075 (010 to 565) 078 minus00003 (minus0005 to 0004) 091Suicide and attempted suicide 45352 24478 167 (033 to 857) 054 00003 (minus0002 to 0003) 081secondary outcomesAbnormal dreams 6035606 2244741 238 (205 to 277) lt0001 006 (005 to 007) lt0001Aggression 394276 243524 091 (052 to 159) 075 minus0001 (minus0005 to 0004) 079Anxiety 2094999 2264457 075 (061 to 093) 0008 minus001 (minus002 to minus00003) 001Death 135760 114887 105 (047 to 238) 09 00001 (minus0003 to 0003) 094Fatigue 2835502 2024701 128 (106 to 155) 001 001 (0002 to 002) 001Insomnia 6795621 3794762 156 (136 to 178) lt0001 004 (003 to 005) lt0001Irritability 2935406 2664615 098 (081 to 117) 079 minus0001 (minus001 to 0008) 079Sleep disorders 2115081 1234284 163 (129 to 207) lt0001 002 (001 to 002) lt0001Somnolence 1395360 914542 123 (094 to 162) 013 0005 (minus0001 to 001) 013
Jorenby 2006 Hughes 2011 Bolliger 2011 Tashkin 2011 Williams 2012 Rennard 2012 Mitchell 2012 Stein 2013 Cinciripini 2013 Meszaros 2013 Anthenelli 2013 Evins 2014 Chengappa 2014 Zhao 2011 Brandon 2011 Ebbert 2011 Steinberg 2011 Wong 2012 McClure 2013 Gonzales 2014Overall I2=0 P=0621
013 (000 to 676)014 (000 to 708)
453 (024 to 8523)014 (000 to 690)084 (019 to 380)011 (001 to 151)013 (000 to 641)
366 (003 to 38784)016 (000 to 842)
100 (009 to 1103)014 (001 to 136)118 (016 to 875)
186 (019 to 1864)ExcludedExcludedExcludedExcludedExcludedExcludedExcluded
058 (028 to 120)
3363
2383239
1013100000000
100
0001 001 01 1 10 100 1000
Study
Favourstreatment
Favoursplacebo
Odds ratio(95 CI)
Odds ratio(95 CI)
Weight()
0343010723900248584
1486033
111108625
0256240231014046038040
0151041
024915799
Treatment
1340111101981251343
2165131033
110625
3269247129110054038039
0135042
0245182191
ControlNo of eventstotal
fig 2 | forest plot of risk of suicidal ideation events (Peto odds ratio) associated with varenicline use in 20 placebo controlled randomised trials
RESEARCH
7thethinspbmj | BMJ 2015350h1109 | doi 101136bmjh1109
This discrepancy with our findings could be explained by the small sample size of their study (288 from four randomised controlled trials versus 10 347 from 35 ran-domised controlled trials in our analysis)
Gibbons and Mann used pooled data from 17 ran-domised controlled trials sponsored by Pfizer to exam-ine neuropsychiatric adverse events associated with varenicline10 Our study included industry and non- industry sponsored trials and more than twice the num-ber of trials that they included Their findings of no increased risk of suicidal events depression and agita-tion are consistent with our study Although the authors did not include references to the published literature for their included studies (which made cross referenc-ing difficult) it is likely that we included most of their studies in our analysis
Another meta-analysis examined the long term effi-cacy and safety of varenicline in trials with a minimum follow-up period of 12 months70 A meta-analysis of the main psychiatric related adverse effects (which com-bined depressed mood other mood disorders bipolar disorder delirium suicidal and self injurious behaviours adjustment disorders and abnormal think-ing into a single outcome) did not show a ldquosignificant increase of psychiatric side effects for varenicline com-pared with placebordquo70 This meta-analysis however included only three trials and the combined psychiat-ric outcome was non-specific The authors reported an increased risk of insomnia (relative risk 165 95 confi-dence interval 129 to 211) abnormal dreams (278 207 to 373) and sleep disturbance (209 162 to 269) but no
increased risk of irritability (114 075 to 173) which is consistent with our findings70
A previous Cochrane review examined the efficacy and tolerability of nicotine receptor partial agonists including varenicline16 Trials were excluded if partici-pants used smokeless tobacco or if there was less than six months of follow-up In addition to the efficacy out-comes meta-analyses were performed for the most commonly reported adverse events nausea insomnia abnormal dreams and headache Findings were consis-tent with our study for insomnia (relative risk 162 95 confidence interval 140 to 188) and abnormal dreams (291 234 to 362)16 The Cochrane review did not report any treatment emergent deaths Although we used a broader definition of deaths in our analysis by includ-ing all deaths irrespective of whether or not we thought they were related to treatment we did not find an increased risk of death in the varenicline group
strengths and limitationsTo the best of our knowledge this is the most compre-hensive published systematic review (and meta-analy-sis) of neuropsychiatric effects associated with use of varenicline Compared with the previous Cochrane review16 our analysis included 16 additional trials for the meta-analysis of the risk of insomnia events and 23 addi-tional trials for the pooled analysis of abnormal dreams
The choice of summary statistics for meta-analyses of rare events caused controversy (about whether the Peto odds ratio should be reported instead of risk differ-ences) when it led to conflicting findings from two sys-tematic reviews examining the risk of cardiovascular side effects associated with varenicline use71 72 We pres-ent results using both measures a relative measure (Peto odds ratio and sensitivity analyses with fixed and random effects odds ratios) as well as an absolute mea-sure (risk difference) Findings were consistent for all examined outcomes
Many study authors did not specify the actual dates that adverse events were reported so we included all reported events this decision would have increased the likelihood of obtaining reports of rare adverse events We contacted authors for all of our included trials to check the data extracted on adverse events and for study protocols and other information to adequately assess the risk of bias in the studies We had a high response rate (75)
There are some limitations Firstly in this analysis we used study level data instead of individual level data so we were unable to determine whether differences in the adverse events were because of greater quit rates in the varenicline group relative to placebo Secondly because of the small number of suicides and attempted suicide reported (n=6) we cannot rule out major beneficial or adverse effects of varenicline for this outcome (Peto odds ratio 167 95 confidence interval 033 to 857) Thirdly there was potential for heterogeneity in the reporting of adverse events Authors used a range of methods to record adverse events including self report open ended questions structured questionnaires side effect check-lists and case reports coded to the Medical Dictionary for
Jorenby 2006 Hughes 2011 Zhao 2011 Brandon 2011 Ebbert 2011 Steinberg 2011 Bolliger 2011 Tashkin 2011 Williams 2012 Rennard 2012 Mitchell 2012 Wong 2012 McClure 2013 Stein 2013 Cinciripini 2013 Meszaros 2013 Anthenelli 2013 Evins 2014 Chengappa 2014 Gonzales 2014Overall I2=0 P=0995
-000 (-001 to 001)-001 (-003 to 002)000 (-015 to 015)000 (-004 to 004)000 (-005 to 005)000 (-005 to 005)001 (-001 to 002)000 (-001 to 001)-001 (-010 to 008)-001 (-003 to 001)-003 (-012 to 005)000 (-001 to 001)000 (-005 to 005)001 (-004 to 005)-001 (-004 to 002)000 (-061 to 061)-001 (-003 to 000)001 (-008 to 010)003 (-008 to 014)000 (-001 to 001)-000 (-001 to 000)
1551222
11112
1016224lt11121
10100
-05 0 05
Study
Favourstreatment
Favoursplacebo
Odds ratio(95 CI)
Odds ratio(95 CI)
Weight()
03430107014046038040
23900248584
1486033
0151041
111108625
0256240231
0249152799
Treatment
13401111010054038039
01981251343
2165131
0135042033
110625
3269247129
0245182191
ControlNo of eventstotal
fig 3 | forest plot of risk of suicidal ideation events (mantel-Haenszel risk difference) associated with varenicline use in 20 placebo controlled randomised trials
RESEARCH
8 doi 101136bmjh1109 | BMJ 2015350h1109 | thethinspbmj
Regulatory Activities (MedDRA wwwmeddraorg) All of the industry sponsored trials coded adverse events using MedDRA Fourthly we excluded two studies69 73 from the review as the maximum dose of varenicline used in these studies was only 1 mg once a daymdashthat is half of the rec-ommended maximum dose Hong and colleagues exam-ined varenicline treatment in 20 smokers and 15 non-smokers with schizophrenia or schizoaffective disor-der and found no evidence that varenicline worsened psychiatric symptoms in these patients69 Mocking and colleagues studied the effects of varenicline on emotional and cognitive processing in 21 healthy adult non-smokers and concluded that it did not cause problems in emo-tional processing or impulsivity providing less support for a possible depressogenic effect of varenicline73 Fur-thermore a secondary analysis which included all doses of varenicline in the original trials and these two excluded randomised controlled trials produced similar findings to our main analysis (see appendix 6)
We tried to minimise reporting bias by including all events (such as deaths) reported regardless of whether or
not we considered them to be related to treatment It is still possible however that reporting bias could have occurred as for certain trials where the corresponding authors did not respond to our requests for additional information we could not determine whether a lack of reporting of deaths in the published paper was synonymous with no deaths It was difficult to interpret the funnel plots to assess whether publication bias might be present as most trials were efficacy trials and were not performed solely to deter-mine the incidence of psychiatric adverse events
Additionally smoking cessation has been shown to have a positive impact on mental health outcomes with a reduction in depression and anxiety compared with those who continue to smoke74 Patients prescribed varenicline were reported to have an approximately threefold increased chance of quitting smoking com-pared with those given placebo (odds ratio 288 95 confidence interval 240 to 347)4 this could explain the reduction in anxiety observed in this meta-analysis
Lastly half of the trials were sponsored by Pfizer the manufacturers of varenicline Although previous research with nicotine replacement therapy has shown that industry sponsored trials were more likely than other trials to report outcomes that were favourable to the study sponsor14 we did not find any evidence for differences in depression and suicidal ideation for industry versus non industry sponsored trials (P=0386 and P=0380 respectively for interaction) In addition all of the industry sponsored trials were assessed over-all as having a low risk of bias
Conclusions and clinical implicationsBased on this comprehensive systematic review of pub-lished randomised controlled trials there is no evi-dence of an increased risk of depression suicidal behaviour (that is suicide or attempted suicide sui-cidal ideation) and death from any cause associated with treatment with varenicline Varenicline users however have an increased risk of abnormal dreams insomnia and sleep disturbances which are consistent with findings from other studies and previously docu-mented commonly reported side effects of varenicline (wwwchantixcom) We reported our findings using two summary statistics (a relative measure and an abso-lute measure) and observed consistency with both methods This meta-analysis adds to previous research (observational and experimental) that found no evi-dence for increased suicidal behaviour or depression with varenicline the most effective drug for smoking cessation4 The dangers of smoking are well docu-mented and the health benefits of stopping smoking are well known Our analysis suggests that the benefits of varenicline for smoking cessation outweigh the as yet unproved risks of suicidal behaviour In the UK vareni-cline is recommended alongside bupropion and nico-tine replacement therapy as first line treatment for smoking cessation75 Therefore the reduction in vareni-cline prescribing in the UK should be as much a cause for concern to clinicians regulatory agencies and policy makers as the unfounded fears regarding vareni-clinersquos association with suicidal behaviour
Nides 2006 Tonstad 2006 Jorenby 2006 Onken 2006 Gonzales 2006 Williams 2007 Tsai 2007 Niaura 2008 Rigotti 2010 Fagerstrom 2010 Hughes 2011 Garza 2011 Ebbert 2011 Steinberg 2011 Bolliger 2011 Tashkin 2011 Williams 2012 Rennard 2012 Wong 2012 Zesiewicz 2012 McClure 2013 Stein 2013 Litten 2013 Cinciripini 2013 Meszaros 2013 Anthenelli 2013 Evins 2014 Chengappa 2014 Gonzales 2014 Faessel 2009 Brandon 2011Overall I2=0 P=0631
193 (020 to 1870)088 (044 to 178)
419 (095 to 1855)070 (018 to 267)057 (017 to 186)148 (051 to 428)050 (005 to 488)148 (025 to 864)164 (041 to 661)043 (010 to 191)053 (005 to 514)
100 (006 to 1619)014 (000 to 682)097 (013 to 719)102 (030 to 340)122 (037 to 402)066 (013 to 326)020 (004 to 090)089 (089 to 642)012 (012 to 208)078 (078 to 185)066 (066 to 185)123 (123 to 378)051 (020 to 130)
100 (005 to 1991)140 (067 to 292)
118 (007 to 1932)381 (099 to 1467)234 (053 to 1040)
ExcludedExcluded
096 (075 to 122)
1123345123311lt1144232186571
1113300
100
0001 001 01 1 10 100 1000
Study
Favourstreatment
Favoursplacebo
Odds ratio(95 CI)
Odds ratio(95 CI)
Weight()
212515602634362534349
1225111263157535322131107155038240
83906248484
44862151
091741
1711179768615
17256140831
5249014046
1635356
Treatment
112317604134041217344412621242155335052182111155138239
41985251343
51652135
292042733
610114106
1513269
147229
224507
0541394487
ControlNo of eventstotal
fig 4 | forest plot of risk of depression events (Peto odds ratio) associated with varenicline use in 31 placebo controlled randomised trials
RESEARCH
9thethinspbmj | BMJ 2015350h1109 | doi 101136bmjh1109
We are grateful to the corresponding authors of the trials and Cristina Russ of Pfizer (for the Pfizer sponsored trials) for their support with providing access to the data on psychiatric adverse events and death used in this studyContributors KHT DG and RMM conceived the study KHT conducted the literature search KHT and DWK screened the abstracts with assistance from DG KHT DG and RMM were responsible for data extraction and the risk of bias assessment KHT did the statistical analysis with support from JPH KHT wrote the paper with contributions from all authors All authors have approved the final draft of the manuscript KHT is study guarantor had full access to all of the data (including statistical reports and tables) and can take responsibility for the integrity of the data and the accuracy of the data analysisFunding KHT is currently funded by a clinical lectureship from the National Institute for Health Research Part of this work was undertaken while KHT was on a National Institute for Health Research doctoral research fellowship (DRF-2010-03-138) DWK is funded by a Wellcome Trust four year studentship (WT099874MA) DG is an NIHR senior investigator The views expressed in this publication are those of the authors and not necessarily those of the NHS the National Institute for Health Research or the Department of HealthCompeting interests All authors have completed the Unified Competing Interest form at wwwicmjeorgcoi_disclosurepdf (available on request from the corresponding author) and declare RMM had specified relationship with the MHRA in the past (was a member of the MHRArsquos Independent Scientific Advisory Committee for CPRD research and received expenses and a small fee for meeting attendance and preparation for meetings) DG had specified relationship with the MHRA in the past (was a member of the MHRArsquos Pharmacovigilance Expert Advisory Group and received travel expenses and a small fee for meeting attendance and preparation for meetings)Ethics approval Not requiredData sharing No additional data are availableTransparency declaration KHT affirms that this manuscript is an honest accurate and transparent account of the study being reported that no important aspects of the study have been omitted and that any discrepancies from the study as planned (and if relevant registered) have been explainedThis is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 40) license which permits others to distribute remix adapt build upon this work non-commercially and license their derivative works on different terms provided the original work is properly cited and the use is non-commercial See httpcreativecommonsorglicensesby-nc401 Peto R Darby S Deo H Silcocks P Whitley E Doll R Smoking
smoking cessation and lung cancer in the UK since 1950 combination of national statistics with two case-control studies BMJ 2000321323ndash9
2 Jha P Peto R Global effects of smoking of quitting and of taxing tobacco N Engl J Med 201437060ndash8
3 Allender S Balakrishnan R Scarborough P Webster P Rayner M The burden of smoking-related ill health in the UK Tob Control 200918262ndash67
4 Cahill K Stevens S Perera R Lancaster T Pharmacological interventions for smoking cessation an overview and network meta-analysis Cochrane Database Syst Rev 20135CD009329
5 Medicines and Healthcare Products Regulatory Agency Varenicline adverse psychiatric reactions including depression Drug Safety Update 200822ndash3
6 US Food and Drug Administration Information for healthcare professionals varenicline (marketed as Chantix) and bupropion (marketed as Zyban Wellbutrin and generics) FDA Drug Safety Newsletter 2009
7 Gunnell D Irvine D Wise L Davies C Martin RM Varenicline and suicidal behaviour a cohort study based on data from the General Practice Research Database BMJ 2009339b3805
8 Meyer TE Taylor LG Xie S Graham DJ Mosholder AD Williams JR et al Neuropsychiatric events in varenicline and nicotine replacement patch users in the Military Health System Addiction 2013108203ndash10
9 Thomas KH Martin RM Davies N Metcalfe C Windmeijer F Gunnell D Smoking cessation treatment and the risk of depression suicide and self-harm in the Clinical Practice Research Datalink prospective cohort study BMJ 2013347f5704
10 Gibbons RD Mann JJ Varenicline smoking cessation and neuropsychiatric adverse events Am J Psychiatry 20131701460ndash7
11 Walker AM Confounding by indication Epidemiology 19967335ndash612 Miller M Hemenway D Bell NS Yore MM Amoroso PJ Cigarette
smoking and suicide a prospective study of 300000 male active-duty Army soldiers Am J Epidemiol 20001511060ndash3
Nides 2006 Tonstad 2006 Jorenby 2006 Onken 2006 Gonzales 2006 Williams 2007 Tsai 2007 Niaura 2008 Faessel 2009 Rigotti 2010 Fagerstrom 2010 Hughes 2011 Garza 2011 Brandon 2011 Ebbert 2011 Steinberg 2011 Bolliger 2011 Tashkin 2011 Williams 2012 Rennard 2012 Wong 2012 Zesiewicz 2012 McClure 2013 Stein 2013 Litten 2013 Cinciripini 2013 Meszaros 2013 Anthenelli 2013 Evins 2014 Chengappa 2014 Gonzales 2014Overall I2=0 P=0783
001 (-002 to 003)-000 (-002 to 001)001 (-000 to 003)-001 (-005 to 003)-001 (-003 to 001)-002 (-002 to 006)001 (-004 to 002)001 (-002 to 003)000 (-019 to 019)001 (-001 to 002)-001 (-004 to 001)-001 (-004 to 002)000 (-005 to 005)000 (-004 to 004)-003 (-010 to 004)-000 (-010 to 010)000 (-002 to 002)000 (-002 to 003)-002 (-011 to 007)-002 (-005 to 001)-000 (-003 to 003)-022 (-052 to 008)-006 (-027 to 015)-006 (-021 to 010)001 (-006 to 008)-006 (-015 to 002)000 (-050 to 050)002 (-002 to 006)000 (-006 to 007)019 (001 to 037)001 (-001 to 003)-000 (-001 to 001)
313737433lt1752111165153lt11122lt16115
100
-05 0 05
Study
Favourstreatment
Favoursplacebo
Odds ratio(95 CI)
Odds ratio(95 CI)
Weight()
212515602634362534349
1225111263157014
535322131107155046038240
83906248484
44862151
091741
1711179768615
17256140831
52491635356
Treatment
112317604134041217344412621242155
07335052182111155054138239
41985251343
51652135
292042733
610114106
1513269
147229
22451394487
ControlNo of eventstotal
fig 5 | forest plot of risk of depression events (mantel-Haenszel risk difference) associated with varenicline use in 31 placebo controlled randomised trials
table 5 | Comparison of Peto fixed effects and random effects odds ratios (Or) for insomnia sleep disorders and abnormal dreams in people treated with varenicline
neuropsychiatric adverse event
no of eventsno treatedOdds ratio (95 Ci)
test for heterogeneity ()varenicline group Placebo group
insomniaPeto OR 6795621 3794762 156 (136 to 178) 0Fixed effects OR 6795621 3794762 156 (135 to 179) 0Random effects OR 6795621 3794762 156 (135 to 179) 0sleep disordersPeto OR 2115081 1234284 163 (129 to 207) 0Fixed effects OR 2115081 1234284 157 (122 to 203) 0Random effects OR 2115081 1234284 157 (122 to 203) 0abnormal dreams Peto OR 6035606 2244741 238 (205 to 277) 223Fixed effects OR 6035606 2244741 237 (199 to 282) 316Random effects OR 6035606 2244741 236 (187 to 298) 316All Plt0001
RESEARCH
10 doi 101136bmjh1109 | BMJ 2015350h1109 | thethinspbmj
13 Miller M Hemenway D Rimm E Cigarettes and suicide a prospective study of 50000 men Am J Public Health 200090768ndash73
14 Etter JF Burri M Stapleton J The impact of pharmaceutical company funding on results of randomized trials of nicotine replacement therapy for smoking cessation a meta-analysis Addiction 2007102815ndash22
15 Prescribing and Primary Care team Health and Social Care Information Centre Prescription cost analysis England 2013 Health and Social Care Information Centre 2014
16 Cahill K Stead LF Lancaster T Nicotine receptor partial agonists for smoking cessation Cochrane Database Syst Rev 20124CD006103
17 Higgins JPT Altman DG Assessing risk of bias in included studies Cochrane handbook for systematic reviews of interventions John Wiley 2008187ndash241
18 Harris R Bradburn M Deeks J Harbord R Altman D Sterne J metan fixed- and random-effects meta-analysis Stata J 200883ndash28
19 Bradburn MJ Deeks JJ Berlin JA Russell Localio A Much ado about nothing a comparison of the performance of meta-analytical methods with rare events Stat Med 20072653ndash77
20 Higgins JP Thompson SG Deeks JJ Altman DG Measuring inconsistency in meta-analyses BMJ 2003327557ndash60
21 Higgins JPT Deeks JJ Altman DG Special topics in statistics Cochrane handbook for systematic reviews of interventions John Wiley 2008481ndash529
22 Sterne JAC Harbord RM Funnel plots in meta-analysis Stata J 20044127ndash41
23 Harbord RM Harris RJ Sterne JAC Updated tests for small-study effects in meta-analyses Stata J 20099197ndash210
24 Anthenelli RM Morris C Ramey TS Dubrava SJ Tsilkos K Russ C et al Effects of varenicline on smoking cessation in adults with stably treated current or past major depression a randomized trial Ann Intern Med 2013159390ndash400
25 Bolliger CT Issa JS Posadas-Valay R Safwat T Abreu P Correia EA et al Effects of varenicline in adult smokers a multinational 24-week randomized double-blind placebo-controlled study Clin Ther 201133465ndash77
26 Brandon TH Drobes DJ Unrod M Heckman BW Oliver JA Roetzheim RC et al Varenicline effects on craving cue reactivity and smoking reward Psychopharmacology (Berl) 2011218391ndash403
27 Burstein AH Fullerton T Clark DJ Faessel HM Pharmacokinetics safety and tolerability after single and multiple oral doses of varenicline in elderly smokers J Clin Pharmacol 2006461234ndash40
28 Cinciripini PM Robinson JD Karam-Hage M Minnix JA Lam C Versace F et al Effects of varenicline and bupropion sustained-release use plus intensive smoking cessation counseling on prolonged abstinence from smoking and on depression negative affect and other symptoms of nicotine withdrawal JAMA Psychiatry 201370522ndash33
29 Ebbert JO Croghan IT Severson HH Schroeder DR Hays JT A pilot study of the efficacy of varenicline for the treatment of smokeless tobacco users in Midwestern United States Nicotine Tob Res 201113820ndash6
30 Evins AE Cather C Pratt SA Pachas GN Hoeppner SS Goff DC et al Maintenance treatment with varenicline for smoking cessation in patients with schizophrenia and bipolar disorder a randomized clinical trial JAMA 2014311145ndash54
31 Faessel H Ravva P Williams K Pharmacokinetics safety and tolerability of varenicline in healthy adolescent smokers a multicenter randomized double-blind placebo-controlled parallel-group study Clin Ther 200931177ndash89
32 Fagerstrom K Gilljam H Metcalfe M Tonstad S Messig M Stopping smokeless tobacco with varenicline randomised double blind placebo controlled trial BMJ 2010341c6549
33 Fatemi SH Yousefi MK Kneeland RE Liesch SB Folsom TD Thuras PD Antismoking and potential antipsychotic effects of varenicline in subjects with schizophrenia or schizoaffective disorder a double-blind placebo and bupropion-controlled study Schizophr Res 2013146376ndash8
34 Garza D Murphy M Tseng LJ Riordan HJ Chatterjee A A double-blind randomized placebo-controlled pilot study of neuropsychiatric adverse events in abstinent smokers treated with varenicline or placebo Biol Psychiatry 2011691075ndash82
35 Gonzales D Rennard SI Nides M Oncken C Azoulay S Billing CB et al Varenicline an alpha4beta2 nicotinic acetylcholine receptor partial agonist vs sustained-release bupropion and placebo for smoking cessation a randomized controlled trial JAMA 200629647ndash55
36 Hughes JR Rennard SI Fingar JR Talbot SK Callas PW Fagerstrom KO Efficacy of varenicline to prompt quit attempts in smokers not currently trying to quit a randomized placebo-controlled trial Nicotine Tob Res 201113955ndash64
37 Jorenby DE Hays JT Rigotti NA Azoulay S Watsky EJ Williams KE et al Efficacy of varenicline an alpha4beta2 nicotinic acetylcholine receptor partial agonist vs placebo or sustained-release bupropion for smoking cessation a randomized controlled trial JAMA 200629656ndash63
38 Litten RZ Ryan ML Fertig JB Falk DE Johnson B Dunn KE et al A double-blind placebo-controlled trial assessing the efficacy of varenicline tartrate for alcohol dependence J Addict Med 20137277ndash86
39 McClure EA Vandrey RG Johnson MW Stitzer ML Effects of varenicline on abstinence and smoking reward following a programmed lapse Nicotine Tob Res 201315139ndash48
40 McKee SA Harrison EL OrsquoMalley SS Krishnan-Sarin S Shi J Tetrault JM et al Varenicline reduces alcohol self-administration in heavy-drinking smokers Biol Psychiatry 200966185ndash90
41 Meszaros ZS Abdul-Malak Y Dimmock JA Wang D Ajagbe TO Batki SL Varenicline treatment of concurrent alcohol and nicotine dependence in schizophrenia a randomized placebo-controlled pilot trial J Clin Psychopharmacol 201333243ndash7
42 Mitchell JM Teague CH Kayser AS Bartlett SE Fields HL Varenicline decreases alcohol consumption in heavy-drinking smokers Psychopharmacology (Berl) 2012223299ndash306
43 Nakamura M Oshima A Fujimoto Y Maruyama N Ishibashi T Reeves KR Efficacy and tolerability of varenicline an alpha4beta2 nicotinic acetylcholine receptor partial agonist in a 12-week randomized placebo-controlled dose-response study with 40-week follow-up for smoking cessation in Japanese smokers Clin Ther 2007291040ndash56
44 Niaura R Hays JT Jorenby DE Leone FT Pappas JE Reeves KR et al The efficacy and safety of varenicline for smoking cessation using a flexible dosing strategy in adult smokers a randomized controlled trial Curr Med Res Opin 2008241931ndash41
45 Nides M Oncken C Gonzales D Rennard S Watsky EJ Anziano R et al Smoking cessation with varenicline a selective alpha4beta2 nicotinic receptor partial agonist results from a 7-week randomized placebo- and bupropion-controlled trial with 1-year follow-up Arch Intern Med 20061661561ndash8
46 Oncken C Gonzales D Nides M Rennard S Watsky E Billing CB et al Efficacy and safety of the novel selective nicotinic acetylcholine receptor partial agonist varenicline for smoking cessation Arch Intern Med 20061661571ndash7
47 Plebani JG Lynch KG Yu Q Pettinati HM OrsquoBrien CP Kampman KM Results of an initial clinical trial of varenicline for the treatment of cocaine dependence Drug Alcohol Depend 2012121163ndash6
48 Plebani JG Lynch KG Rennert L Pettinati HM OrsquoBrien CP Kampman KM Results from a pilot clinical trial of varenicline for the treatment of alcohol dependence Drug Alcohol Depend 2013133754ndash8
49 Poling J Rounsaville B Gonsai K Severino K Sofuoglu M The safety and efficacy of varenicline in cocaine using smokers maintained on methadone a pilot study Am J Addict 201019401ndash8
50 Rennard S Hughes J Cinciripini PM Kralikova E Raupach T Arteaga C et al A randomized placebo-controlled trial of varenicline for smoking cessation allowing flexible quit dates Nicotine Tob Res 201214343ndash50
51 Rigotti NA Pipe AL Benowitz NL Arteaga C Garza D Tonstad S Efficacy and safety of varenicline for smoking cessation in patients with cardiovascular disease a randomized trial Circulation 2010121221ndash9
52 Shim JC Jung DU Jung SS Seo YS Cho DM Lee JH et al Adjunctive varenicline treatment with antipsychotic medications for cognitive impairments in people with schizophrenia a randomized double-blind placebo-controlled trial Neuropsychopharmacology 201237660ndash8
53 Stein MD Caviness CM Kurth ME Audet D Olson J Anderson BJ Varenicline for smoking cessation among methadone-maintained smokers a randomized clinical trial Drug Alcohol Depend 2013133486ndash93
54 Steinberg MB Randall J Greenhaus S Schmelzer AC Richardson DL Carson JL Tobacco dependence treatment for hospitalized smokers a randomized controlled pilot trial using varenicline Addic Behav 2011361127ndash32
55 Tashkin DP Rennard S Hays JT Ma W Lawrence D Lee TC Effects of varenicline on smoking cessation in patients with mild to moderate COPD a randomized controlled trial Chest 2011139591ndash9
56 Tonnesen P Mikkelsen K Varenicline to stop long-term nicotine replacement use a double-blind randomized placebo-controlled trial Nicotine Tob Res 201315419ndash27
57 Tonstad S Tonnesen P Hajek P Williams KE Billing CB Reeves KR et al Effect of maintenance therapy with varenicline on smoking cessation a randomized controlled trial JAMA 200629664ndash71
58 Tsai ST Cho HJ Cheng HS Kim CH Hsueh KC Billing CB Jr et al A randomized placebo-controlled trial of varenicline a selective alpha4beta2 nicotinic acetylcholine receptor partial agonist as a new therapy for smoking cessation in Asian smokers Clin Ther 2007291027ndash39
59 Wang C Xiao D Chan KPW Pothirat C Garza D Davies S Varenicline for smoking cessation A placebo-controlled randomized study Respirology 200914384ndash92
60 Weiner E Buchholz A Coffay A Liu F McMahon RP Buchanan RW et al Varenicline for smoking cessation in people with schizophrenia a double blind randomized pilot study Schizophr Res 201112994ndash5
RESEARCH
11thethinspbmj | BMJ 2015350h1109 | doi 101136bmjh1109
61 Williams K Reeves K Billing C Pennington A Gong J A double-blind study evaluating the long-term safety of varenicline for smoking cessation Curr Med Res Opin 200723793ndash801
62 Williams JM Anthenelli RM Morris CD Treadow J Thompson JR Yunis C et al A randomized double-blind placebo-controlled study evaluating the safety and efficacy of varenicline for smoking cessation in patients with schizophrenia or schizoaffective disorder J Clin Psychiatry 201273654ndash60
63 Wong J Abrishami A Yang Y Zaki A Friedman Z Selby P et al A perioperative smoking cessation intervention with varenicline a double-blind randomized placebo-controlled trial Anesthesiology 2012117755ndash64
64 Zesiewicz TA Greenstein PE Sullivan KL Wecker L Miller A Jahan I et al A randomized trial of varenicline (Chantix) for the treatment of spinocerebellar ataxia type 3 Neurology 201278545ndash50
65 Zhao Q Schwam E Fullerton T OrsquoGorman M Burstein AH Pharmacokinetics safety and tolerability following multiple oral doses of varenicline under various titration schedules in elderly nonsmokers J Clin Pharmacol 201151492ndash501
66 Chengappa KN Perkins KA Brar JS Schlicht PJ Turkin SR Hetrick ML et al Varenicline for smoking cessation in bipolar disorder a randomized double-blind placebo-controlled study J Clin Psychiatry 201475765ndash72
67 Gonzales D Hajek P Pliamm L Nackaerts K Tseng LJ McRae TD et al Retreatment with varenicline for smoking cessation in smokers who have previously taken varenicline a randomized placebo-controlled trial Clin Pharmacol Ther 201496390ndash6
68 Kishi T Iwata N Varenicline for smoking cessation in people with schizophrenia systematic review and meta-analysis Eur Arch Psychiatry Clin Neurosci 2014 Oct 5 [Epub ahead of print]
69 Hong LE Thaker GK McMahon RP Summerfelt A Rachbeisel J Fuller RL et al Effects of moderate-dose treatment with varenicline on neurobiological and cognitive biomarkers in smokers and nonsmokers with schizophrenia or schizoaffective disorder Arch Gen Psychiatry 2011681195ndash206
70 Huang Y Li W Yang L Jiang Y Wu Y Long-term efficacy and safety of varenicline for smoking cessation a systematic review and
meta-analysis of randomized controlled trials J Public Health 201220355ndash65
71 Singh S Loke YK Spangler JG Furberg CD Risk of serious adverse cardiovascular events associated with varenicline a systematic review and meta-analysis CMAJ 20111831359ndash66
72 Prochaska JJ Hilton JF Risk of cardiovascular serious adverse events associated with varenicline use for tobacco cessation systematic review and meta-analysis BMJ 2012344e2856
73 Mocking RJ Patrick Pflanz C Pringle A Parsons E McTavish SF Cowen PJ et al Effects of short-term varenicline administration on emotional and cognitive processing in healthy non-smoking adults a randomized double-blind study Neuropsychopharmacology 201338476ndash84
74 Taylor G McNeill A Girling A Farley A Lindson-Hawley N Aveyard P Change in mental health after smoking cessation systematic review and meta-analysis BMJ 2014348g1151
75 Smoking cessation services in primary care pharmacies local authorities and workplaces particularly for manual working groups pregnant women and hard to reach communities NICE public health guidance 10 National Institute for Health and Care Excellence 2008
copy BMJ Publishing Group Ltd 2015
Appendix 1 Search strategy to identify relevant articles in MedlineAppendix 2 Further characteristics of included ran-domised controlled trialsAppendix 3 Forest plots for secondary outcomesAppendix 4 Subgroup analysesAppendix 5 Funnel plots Appendix 6 Summary of Peto odds ratios risk differ-ences and 95 confidence intervals for neuropsychiat-ric events
RESEARCH
5thethinspbmj | BMJ 2015350h1109 | doi 101136bmjh1109
side effects of depression and suicidal ideation by age group (P=0391 and P=0933 respectively for interac-tion) percentage of men in the study (P=0418 and P=0925) percentage of white people in the study (P=0685 and P=0254) presence or absence of psychi-atric illness (P=0126 and P=0304) smoking status (P=0906 for depression but not calculated for suicidal ideation as there were no reports of suicidal ideation in studies that included non-smokers) and whether the trial was industry sponsored or not (P=0386 and P=0380) The effect estimates (odds ratio) for the trials in which all participants had psychiatric illnesses com-pared with those where none of the participants had psychiatric illness were 149 (95 confidence interval 084 to 265) versus 091 (069 to 121) for depression and 079 (032 to 193) versus 034 (009 to 129) for suicidal ideation
table 2 | summary of characteristics of patients enrolled in 44 randomised controlled trials of vareniclineCharacteristics of trial participants no of trialsSmokers from general population 18Smokers with psychiatric illness 8Heavy drinking smokersalcohol dependence 4People dependent on cocaine or opioid dependent 3Smokeless tobacco users 2Smokers with mild to moderate COPD 1Smokers with cardiovascular disease 1Smokers about to undergo surgery 1Patients with spinocerebellar ataxia type 3 1Adolescent smokers 1Elderly non-smokers 1Smokers in hospital 1Smokers previously treated with varenicline 1Ex-smokers on long term NRT 1COPD=chronic obstructive pulmonary disease NRT=nicotine replacement therapy
table 3 | risk of bias assessment for each trial of varenicline using Cochrane risk of assessment of bias tool
studyrandom sequence generation
allocation concealment used
blindingincomplete outcome data
selective reporting Other bias
Participants and personnel
Outcome assessment
Anthenelli 201324 Low Low Low Low Low Low LowBolliger 201125 Low Low Low Low Low Low LowBrandon 201126 Low Low Low Low Low Low LowBurstein 200627 Low Low Low Low Low Low LowChengappa 201466 Low Low Low Low Low Low LowCinciripini 201328 Low Low Low Low Low Low LowEbbert 201129 Low Unclear Low Low Low Low LowEvins 201430 Low Low Low Low Low Low LowFaessel 200931 Low Low Low Low Low Low LowFagerstrom 201032 Low Low Low Low Low Low LowFatemi 201333 Unclear Low Low Low Low Low LowGarza 201134 Unclear Low Low Low Low Low LowGonzales 206635 Low Low Low Low Low Low LowGonzales 201467 Low Low Low Low Low Low LowHughes 201136 Low Low Low Low Low Unclear LowJorenby 200637 Low Low Low Low Low Low LowLitten 201338 Low Low Low Low Low Low LowMcClure 201339 Low Low Low Low Low Low LowMcKee 200940 Unclear Unclear Low Unclear Low Low LowMeszaros 201341 Low Low Low Low Low Low LowMitchell 201242 Low Low Low Low Low Low LowNakamura 200743 Low Low Low Low Low Low LowNiaura 200844 Low Low Low Low Low Low LowNides 200645 Low Low Low Low Low Low LowOncken 200646 Low Low Low Low Low Low LowPlebani 201247 Unclear Unclear Unclear Unclear Low Unclear LowPlebani 201348 Low Low Low Unclear Unclear Unclear LowPoling 201049 Low Unclear Low Unclear Low Low LowRennard 201250 Low Low Low Low Low Low LowRigotti 201051 Low Low Low Low Low Low LowShim 201252 Unclear Unclear Low Unclear Unclear Unclear UnclearStein 201353 Low Low Low Low Low Low LowSteinberg 201154 Low Low Low Low Low Low LowTashkin 201155 Low Low Low Low Low Low LowTonnesen 201356 Low Unclear Low Low Low Low LowTonstad 200657 Low Low Low Low Low Low LowTsai 200758 Low Low Low Low Low Low LowWang 200959 Low Low Low Low Low Low UnclearWeiner 201160 Unclear Unclear Unclear Unclear Low Unclear UnclearWilliams 200761 Low Low Low Low Low Low LowWilliams 201262 Low Low Low Low Low Low LowWong 201263 Low Low Low Low Low Low LowZesiewicz 201264 Low Low Low Low Low Low LowZhao 201165 Low Low Low Low Low Low Unclear
RESEARCH
6 doi 101136bmjh1109 | BMJ 2015350h1109 | thethinspbmj
small study effectsThe funnel plots for depression and insomnia are shown in appendix 5 The P values for funnel plot asym-metry were 053 for depression and 093 for insomnia (that is there was no evidence against the null hypoth-esis of no small study effects)
discussionThis meta-analysis of 39 randomised controlled trials involving 5817 patients prescribed varenicline 1 mg twice daily and 4944 patients prescribed placebo found no increased risk of suicide or attempted suicide
suicidal ideation depression or death in individuals treated with varenicline Almost half of the trial partici-pants were chronic heavy smokers (that is they had smoked on average 20 cigarettes a day for 26 years) Five separate trials (including 1281 participants randomised to varenicline and 1143 to placebo) reported a suicide andor suicide attempt (see appendix 3) one reported suicide only three reported attempted suicide only and one reported both suicide and attempted suicide Two suicides and two attempts occurred in the varenicline group of the trials (008) and two attempts occurred in the placebo group (005) Use of the maximum dose of varenicline (1 mg twice daily) was associated with a 28 increased risk of fatigue a 56 increased risk of insomnia a 63 increased risk of sleep disorders and more than twice the risk of abnormal dreams There was evidence of a 25 reduction in the risk of anxiety When we used risk differences for every 1000 patients there were an additional 10 cases of fatigue 40 cases of insomnia 20 cases of sleep disorders and 60 cases of abnormal dreams in those prescribed varenicline com-pared with placebo Similarly there were 10 fewer epi-sodes of anxiety per 1000 participants in the varenicline group compared with the placebo group (risk difference minus001 95 confidence interval minus002 to minus00003) There was no evidence of a variation in depression and sui-cidal ideation by age sex ethnicity presence or absence of psychiatric illness or type of study sponsor
Comparison with other studiesA recent study by Kishi and Iwata examined the effects of varenicline for smoking cessation in people with schizo-phrenia in a meta-analysis of seven randomised con-trolled trials68 With the exception of the study by Hong and colleagues69 we included all their randomised con-trolled trials in the current analysis Similar to our find-ings Kishi and Iwata found no significant differences in depression and suicidal ideation between the vareni-cline and placebo groups They reported however that varenicline use was associated with a lower risk of abnor-mal dreamsnightmares than placebo (relative risk 047 95 confidence interval 022 to 099 P=005)68
table 4 | summary of Peto odds ratios risk differences and 95 confidence intervals for neuropsychiatric events in people treated with varenicline
neuropsychiatric adverse eventno of eventsno treated
Odds ratio (95 Ci) P value risk difference (95 Ci) P valuevarenicline group Placebo groupPrimary outcomesDepression 1635356 1394487 096 (075 to 122) 074 minus0001 (minus001 to 001) 074Suicidal ideation 152799 182191 058 (028 to 120) 014 minus0003 (minus0009 to 0002) 024Attempted suicide 22184 21842 075 (010 to 565) 078 minus00003 (minus0005 to 0004) 091Suicide and attempted suicide 45352 24478 167 (033 to 857) 054 00003 (minus0002 to 0003) 081secondary outcomesAbnormal dreams 6035606 2244741 238 (205 to 277) lt0001 006 (005 to 007) lt0001Aggression 394276 243524 091 (052 to 159) 075 minus0001 (minus0005 to 0004) 079Anxiety 2094999 2264457 075 (061 to 093) 0008 minus001 (minus002 to minus00003) 001Death 135760 114887 105 (047 to 238) 09 00001 (minus0003 to 0003) 094Fatigue 2835502 2024701 128 (106 to 155) 001 001 (0002 to 002) 001Insomnia 6795621 3794762 156 (136 to 178) lt0001 004 (003 to 005) lt0001Irritability 2935406 2664615 098 (081 to 117) 079 minus0001 (minus001 to 0008) 079Sleep disorders 2115081 1234284 163 (129 to 207) lt0001 002 (001 to 002) lt0001Somnolence 1395360 914542 123 (094 to 162) 013 0005 (minus0001 to 001) 013
Jorenby 2006 Hughes 2011 Bolliger 2011 Tashkin 2011 Williams 2012 Rennard 2012 Mitchell 2012 Stein 2013 Cinciripini 2013 Meszaros 2013 Anthenelli 2013 Evins 2014 Chengappa 2014 Zhao 2011 Brandon 2011 Ebbert 2011 Steinberg 2011 Wong 2012 McClure 2013 Gonzales 2014Overall I2=0 P=0621
013 (000 to 676)014 (000 to 708)
453 (024 to 8523)014 (000 to 690)084 (019 to 380)011 (001 to 151)013 (000 to 641)
366 (003 to 38784)016 (000 to 842)
100 (009 to 1103)014 (001 to 136)118 (016 to 875)
186 (019 to 1864)ExcludedExcludedExcludedExcludedExcludedExcludedExcluded
058 (028 to 120)
3363
2383239
1013100000000
100
0001 001 01 1 10 100 1000
Study
Favourstreatment
Favoursplacebo
Odds ratio(95 CI)
Odds ratio(95 CI)
Weight()
0343010723900248584
1486033
111108625
0256240231014046038040
0151041
024915799
Treatment
1340111101981251343
2165131033
110625
3269247129110054038039
0135042
0245182191
ControlNo of eventstotal
fig 2 | forest plot of risk of suicidal ideation events (Peto odds ratio) associated with varenicline use in 20 placebo controlled randomised trials
RESEARCH
7thethinspbmj | BMJ 2015350h1109 | doi 101136bmjh1109
This discrepancy with our findings could be explained by the small sample size of their study (288 from four randomised controlled trials versus 10 347 from 35 ran-domised controlled trials in our analysis)
Gibbons and Mann used pooled data from 17 ran-domised controlled trials sponsored by Pfizer to exam-ine neuropsychiatric adverse events associated with varenicline10 Our study included industry and non- industry sponsored trials and more than twice the num-ber of trials that they included Their findings of no increased risk of suicidal events depression and agita-tion are consistent with our study Although the authors did not include references to the published literature for their included studies (which made cross referenc-ing difficult) it is likely that we included most of their studies in our analysis
Another meta-analysis examined the long term effi-cacy and safety of varenicline in trials with a minimum follow-up period of 12 months70 A meta-analysis of the main psychiatric related adverse effects (which com-bined depressed mood other mood disorders bipolar disorder delirium suicidal and self injurious behaviours adjustment disorders and abnormal think-ing into a single outcome) did not show a ldquosignificant increase of psychiatric side effects for varenicline com-pared with placebordquo70 This meta-analysis however included only three trials and the combined psychiat-ric outcome was non-specific The authors reported an increased risk of insomnia (relative risk 165 95 confi-dence interval 129 to 211) abnormal dreams (278 207 to 373) and sleep disturbance (209 162 to 269) but no
increased risk of irritability (114 075 to 173) which is consistent with our findings70
A previous Cochrane review examined the efficacy and tolerability of nicotine receptor partial agonists including varenicline16 Trials were excluded if partici-pants used smokeless tobacco or if there was less than six months of follow-up In addition to the efficacy out-comes meta-analyses were performed for the most commonly reported adverse events nausea insomnia abnormal dreams and headache Findings were consis-tent with our study for insomnia (relative risk 162 95 confidence interval 140 to 188) and abnormal dreams (291 234 to 362)16 The Cochrane review did not report any treatment emergent deaths Although we used a broader definition of deaths in our analysis by includ-ing all deaths irrespective of whether or not we thought they were related to treatment we did not find an increased risk of death in the varenicline group
strengths and limitationsTo the best of our knowledge this is the most compre-hensive published systematic review (and meta-analy-sis) of neuropsychiatric effects associated with use of varenicline Compared with the previous Cochrane review16 our analysis included 16 additional trials for the meta-analysis of the risk of insomnia events and 23 addi-tional trials for the pooled analysis of abnormal dreams
The choice of summary statistics for meta-analyses of rare events caused controversy (about whether the Peto odds ratio should be reported instead of risk differ-ences) when it led to conflicting findings from two sys-tematic reviews examining the risk of cardiovascular side effects associated with varenicline use71 72 We pres-ent results using both measures a relative measure (Peto odds ratio and sensitivity analyses with fixed and random effects odds ratios) as well as an absolute mea-sure (risk difference) Findings were consistent for all examined outcomes
Many study authors did not specify the actual dates that adverse events were reported so we included all reported events this decision would have increased the likelihood of obtaining reports of rare adverse events We contacted authors for all of our included trials to check the data extracted on adverse events and for study protocols and other information to adequately assess the risk of bias in the studies We had a high response rate (75)
There are some limitations Firstly in this analysis we used study level data instead of individual level data so we were unable to determine whether differences in the adverse events were because of greater quit rates in the varenicline group relative to placebo Secondly because of the small number of suicides and attempted suicide reported (n=6) we cannot rule out major beneficial or adverse effects of varenicline for this outcome (Peto odds ratio 167 95 confidence interval 033 to 857) Thirdly there was potential for heterogeneity in the reporting of adverse events Authors used a range of methods to record adverse events including self report open ended questions structured questionnaires side effect check-lists and case reports coded to the Medical Dictionary for
Jorenby 2006 Hughes 2011 Zhao 2011 Brandon 2011 Ebbert 2011 Steinberg 2011 Bolliger 2011 Tashkin 2011 Williams 2012 Rennard 2012 Mitchell 2012 Wong 2012 McClure 2013 Stein 2013 Cinciripini 2013 Meszaros 2013 Anthenelli 2013 Evins 2014 Chengappa 2014 Gonzales 2014Overall I2=0 P=0995
-000 (-001 to 001)-001 (-003 to 002)000 (-015 to 015)000 (-004 to 004)000 (-005 to 005)000 (-005 to 005)001 (-001 to 002)000 (-001 to 001)-001 (-010 to 008)-001 (-003 to 001)-003 (-012 to 005)000 (-001 to 001)000 (-005 to 005)001 (-004 to 005)-001 (-004 to 002)000 (-061 to 061)-001 (-003 to 000)001 (-008 to 010)003 (-008 to 014)000 (-001 to 001)-000 (-001 to 000)
1551222
11112
1016224lt11121
10100
-05 0 05
Study
Favourstreatment
Favoursplacebo
Odds ratio(95 CI)
Odds ratio(95 CI)
Weight()
03430107014046038040
23900248584
1486033
0151041
111108625
0256240231
0249152799
Treatment
13401111010054038039
01981251343
2165131
0135042033
110625
3269247129
0245182191
ControlNo of eventstotal
fig 3 | forest plot of risk of suicidal ideation events (mantel-Haenszel risk difference) associated with varenicline use in 20 placebo controlled randomised trials
RESEARCH
8 doi 101136bmjh1109 | BMJ 2015350h1109 | thethinspbmj
Regulatory Activities (MedDRA wwwmeddraorg) All of the industry sponsored trials coded adverse events using MedDRA Fourthly we excluded two studies69 73 from the review as the maximum dose of varenicline used in these studies was only 1 mg once a daymdashthat is half of the rec-ommended maximum dose Hong and colleagues exam-ined varenicline treatment in 20 smokers and 15 non-smokers with schizophrenia or schizoaffective disor-der and found no evidence that varenicline worsened psychiatric symptoms in these patients69 Mocking and colleagues studied the effects of varenicline on emotional and cognitive processing in 21 healthy adult non-smokers and concluded that it did not cause problems in emo-tional processing or impulsivity providing less support for a possible depressogenic effect of varenicline73 Fur-thermore a secondary analysis which included all doses of varenicline in the original trials and these two excluded randomised controlled trials produced similar findings to our main analysis (see appendix 6)
We tried to minimise reporting bias by including all events (such as deaths) reported regardless of whether or
not we considered them to be related to treatment It is still possible however that reporting bias could have occurred as for certain trials where the corresponding authors did not respond to our requests for additional information we could not determine whether a lack of reporting of deaths in the published paper was synonymous with no deaths It was difficult to interpret the funnel plots to assess whether publication bias might be present as most trials were efficacy trials and were not performed solely to deter-mine the incidence of psychiatric adverse events
Additionally smoking cessation has been shown to have a positive impact on mental health outcomes with a reduction in depression and anxiety compared with those who continue to smoke74 Patients prescribed varenicline were reported to have an approximately threefold increased chance of quitting smoking com-pared with those given placebo (odds ratio 288 95 confidence interval 240 to 347)4 this could explain the reduction in anxiety observed in this meta-analysis
Lastly half of the trials were sponsored by Pfizer the manufacturers of varenicline Although previous research with nicotine replacement therapy has shown that industry sponsored trials were more likely than other trials to report outcomes that were favourable to the study sponsor14 we did not find any evidence for differences in depression and suicidal ideation for industry versus non industry sponsored trials (P=0386 and P=0380 respectively for interaction) In addition all of the industry sponsored trials were assessed over-all as having a low risk of bias
Conclusions and clinical implicationsBased on this comprehensive systematic review of pub-lished randomised controlled trials there is no evi-dence of an increased risk of depression suicidal behaviour (that is suicide or attempted suicide sui-cidal ideation) and death from any cause associated with treatment with varenicline Varenicline users however have an increased risk of abnormal dreams insomnia and sleep disturbances which are consistent with findings from other studies and previously docu-mented commonly reported side effects of varenicline (wwwchantixcom) We reported our findings using two summary statistics (a relative measure and an abso-lute measure) and observed consistency with both methods This meta-analysis adds to previous research (observational and experimental) that found no evi-dence for increased suicidal behaviour or depression with varenicline the most effective drug for smoking cessation4 The dangers of smoking are well docu-mented and the health benefits of stopping smoking are well known Our analysis suggests that the benefits of varenicline for smoking cessation outweigh the as yet unproved risks of suicidal behaviour In the UK vareni-cline is recommended alongside bupropion and nico-tine replacement therapy as first line treatment for smoking cessation75 Therefore the reduction in vareni-cline prescribing in the UK should be as much a cause for concern to clinicians regulatory agencies and policy makers as the unfounded fears regarding vareni-clinersquos association with suicidal behaviour
Nides 2006 Tonstad 2006 Jorenby 2006 Onken 2006 Gonzales 2006 Williams 2007 Tsai 2007 Niaura 2008 Rigotti 2010 Fagerstrom 2010 Hughes 2011 Garza 2011 Ebbert 2011 Steinberg 2011 Bolliger 2011 Tashkin 2011 Williams 2012 Rennard 2012 Wong 2012 Zesiewicz 2012 McClure 2013 Stein 2013 Litten 2013 Cinciripini 2013 Meszaros 2013 Anthenelli 2013 Evins 2014 Chengappa 2014 Gonzales 2014 Faessel 2009 Brandon 2011Overall I2=0 P=0631
193 (020 to 1870)088 (044 to 178)
419 (095 to 1855)070 (018 to 267)057 (017 to 186)148 (051 to 428)050 (005 to 488)148 (025 to 864)164 (041 to 661)043 (010 to 191)053 (005 to 514)
100 (006 to 1619)014 (000 to 682)097 (013 to 719)102 (030 to 340)122 (037 to 402)066 (013 to 326)020 (004 to 090)089 (089 to 642)012 (012 to 208)078 (078 to 185)066 (066 to 185)123 (123 to 378)051 (020 to 130)
100 (005 to 1991)140 (067 to 292)
118 (007 to 1932)381 (099 to 1467)234 (053 to 1040)
ExcludedExcluded
096 (075 to 122)
1123345123311lt1144232186571
1113300
100
0001 001 01 1 10 100 1000
Study
Favourstreatment
Favoursplacebo
Odds ratio(95 CI)
Odds ratio(95 CI)
Weight()
212515602634362534349
1225111263157535322131107155038240
83906248484
44862151
091741
1711179768615
17256140831
5249014046
1635356
Treatment
112317604134041217344412621242155335052182111155138239
41985251343
51652135
292042733
610114106
1513269
147229
224507
0541394487
ControlNo of eventstotal
fig 4 | forest plot of risk of depression events (Peto odds ratio) associated with varenicline use in 31 placebo controlled randomised trials
RESEARCH
9thethinspbmj | BMJ 2015350h1109 | doi 101136bmjh1109
We are grateful to the corresponding authors of the trials and Cristina Russ of Pfizer (for the Pfizer sponsored trials) for their support with providing access to the data on psychiatric adverse events and death used in this studyContributors KHT DG and RMM conceived the study KHT conducted the literature search KHT and DWK screened the abstracts with assistance from DG KHT DG and RMM were responsible for data extraction and the risk of bias assessment KHT did the statistical analysis with support from JPH KHT wrote the paper with contributions from all authors All authors have approved the final draft of the manuscript KHT is study guarantor had full access to all of the data (including statistical reports and tables) and can take responsibility for the integrity of the data and the accuracy of the data analysisFunding KHT is currently funded by a clinical lectureship from the National Institute for Health Research Part of this work was undertaken while KHT was on a National Institute for Health Research doctoral research fellowship (DRF-2010-03-138) DWK is funded by a Wellcome Trust four year studentship (WT099874MA) DG is an NIHR senior investigator The views expressed in this publication are those of the authors and not necessarily those of the NHS the National Institute for Health Research or the Department of HealthCompeting interests All authors have completed the Unified Competing Interest form at wwwicmjeorgcoi_disclosurepdf (available on request from the corresponding author) and declare RMM had specified relationship with the MHRA in the past (was a member of the MHRArsquos Independent Scientific Advisory Committee for CPRD research and received expenses and a small fee for meeting attendance and preparation for meetings) DG had specified relationship with the MHRA in the past (was a member of the MHRArsquos Pharmacovigilance Expert Advisory Group and received travel expenses and a small fee for meeting attendance and preparation for meetings)Ethics approval Not requiredData sharing No additional data are availableTransparency declaration KHT affirms that this manuscript is an honest accurate and transparent account of the study being reported that no important aspects of the study have been omitted and that any discrepancies from the study as planned (and if relevant registered) have been explainedThis is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 40) license which permits others to distribute remix adapt build upon this work non-commercially and license their derivative works on different terms provided the original work is properly cited and the use is non-commercial See httpcreativecommonsorglicensesby-nc401 Peto R Darby S Deo H Silcocks P Whitley E Doll R Smoking
smoking cessation and lung cancer in the UK since 1950 combination of national statistics with two case-control studies BMJ 2000321323ndash9
2 Jha P Peto R Global effects of smoking of quitting and of taxing tobacco N Engl J Med 201437060ndash8
3 Allender S Balakrishnan R Scarborough P Webster P Rayner M The burden of smoking-related ill health in the UK Tob Control 200918262ndash67
4 Cahill K Stevens S Perera R Lancaster T Pharmacological interventions for smoking cessation an overview and network meta-analysis Cochrane Database Syst Rev 20135CD009329
5 Medicines and Healthcare Products Regulatory Agency Varenicline adverse psychiatric reactions including depression Drug Safety Update 200822ndash3
6 US Food and Drug Administration Information for healthcare professionals varenicline (marketed as Chantix) and bupropion (marketed as Zyban Wellbutrin and generics) FDA Drug Safety Newsletter 2009
7 Gunnell D Irvine D Wise L Davies C Martin RM Varenicline and suicidal behaviour a cohort study based on data from the General Practice Research Database BMJ 2009339b3805
8 Meyer TE Taylor LG Xie S Graham DJ Mosholder AD Williams JR et al Neuropsychiatric events in varenicline and nicotine replacement patch users in the Military Health System Addiction 2013108203ndash10
9 Thomas KH Martin RM Davies N Metcalfe C Windmeijer F Gunnell D Smoking cessation treatment and the risk of depression suicide and self-harm in the Clinical Practice Research Datalink prospective cohort study BMJ 2013347f5704
10 Gibbons RD Mann JJ Varenicline smoking cessation and neuropsychiatric adverse events Am J Psychiatry 20131701460ndash7
11 Walker AM Confounding by indication Epidemiology 19967335ndash612 Miller M Hemenway D Bell NS Yore MM Amoroso PJ Cigarette
smoking and suicide a prospective study of 300000 male active-duty Army soldiers Am J Epidemiol 20001511060ndash3
Nides 2006 Tonstad 2006 Jorenby 2006 Onken 2006 Gonzales 2006 Williams 2007 Tsai 2007 Niaura 2008 Faessel 2009 Rigotti 2010 Fagerstrom 2010 Hughes 2011 Garza 2011 Brandon 2011 Ebbert 2011 Steinberg 2011 Bolliger 2011 Tashkin 2011 Williams 2012 Rennard 2012 Wong 2012 Zesiewicz 2012 McClure 2013 Stein 2013 Litten 2013 Cinciripini 2013 Meszaros 2013 Anthenelli 2013 Evins 2014 Chengappa 2014 Gonzales 2014Overall I2=0 P=0783
001 (-002 to 003)-000 (-002 to 001)001 (-000 to 003)-001 (-005 to 003)-001 (-003 to 001)-002 (-002 to 006)001 (-004 to 002)001 (-002 to 003)000 (-019 to 019)001 (-001 to 002)-001 (-004 to 001)-001 (-004 to 002)000 (-005 to 005)000 (-004 to 004)-003 (-010 to 004)-000 (-010 to 010)000 (-002 to 002)000 (-002 to 003)-002 (-011 to 007)-002 (-005 to 001)-000 (-003 to 003)-022 (-052 to 008)-006 (-027 to 015)-006 (-021 to 010)001 (-006 to 008)-006 (-015 to 002)000 (-050 to 050)002 (-002 to 006)000 (-006 to 007)019 (001 to 037)001 (-001 to 003)-000 (-001 to 001)
313737433lt1752111165153lt11122lt16115
100
-05 0 05
Study
Favourstreatment
Favoursplacebo
Odds ratio(95 CI)
Odds ratio(95 CI)
Weight()
212515602634362534349
1225111263157014
535322131107155046038240
83906248484
44862151
091741
1711179768615
17256140831
52491635356
Treatment
112317604134041217344412621242155
07335052182111155054138239
41985251343
51652135
292042733
610114106
1513269
147229
22451394487
ControlNo of eventstotal
fig 5 | forest plot of risk of depression events (mantel-Haenszel risk difference) associated with varenicline use in 31 placebo controlled randomised trials
table 5 | Comparison of Peto fixed effects and random effects odds ratios (Or) for insomnia sleep disorders and abnormal dreams in people treated with varenicline
neuropsychiatric adverse event
no of eventsno treatedOdds ratio (95 Ci)
test for heterogeneity ()varenicline group Placebo group
insomniaPeto OR 6795621 3794762 156 (136 to 178) 0Fixed effects OR 6795621 3794762 156 (135 to 179) 0Random effects OR 6795621 3794762 156 (135 to 179) 0sleep disordersPeto OR 2115081 1234284 163 (129 to 207) 0Fixed effects OR 2115081 1234284 157 (122 to 203) 0Random effects OR 2115081 1234284 157 (122 to 203) 0abnormal dreams Peto OR 6035606 2244741 238 (205 to 277) 223Fixed effects OR 6035606 2244741 237 (199 to 282) 316Random effects OR 6035606 2244741 236 (187 to 298) 316All Plt0001
RESEARCH
10 doi 101136bmjh1109 | BMJ 2015350h1109 | thethinspbmj
13 Miller M Hemenway D Rimm E Cigarettes and suicide a prospective study of 50000 men Am J Public Health 200090768ndash73
14 Etter JF Burri M Stapleton J The impact of pharmaceutical company funding on results of randomized trials of nicotine replacement therapy for smoking cessation a meta-analysis Addiction 2007102815ndash22
15 Prescribing and Primary Care team Health and Social Care Information Centre Prescription cost analysis England 2013 Health and Social Care Information Centre 2014
16 Cahill K Stead LF Lancaster T Nicotine receptor partial agonists for smoking cessation Cochrane Database Syst Rev 20124CD006103
17 Higgins JPT Altman DG Assessing risk of bias in included studies Cochrane handbook for systematic reviews of interventions John Wiley 2008187ndash241
18 Harris R Bradburn M Deeks J Harbord R Altman D Sterne J metan fixed- and random-effects meta-analysis Stata J 200883ndash28
19 Bradburn MJ Deeks JJ Berlin JA Russell Localio A Much ado about nothing a comparison of the performance of meta-analytical methods with rare events Stat Med 20072653ndash77
20 Higgins JP Thompson SG Deeks JJ Altman DG Measuring inconsistency in meta-analyses BMJ 2003327557ndash60
21 Higgins JPT Deeks JJ Altman DG Special topics in statistics Cochrane handbook for systematic reviews of interventions John Wiley 2008481ndash529
22 Sterne JAC Harbord RM Funnel plots in meta-analysis Stata J 20044127ndash41
23 Harbord RM Harris RJ Sterne JAC Updated tests for small-study effects in meta-analyses Stata J 20099197ndash210
24 Anthenelli RM Morris C Ramey TS Dubrava SJ Tsilkos K Russ C et al Effects of varenicline on smoking cessation in adults with stably treated current or past major depression a randomized trial Ann Intern Med 2013159390ndash400
25 Bolliger CT Issa JS Posadas-Valay R Safwat T Abreu P Correia EA et al Effects of varenicline in adult smokers a multinational 24-week randomized double-blind placebo-controlled study Clin Ther 201133465ndash77
26 Brandon TH Drobes DJ Unrod M Heckman BW Oliver JA Roetzheim RC et al Varenicline effects on craving cue reactivity and smoking reward Psychopharmacology (Berl) 2011218391ndash403
27 Burstein AH Fullerton T Clark DJ Faessel HM Pharmacokinetics safety and tolerability after single and multiple oral doses of varenicline in elderly smokers J Clin Pharmacol 2006461234ndash40
28 Cinciripini PM Robinson JD Karam-Hage M Minnix JA Lam C Versace F et al Effects of varenicline and bupropion sustained-release use plus intensive smoking cessation counseling on prolonged abstinence from smoking and on depression negative affect and other symptoms of nicotine withdrawal JAMA Psychiatry 201370522ndash33
29 Ebbert JO Croghan IT Severson HH Schroeder DR Hays JT A pilot study of the efficacy of varenicline for the treatment of smokeless tobacco users in Midwestern United States Nicotine Tob Res 201113820ndash6
30 Evins AE Cather C Pratt SA Pachas GN Hoeppner SS Goff DC et al Maintenance treatment with varenicline for smoking cessation in patients with schizophrenia and bipolar disorder a randomized clinical trial JAMA 2014311145ndash54
31 Faessel H Ravva P Williams K Pharmacokinetics safety and tolerability of varenicline in healthy adolescent smokers a multicenter randomized double-blind placebo-controlled parallel-group study Clin Ther 200931177ndash89
32 Fagerstrom K Gilljam H Metcalfe M Tonstad S Messig M Stopping smokeless tobacco with varenicline randomised double blind placebo controlled trial BMJ 2010341c6549
33 Fatemi SH Yousefi MK Kneeland RE Liesch SB Folsom TD Thuras PD Antismoking and potential antipsychotic effects of varenicline in subjects with schizophrenia or schizoaffective disorder a double-blind placebo and bupropion-controlled study Schizophr Res 2013146376ndash8
34 Garza D Murphy M Tseng LJ Riordan HJ Chatterjee A A double-blind randomized placebo-controlled pilot study of neuropsychiatric adverse events in abstinent smokers treated with varenicline or placebo Biol Psychiatry 2011691075ndash82
35 Gonzales D Rennard SI Nides M Oncken C Azoulay S Billing CB et al Varenicline an alpha4beta2 nicotinic acetylcholine receptor partial agonist vs sustained-release bupropion and placebo for smoking cessation a randomized controlled trial JAMA 200629647ndash55
36 Hughes JR Rennard SI Fingar JR Talbot SK Callas PW Fagerstrom KO Efficacy of varenicline to prompt quit attempts in smokers not currently trying to quit a randomized placebo-controlled trial Nicotine Tob Res 201113955ndash64
37 Jorenby DE Hays JT Rigotti NA Azoulay S Watsky EJ Williams KE et al Efficacy of varenicline an alpha4beta2 nicotinic acetylcholine receptor partial agonist vs placebo or sustained-release bupropion for smoking cessation a randomized controlled trial JAMA 200629656ndash63
38 Litten RZ Ryan ML Fertig JB Falk DE Johnson B Dunn KE et al A double-blind placebo-controlled trial assessing the efficacy of varenicline tartrate for alcohol dependence J Addict Med 20137277ndash86
39 McClure EA Vandrey RG Johnson MW Stitzer ML Effects of varenicline on abstinence and smoking reward following a programmed lapse Nicotine Tob Res 201315139ndash48
40 McKee SA Harrison EL OrsquoMalley SS Krishnan-Sarin S Shi J Tetrault JM et al Varenicline reduces alcohol self-administration in heavy-drinking smokers Biol Psychiatry 200966185ndash90
41 Meszaros ZS Abdul-Malak Y Dimmock JA Wang D Ajagbe TO Batki SL Varenicline treatment of concurrent alcohol and nicotine dependence in schizophrenia a randomized placebo-controlled pilot trial J Clin Psychopharmacol 201333243ndash7
42 Mitchell JM Teague CH Kayser AS Bartlett SE Fields HL Varenicline decreases alcohol consumption in heavy-drinking smokers Psychopharmacology (Berl) 2012223299ndash306
43 Nakamura M Oshima A Fujimoto Y Maruyama N Ishibashi T Reeves KR Efficacy and tolerability of varenicline an alpha4beta2 nicotinic acetylcholine receptor partial agonist in a 12-week randomized placebo-controlled dose-response study with 40-week follow-up for smoking cessation in Japanese smokers Clin Ther 2007291040ndash56
44 Niaura R Hays JT Jorenby DE Leone FT Pappas JE Reeves KR et al The efficacy and safety of varenicline for smoking cessation using a flexible dosing strategy in adult smokers a randomized controlled trial Curr Med Res Opin 2008241931ndash41
45 Nides M Oncken C Gonzales D Rennard S Watsky EJ Anziano R et al Smoking cessation with varenicline a selective alpha4beta2 nicotinic receptor partial agonist results from a 7-week randomized placebo- and bupropion-controlled trial with 1-year follow-up Arch Intern Med 20061661561ndash8
46 Oncken C Gonzales D Nides M Rennard S Watsky E Billing CB et al Efficacy and safety of the novel selective nicotinic acetylcholine receptor partial agonist varenicline for smoking cessation Arch Intern Med 20061661571ndash7
47 Plebani JG Lynch KG Yu Q Pettinati HM OrsquoBrien CP Kampman KM Results of an initial clinical trial of varenicline for the treatment of cocaine dependence Drug Alcohol Depend 2012121163ndash6
48 Plebani JG Lynch KG Rennert L Pettinati HM OrsquoBrien CP Kampman KM Results from a pilot clinical trial of varenicline for the treatment of alcohol dependence Drug Alcohol Depend 2013133754ndash8
49 Poling J Rounsaville B Gonsai K Severino K Sofuoglu M The safety and efficacy of varenicline in cocaine using smokers maintained on methadone a pilot study Am J Addict 201019401ndash8
50 Rennard S Hughes J Cinciripini PM Kralikova E Raupach T Arteaga C et al A randomized placebo-controlled trial of varenicline for smoking cessation allowing flexible quit dates Nicotine Tob Res 201214343ndash50
51 Rigotti NA Pipe AL Benowitz NL Arteaga C Garza D Tonstad S Efficacy and safety of varenicline for smoking cessation in patients with cardiovascular disease a randomized trial Circulation 2010121221ndash9
52 Shim JC Jung DU Jung SS Seo YS Cho DM Lee JH et al Adjunctive varenicline treatment with antipsychotic medications for cognitive impairments in people with schizophrenia a randomized double-blind placebo-controlled trial Neuropsychopharmacology 201237660ndash8
53 Stein MD Caviness CM Kurth ME Audet D Olson J Anderson BJ Varenicline for smoking cessation among methadone-maintained smokers a randomized clinical trial Drug Alcohol Depend 2013133486ndash93
54 Steinberg MB Randall J Greenhaus S Schmelzer AC Richardson DL Carson JL Tobacco dependence treatment for hospitalized smokers a randomized controlled pilot trial using varenicline Addic Behav 2011361127ndash32
55 Tashkin DP Rennard S Hays JT Ma W Lawrence D Lee TC Effects of varenicline on smoking cessation in patients with mild to moderate COPD a randomized controlled trial Chest 2011139591ndash9
56 Tonnesen P Mikkelsen K Varenicline to stop long-term nicotine replacement use a double-blind randomized placebo-controlled trial Nicotine Tob Res 201315419ndash27
57 Tonstad S Tonnesen P Hajek P Williams KE Billing CB Reeves KR et al Effect of maintenance therapy with varenicline on smoking cessation a randomized controlled trial JAMA 200629664ndash71
58 Tsai ST Cho HJ Cheng HS Kim CH Hsueh KC Billing CB Jr et al A randomized placebo-controlled trial of varenicline a selective alpha4beta2 nicotinic acetylcholine receptor partial agonist as a new therapy for smoking cessation in Asian smokers Clin Ther 2007291027ndash39
59 Wang C Xiao D Chan KPW Pothirat C Garza D Davies S Varenicline for smoking cessation A placebo-controlled randomized study Respirology 200914384ndash92
60 Weiner E Buchholz A Coffay A Liu F McMahon RP Buchanan RW et al Varenicline for smoking cessation in people with schizophrenia a double blind randomized pilot study Schizophr Res 201112994ndash5
RESEARCH
11thethinspbmj | BMJ 2015350h1109 | doi 101136bmjh1109
61 Williams K Reeves K Billing C Pennington A Gong J A double-blind study evaluating the long-term safety of varenicline for smoking cessation Curr Med Res Opin 200723793ndash801
62 Williams JM Anthenelli RM Morris CD Treadow J Thompson JR Yunis C et al A randomized double-blind placebo-controlled study evaluating the safety and efficacy of varenicline for smoking cessation in patients with schizophrenia or schizoaffective disorder J Clin Psychiatry 201273654ndash60
63 Wong J Abrishami A Yang Y Zaki A Friedman Z Selby P et al A perioperative smoking cessation intervention with varenicline a double-blind randomized placebo-controlled trial Anesthesiology 2012117755ndash64
64 Zesiewicz TA Greenstein PE Sullivan KL Wecker L Miller A Jahan I et al A randomized trial of varenicline (Chantix) for the treatment of spinocerebellar ataxia type 3 Neurology 201278545ndash50
65 Zhao Q Schwam E Fullerton T OrsquoGorman M Burstein AH Pharmacokinetics safety and tolerability following multiple oral doses of varenicline under various titration schedules in elderly nonsmokers J Clin Pharmacol 201151492ndash501
66 Chengappa KN Perkins KA Brar JS Schlicht PJ Turkin SR Hetrick ML et al Varenicline for smoking cessation in bipolar disorder a randomized double-blind placebo-controlled study J Clin Psychiatry 201475765ndash72
67 Gonzales D Hajek P Pliamm L Nackaerts K Tseng LJ McRae TD et al Retreatment with varenicline for smoking cessation in smokers who have previously taken varenicline a randomized placebo-controlled trial Clin Pharmacol Ther 201496390ndash6
68 Kishi T Iwata N Varenicline for smoking cessation in people with schizophrenia systematic review and meta-analysis Eur Arch Psychiatry Clin Neurosci 2014 Oct 5 [Epub ahead of print]
69 Hong LE Thaker GK McMahon RP Summerfelt A Rachbeisel J Fuller RL et al Effects of moderate-dose treatment with varenicline on neurobiological and cognitive biomarkers in smokers and nonsmokers with schizophrenia or schizoaffective disorder Arch Gen Psychiatry 2011681195ndash206
70 Huang Y Li W Yang L Jiang Y Wu Y Long-term efficacy and safety of varenicline for smoking cessation a systematic review and
meta-analysis of randomized controlled trials J Public Health 201220355ndash65
71 Singh S Loke YK Spangler JG Furberg CD Risk of serious adverse cardiovascular events associated with varenicline a systematic review and meta-analysis CMAJ 20111831359ndash66
72 Prochaska JJ Hilton JF Risk of cardiovascular serious adverse events associated with varenicline use for tobacco cessation systematic review and meta-analysis BMJ 2012344e2856
73 Mocking RJ Patrick Pflanz C Pringle A Parsons E McTavish SF Cowen PJ et al Effects of short-term varenicline administration on emotional and cognitive processing in healthy non-smoking adults a randomized double-blind study Neuropsychopharmacology 201338476ndash84
74 Taylor G McNeill A Girling A Farley A Lindson-Hawley N Aveyard P Change in mental health after smoking cessation systematic review and meta-analysis BMJ 2014348g1151
75 Smoking cessation services in primary care pharmacies local authorities and workplaces particularly for manual working groups pregnant women and hard to reach communities NICE public health guidance 10 National Institute for Health and Care Excellence 2008
copy BMJ Publishing Group Ltd 2015
Appendix 1 Search strategy to identify relevant articles in MedlineAppendix 2 Further characteristics of included ran-domised controlled trialsAppendix 3 Forest plots for secondary outcomesAppendix 4 Subgroup analysesAppendix 5 Funnel plots Appendix 6 Summary of Peto odds ratios risk differ-ences and 95 confidence intervals for neuropsychiat-ric events
RESEARCH
6 doi 101136bmjh1109 | BMJ 2015350h1109 | thethinspbmj
small study effectsThe funnel plots for depression and insomnia are shown in appendix 5 The P values for funnel plot asym-metry were 053 for depression and 093 for insomnia (that is there was no evidence against the null hypoth-esis of no small study effects)
discussionThis meta-analysis of 39 randomised controlled trials involving 5817 patients prescribed varenicline 1 mg twice daily and 4944 patients prescribed placebo found no increased risk of suicide or attempted suicide
suicidal ideation depression or death in individuals treated with varenicline Almost half of the trial partici-pants were chronic heavy smokers (that is they had smoked on average 20 cigarettes a day for 26 years) Five separate trials (including 1281 participants randomised to varenicline and 1143 to placebo) reported a suicide andor suicide attempt (see appendix 3) one reported suicide only three reported attempted suicide only and one reported both suicide and attempted suicide Two suicides and two attempts occurred in the varenicline group of the trials (008) and two attempts occurred in the placebo group (005) Use of the maximum dose of varenicline (1 mg twice daily) was associated with a 28 increased risk of fatigue a 56 increased risk of insomnia a 63 increased risk of sleep disorders and more than twice the risk of abnormal dreams There was evidence of a 25 reduction in the risk of anxiety When we used risk differences for every 1000 patients there were an additional 10 cases of fatigue 40 cases of insomnia 20 cases of sleep disorders and 60 cases of abnormal dreams in those prescribed varenicline com-pared with placebo Similarly there were 10 fewer epi-sodes of anxiety per 1000 participants in the varenicline group compared with the placebo group (risk difference minus001 95 confidence interval minus002 to minus00003) There was no evidence of a variation in depression and sui-cidal ideation by age sex ethnicity presence or absence of psychiatric illness or type of study sponsor
Comparison with other studiesA recent study by Kishi and Iwata examined the effects of varenicline for smoking cessation in people with schizo-phrenia in a meta-analysis of seven randomised con-trolled trials68 With the exception of the study by Hong and colleagues69 we included all their randomised con-trolled trials in the current analysis Similar to our find-ings Kishi and Iwata found no significant differences in depression and suicidal ideation between the vareni-cline and placebo groups They reported however that varenicline use was associated with a lower risk of abnor-mal dreamsnightmares than placebo (relative risk 047 95 confidence interval 022 to 099 P=005)68
table 4 | summary of Peto odds ratios risk differences and 95 confidence intervals for neuropsychiatric events in people treated with varenicline
neuropsychiatric adverse eventno of eventsno treated
Odds ratio (95 Ci) P value risk difference (95 Ci) P valuevarenicline group Placebo groupPrimary outcomesDepression 1635356 1394487 096 (075 to 122) 074 minus0001 (minus001 to 001) 074Suicidal ideation 152799 182191 058 (028 to 120) 014 minus0003 (minus0009 to 0002) 024Attempted suicide 22184 21842 075 (010 to 565) 078 minus00003 (minus0005 to 0004) 091Suicide and attempted suicide 45352 24478 167 (033 to 857) 054 00003 (minus0002 to 0003) 081secondary outcomesAbnormal dreams 6035606 2244741 238 (205 to 277) lt0001 006 (005 to 007) lt0001Aggression 394276 243524 091 (052 to 159) 075 minus0001 (minus0005 to 0004) 079Anxiety 2094999 2264457 075 (061 to 093) 0008 minus001 (minus002 to minus00003) 001Death 135760 114887 105 (047 to 238) 09 00001 (minus0003 to 0003) 094Fatigue 2835502 2024701 128 (106 to 155) 001 001 (0002 to 002) 001Insomnia 6795621 3794762 156 (136 to 178) lt0001 004 (003 to 005) lt0001Irritability 2935406 2664615 098 (081 to 117) 079 minus0001 (minus001 to 0008) 079Sleep disorders 2115081 1234284 163 (129 to 207) lt0001 002 (001 to 002) lt0001Somnolence 1395360 914542 123 (094 to 162) 013 0005 (minus0001 to 001) 013
Jorenby 2006 Hughes 2011 Bolliger 2011 Tashkin 2011 Williams 2012 Rennard 2012 Mitchell 2012 Stein 2013 Cinciripini 2013 Meszaros 2013 Anthenelli 2013 Evins 2014 Chengappa 2014 Zhao 2011 Brandon 2011 Ebbert 2011 Steinberg 2011 Wong 2012 McClure 2013 Gonzales 2014Overall I2=0 P=0621
013 (000 to 676)014 (000 to 708)
453 (024 to 8523)014 (000 to 690)084 (019 to 380)011 (001 to 151)013 (000 to 641)
366 (003 to 38784)016 (000 to 842)
100 (009 to 1103)014 (001 to 136)118 (016 to 875)
186 (019 to 1864)ExcludedExcludedExcludedExcludedExcludedExcludedExcluded
058 (028 to 120)
3363
2383239
1013100000000
100
0001 001 01 1 10 100 1000
Study
Favourstreatment
Favoursplacebo
Odds ratio(95 CI)
Odds ratio(95 CI)
Weight()
0343010723900248584
1486033
111108625
0256240231014046038040
0151041
024915799
Treatment
1340111101981251343
2165131033
110625
3269247129110054038039
0135042
0245182191
ControlNo of eventstotal
fig 2 | forest plot of risk of suicidal ideation events (Peto odds ratio) associated with varenicline use in 20 placebo controlled randomised trials
RESEARCH
7thethinspbmj | BMJ 2015350h1109 | doi 101136bmjh1109
This discrepancy with our findings could be explained by the small sample size of their study (288 from four randomised controlled trials versus 10 347 from 35 ran-domised controlled trials in our analysis)
Gibbons and Mann used pooled data from 17 ran-domised controlled trials sponsored by Pfizer to exam-ine neuropsychiatric adverse events associated with varenicline10 Our study included industry and non- industry sponsored trials and more than twice the num-ber of trials that they included Their findings of no increased risk of suicidal events depression and agita-tion are consistent with our study Although the authors did not include references to the published literature for their included studies (which made cross referenc-ing difficult) it is likely that we included most of their studies in our analysis
Another meta-analysis examined the long term effi-cacy and safety of varenicline in trials with a minimum follow-up period of 12 months70 A meta-analysis of the main psychiatric related adverse effects (which com-bined depressed mood other mood disorders bipolar disorder delirium suicidal and self injurious behaviours adjustment disorders and abnormal think-ing into a single outcome) did not show a ldquosignificant increase of psychiatric side effects for varenicline com-pared with placebordquo70 This meta-analysis however included only three trials and the combined psychiat-ric outcome was non-specific The authors reported an increased risk of insomnia (relative risk 165 95 confi-dence interval 129 to 211) abnormal dreams (278 207 to 373) and sleep disturbance (209 162 to 269) but no
increased risk of irritability (114 075 to 173) which is consistent with our findings70
A previous Cochrane review examined the efficacy and tolerability of nicotine receptor partial agonists including varenicline16 Trials were excluded if partici-pants used smokeless tobacco or if there was less than six months of follow-up In addition to the efficacy out-comes meta-analyses were performed for the most commonly reported adverse events nausea insomnia abnormal dreams and headache Findings were consis-tent with our study for insomnia (relative risk 162 95 confidence interval 140 to 188) and abnormal dreams (291 234 to 362)16 The Cochrane review did not report any treatment emergent deaths Although we used a broader definition of deaths in our analysis by includ-ing all deaths irrespective of whether or not we thought they were related to treatment we did not find an increased risk of death in the varenicline group
strengths and limitationsTo the best of our knowledge this is the most compre-hensive published systematic review (and meta-analy-sis) of neuropsychiatric effects associated with use of varenicline Compared with the previous Cochrane review16 our analysis included 16 additional trials for the meta-analysis of the risk of insomnia events and 23 addi-tional trials for the pooled analysis of abnormal dreams
The choice of summary statistics for meta-analyses of rare events caused controversy (about whether the Peto odds ratio should be reported instead of risk differ-ences) when it led to conflicting findings from two sys-tematic reviews examining the risk of cardiovascular side effects associated with varenicline use71 72 We pres-ent results using both measures a relative measure (Peto odds ratio and sensitivity analyses with fixed and random effects odds ratios) as well as an absolute mea-sure (risk difference) Findings were consistent for all examined outcomes
Many study authors did not specify the actual dates that adverse events were reported so we included all reported events this decision would have increased the likelihood of obtaining reports of rare adverse events We contacted authors for all of our included trials to check the data extracted on adverse events and for study protocols and other information to adequately assess the risk of bias in the studies We had a high response rate (75)
There are some limitations Firstly in this analysis we used study level data instead of individual level data so we were unable to determine whether differences in the adverse events were because of greater quit rates in the varenicline group relative to placebo Secondly because of the small number of suicides and attempted suicide reported (n=6) we cannot rule out major beneficial or adverse effects of varenicline for this outcome (Peto odds ratio 167 95 confidence interval 033 to 857) Thirdly there was potential for heterogeneity in the reporting of adverse events Authors used a range of methods to record adverse events including self report open ended questions structured questionnaires side effect check-lists and case reports coded to the Medical Dictionary for
Jorenby 2006 Hughes 2011 Zhao 2011 Brandon 2011 Ebbert 2011 Steinberg 2011 Bolliger 2011 Tashkin 2011 Williams 2012 Rennard 2012 Mitchell 2012 Wong 2012 McClure 2013 Stein 2013 Cinciripini 2013 Meszaros 2013 Anthenelli 2013 Evins 2014 Chengappa 2014 Gonzales 2014Overall I2=0 P=0995
-000 (-001 to 001)-001 (-003 to 002)000 (-015 to 015)000 (-004 to 004)000 (-005 to 005)000 (-005 to 005)001 (-001 to 002)000 (-001 to 001)-001 (-010 to 008)-001 (-003 to 001)-003 (-012 to 005)000 (-001 to 001)000 (-005 to 005)001 (-004 to 005)-001 (-004 to 002)000 (-061 to 061)-001 (-003 to 000)001 (-008 to 010)003 (-008 to 014)000 (-001 to 001)-000 (-001 to 000)
1551222
11112
1016224lt11121
10100
-05 0 05
Study
Favourstreatment
Favoursplacebo
Odds ratio(95 CI)
Odds ratio(95 CI)
Weight()
03430107014046038040
23900248584
1486033
0151041
111108625
0256240231
0249152799
Treatment
13401111010054038039
01981251343
2165131
0135042033
110625
3269247129
0245182191
ControlNo of eventstotal
fig 3 | forest plot of risk of suicidal ideation events (mantel-Haenszel risk difference) associated with varenicline use in 20 placebo controlled randomised trials
RESEARCH
8 doi 101136bmjh1109 | BMJ 2015350h1109 | thethinspbmj
Regulatory Activities (MedDRA wwwmeddraorg) All of the industry sponsored trials coded adverse events using MedDRA Fourthly we excluded two studies69 73 from the review as the maximum dose of varenicline used in these studies was only 1 mg once a daymdashthat is half of the rec-ommended maximum dose Hong and colleagues exam-ined varenicline treatment in 20 smokers and 15 non-smokers with schizophrenia or schizoaffective disor-der and found no evidence that varenicline worsened psychiatric symptoms in these patients69 Mocking and colleagues studied the effects of varenicline on emotional and cognitive processing in 21 healthy adult non-smokers and concluded that it did not cause problems in emo-tional processing or impulsivity providing less support for a possible depressogenic effect of varenicline73 Fur-thermore a secondary analysis which included all doses of varenicline in the original trials and these two excluded randomised controlled trials produced similar findings to our main analysis (see appendix 6)
We tried to minimise reporting bias by including all events (such as deaths) reported regardless of whether or
not we considered them to be related to treatment It is still possible however that reporting bias could have occurred as for certain trials where the corresponding authors did not respond to our requests for additional information we could not determine whether a lack of reporting of deaths in the published paper was synonymous with no deaths It was difficult to interpret the funnel plots to assess whether publication bias might be present as most trials were efficacy trials and were not performed solely to deter-mine the incidence of psychiatric adverse events
Additionally smoking cessation has been shown to have a positive impact on mental health outcomes with a reduction in depression and anxiety compared with those who continue to smoke74 Patients prescribed varenicline were reported to have an approximately threefold increased chance of quitting smoking com-pared with those given placebo (odds ratio 288 95 confidence interval 240 to 347)4 this could explain the reduction in anxiety observed in this meta-analysis
Lastly half of the trials were sponsored by Pfizer the manufacturers of varenicline Although previous research with nicotine replacement therapy has shown that industry sponsored trials were more likely than other trials to report outcomes that were favourable to the study sponsor14 we did not find any evidence for differences in depression and suicidal ideation for industry versus non industry sponsored trials (P=0386 and P=0380 respectively for interaction) In addition all of the industry sponsored trials were assessed over-all as having a low risk of bias
Conclusions and clinical implicationsBased on this comprehensive systematic review of pub-lished randomised controlled trials there is no evi-dence of an increased risk of depression suicidal behaviour (that is suicide or attempted suicide sui-cidal ideation) and death from any cause associated with treatment with varenicline Varenicline users however have an increased risk of abnormal dreams insomnia and sleep disturbances which are consistent with findings from other studies and previously docu-mented commonly reported side effects of varenicline (wwwchantixcom) We reported our findings using two summary statistics (a relative measure and an abso-lute measure) and observed consistency with both methods This meta-analysis adds to previous research (observational and experimental) that found no evi-dence for increased suicidal behaviour or depression with varenicline the most effective drug for smoking cessation4 The dangers of smoking are well docu-mented and the health benefits of stopping smoking are well known Our analysis suggests that the benefits of varenicline for smoking cessation outweigh the as yet unproved risks of suicidal behaviour In the UK vareni-cline is recommended alongside bupropion and nico-tine replacement therapy as first line treatment for smoking cessation75 Therefore the reduction in vareni-cline prescribing in the UK should be as much a cause for concern to clinicians regulatory agencies and policy makers as the unfounded fears regarding vareni-clinersquos association with suicidal behaviour
Nides 2006 Tonstad 2006 Jorenby 2006 Onken 2006 Gonzales 2006 Williams 2007 Tsai 2007 Niaura 2008 Rigotti 2010 Fagerstrom 2010 Hughes 2011 Garza 2011 Ebbert 2011 Steinberg 2011 Bolliger 2011 Tashkin 2011 Williams 2012 Rennard 2012 Wong 2012 Zesiewicz 2012 McClure 2013 Stein 2013 Litten 2013 Cinciripini 2013 Meszaros 2013 Anthenelli 2013 Evins 2014 Chengappa 2014 Gonzales 2014 Faessel 2009 Brandon 2011Overall I2=0 P=0631
193 (020 to 1870)088 (044 to 178)
419 (095 to 1855)070 (018 to 267)057 (017 to 186)148 (051 to 428)050 (005 to 488)148 (025 to 864)164 (041 to 661)043 (010 to 191)053 (005 to 514)
100 (006 to 1619)014 (000 to 682)097 (013 to 719)102 (030 to 340)122 (037 to 402)066 (013 to 326)020 (004 to 090)089 (089 to 642)012 (012 to 208)078 (078 to 185)066 (066 to 185)123 (123 to 378)051 (020 to 130)
100 (005 to 1991)140 (067 to 292)
118 (007 to 1932)381 (099 to 1467)234 (053 to 1040)
ExcludedExcluded
096 (075 to 122)
1123345123311lt1144232186571
1113300
100
0001 001 01 1 10 100 1000
Study
Favourstreatment
Favoursplacebo
Odds ratio(95 CI)
Odds ratio(95 CI)
Weight()
212515602634362534349
1225111263157535322131107155038240
83906248484
44862151
091741
1711179768615
17256140831
5249014046
1635356
Treatment
112317604134041217344412621242155335052182111155138239
41985251343
51652135
292042733
610114106
1513269
147229
224507
0541394487
ControlNo of eventstotal
fig 4 | forest plot of risk of depression events (Peto odds ratio) associated with varenicline use in 31 placebo controlled randomised trials
RESEARCH
9thethinspbmj | BMJ 2015350h1109 | doi 101136bmjh1109
We are grateful to the corresponding authors of the trials and Cristina Russ of Pfizer (for the Pfizer sponsored trials) for their support with providing access to the data on psychiatric adverse events and death used in this studyContributors KHT DG and RMM conceived the study KHT conducted the literature search KHT and DWK screened the abstracts with assistance from DG KHT DG and RMM were responsible for data extraction and the risk of bias assessment KHT did the statistical analysis with support from JPH KHT wrote the paper with contributions from all authors All authors have approved the final draft of the manuscript KHT is study guarantor had full access to all of the data (including statistical reports and tables) and can take responsibility for the integrity of the data and the accuracy of the data analysisFunding KHT is currently funded by a clinical lectureship from the National Institute for Health Research Part of this work was undertaken while KHT was on a National Institute for Health Research doctoral research fellowship (DRF-2010-03-138) DWK is funded by a Wellcome Trust four year studentship (WT099874MA) DG is an NIHR senior investigator The views expressed in this publication are those of the authors and not necessarily those of the NHS the National Institute for Health Research or the Department of HealthCompeting interests All authors have completed the Unified Competing Interest form at wwwicmjeorgcoi_disclosurepdf (available on request from the corresponding author) and declare RMM had specified relationship with the MHRA in the past (was a member of the MHRArsquos Independent Scientific Advisory Committee for CPRD research and received expenses and a small fee for meeting attendance and preparation for meetings) DG had specified relationship with the MHRA in the past (was a member of the MHRArsquos Pharmacovigilance Expert Advisory Group and received travel expenses and a small fee for meeting attendance and preparation for meetings)Ethics approval Not requiredData sharing No additional data are availableTransparency declaration KHT affirms that this manuscript is an honest accurate and transparent account of the study being reported that no important aspects of the study have been omitted and that any discrepancies from the study as planned (and if relevant registered) have been explainedThis is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 40) license which permits others to distribute remix adapt build upon this work non-commercially and license their derivative works on different terms provided the original work is properly cited and the use is non-commercial See httpcreativecommonsorglicensesby-nc401 Peto R Darby S Deo H Silcocks P Whitley E Doll R Smoking
smoking cessation and lung cancer in the UK since 1950 combination of national statistics with two case-control studies BMJ 2000321323ndash9
2 Jha P Peto R Global effects of smoking of quitting and of taxing tobacco N Engl J Med 201437060ndash8
3 Allender S Balakrishnan R Scarborough P Webster P Rayner M The burden of smoking-related ill health in the UK Tob Control 200918262ndash67
4 Cahill K Stevens S Perera R Lancaster T Pharmacological interventions for smoking cessation an overview and network meta-analysis Cochrane Database Syst Rev 20135CD009329
5 Medicines and Healthcare Products Regulatory Agency Varenicline adverse psychiatric reactions including depression Drug Safety Update 200822ndash3
6 US Food and Drug Administration Information for healthcare professionals varenicline (marketed as Chantix) and bupropion (marketed as Zyban Wellbutrin and generics) FDA Drug Safety Newsletter 2009
7 Gunnell D Irvine D Wise L Davies C Martin RM Varenicline and suicidal behaviour a cohort study based on data from the General Practice Research Database BMJ 2009339b3805
8 Meyer TE Taylor LG Xie S Graham DJ Mosholder AD Williams JR et al Neuropsychiatric events in varenicline and nicotine replacement patch users in the Military Health System Addiction 2013108203ndash10
9 Thomas KH Martin RM Davies N Metcalfe C Windmeijer F Gunnell D Smoking cessation treatment and the risk of depression suicide and self-harm in the Clinical Practice Research Datalink prospective cohort study BMJ 2013347f5704
10 Gibbons RD Mann JJ Varenicline smoking cessation and neuropsychiatric adverse events Am J Psychiatry 20131701460ndash7
11 Walker AM Confounding by indication Epidemiology 19967335ndash612 Miller M Hemenway D Bell NS Yore MM Amoroso PJ Cigarette
smoking and suicide a prospective study of 300000 male active-duty Army soldiers Am J Epidemiol 20001511060ndash3
Nides 2006 Tonstad 2006 Jorenby 2006 Onken 2006 Gonzales 2006 Williams 2007 Tsai 2007 Niaura 2008 Faessel 2009 Rigotti 2010 Fagerstrom 2010 Hughes 2011 Garza 2011 Brandon 2011 Ebbert 2011 Steinberg 2011 Bolliger 2011 Tashkin 2011 Williams 2012 Rennard 2012 Wong 2012 Zesiewicz 2012 McClure 2013 Stein 2013 Litten 2013 Cinciripini 2013 Meszaros 2013 Anthenelli 2013 Evins 2014 Chengappa 2014 Gonzales 2014Overall I2=0 P=0783
001 (-002 to 003)-000 (-002 to 001)001 (-000 to 003)-001 (-005 to 003)-001 (-003 to 001)-002 (-002 to 006)001 (-004 to 002)001 (-002 to 003)000 (-019 to 019)001 (-001 to 002)-001 (-004 to 001)-001 (-004 to 002)000 (-005 to 005)000 (-004 to 004)-003 (-010 to 004)-000 (-010 to 010)000 (-002 to 002)000 (-002 to 003)-002 (-011 to 007)-002 (-005 to 001)-000 (-003 to 003)-022 (-052 to 008)-006 (-027 to 015)-006 (-021 to 010)001 (-006 to 008)-006 (-015 to 002)000 (-050 to 050)002 (-002 to 006)000 (-006 to 007)019 (001 to 037)001 (-001 to 003)-000 (-001 to 001)
313737433lt1752111165153lt11122lt16115
100
-05 0 05
Study
Favourstreatment
Favoursplacebo
Odds ratio(95 CI)
Odds ratio(95 CI)
Weight()
212515602634362534349
1225111263157014
535322131107155046038240
83906248484
44862151
091741
1711179768615
17256140831
52491635356
Treatment
112317604134041217344412621242155
07335052182111155054138239
41985251343
51652135
292042733
610114106
1513269
147229
22451394487
ControlNo of eventstotal
fig 5 | forest plot of risk of depression events (mantel-Haenszel risk difference) associated with varenicline use in 31 placebo controlled randomised trials
table 5 | Comparison of Peto fixed effects and random effects odds ratios (Or) for insomnia sleep disorders and abnormal dreams in people treated with varenicline
neuropsychiatric adverse event
no of eventsno treatedOdds ratio (95 Ci)
test for heterogeneity ()varenicline group Placebo group
insomniaPeto OR 6795621 3794762 156 (136 to 178) 0Fixed effects OR 6795621 3794762 156 (135 to 179) 0Random effects OR 6795621 3794762 156 (135 to 179) 0sleep disordersPeto OR 2115081 1234284 163 (129 to 207) 0Fixed effects OR 2115081 1234284 157 (122 to 203) 0Random effects OR 2115081 1234284 157 (122 to 203) 0abnormal dreams Peto OR 6035606 2244741 238 (205 to 277) 223Fixed effects OR 6035606 2244741 237 (199 to 282) 316Random effects OR 6035606 2244741 236 (187 to 298) 316All Plt0001
RESEARCH
10 doi 101136bmjh1109 | BMJ 2015350h1109 | thethinspbmj
13 Miller M Hemenway D Rimm E Cigarettes and suicide a prospective study of 50000 men Am J Public Health 200090768ndash73
14 Etter JF Burri M Stapleton J The impact of pharmaceutical company funding on results of randomized trials of nicotine replacement therapy for smoking cessation a meta-analysis Addiction 2007102815ndash22
15 Prescribing and Primary Care team Health and Social Care Information Centre Prescription cost analysis England 2013 Health and Social Care Information Centre 2014
16 Cahill K Stead LF Lancaster T Nicotine receptor partial agonists for smoking cessation Cochrane Database Syst Rev 20124CD006103
17 Higgins JPT Altman DG Assessing risk of bias in included studies Cochrane handbook for systematic reviews of interventions John Wiley 2008187ndash241
18 Harris R Bradburn M Deeks J Harbord R Altman D Sterne J metan fixed- and random-effects meta-analysis Stata J 200883ndash28
19 Bradburn MJ Deeks JJ Berlin JA Russell Localio A Much ado about nothing a comparison of the performance of meta-analytical methods with rare events Stat Med 20072653ndash77
20 Higgins JP Thompson SG Deeks JJ Altman DG Measuring inconsistency in meta-analyses BMJ 2003327557ndash60
21 Higgins JPT Deeks JJ Altman DG Special topics in statistics Cochrane handbook for systematic reviews of interventions John Wiley 2008481ndash529
22 Sterne JAC Harbord RM Funnel plots in meta-analysis Stata J 20044127ndash41
23 Harbord RM Harris RJ Sterne JAC Updated tests for small-study effects in meta-analyses Stata J 20099197ndash210
24 Anthenelli RM Morris C Ramey TS Dubrava SJ Tsilkos K Russ C et al Effects of varenicline on smoking cessation in adults with stably treated current or past major depression a randomized trial Ann Intern Med 2013159390ndash400
25 Bolliger CT Issa JS Posadas-Valay R Safwat T Abreu P Correia EA et al Effects of varenicline in adult smokers a multinational 24-week randomized double-blind placebo-controlled study Clin Ther 201133465ndash77
26 Brandon TH Drobes DJ Unrod M Heckman BW Oliver JA Roetzheim RC et al Varenicline effects on craving cue reactivity and smoking reward Psychopharmacology (Berl) 2011218391ndash403
27 Burstein AH Fullerton T Clark DJ Faessel HM Pharmacokinetics safety and tolerability after single and multiple oral doses of varenicline in elderly smokers J Clin Pharmacol 2006461234ndash40
28 Cinciripini PM Robinson JD Karam-Hage M Minnix JA Lam C Versace F et al Effects of varenicline and bupropion sustained-release use plus intensive smoking cessation counseling on prolonged abstinence from smoking and on depression negative affect and other symptoms of nicotine withdrawal JAMA Psychiatry 201370522ndash33
29 Ebbert JO Croghan IT Severson HH Schroeder DR Hays JT A pilot study of the efficacy of varenicline for the treatment of smokeless tobacco users in Midwestern United States Nicotine Tob Res 201113820ndash6
30 Evins AE Cather C Pratt SA Pachas GN Hoeppner SS Goff DC et al Maintenance treatment with varenicline for smoking cessation in patients with schizophrenia and bipolar disorder a randomized clinical trial JAMA 2014311145ndash54
31 Faessel H Ravva P Williams K Pharmacokinetics safety and tolerability of varenicline in healthy adolescent smokers a multicenter randomized double-blind placebo-controlled parallel-group study Clin Ther 200931177ndash89
32 Fagerstrom K Gilljam H Metcalfe M Tonstad S Messig M Stopping smokeless tobacco with varenicline randomised double blind placebo controlled trial BMJ 2010341c6549
33 Fatemi SH Yousefi MK Kneeland RE Liesch SB Folsom TD Thuras PD Antismoking and potential antipsychotic effects of varenicline in subjects with schizophrenia or schizoaffective disorder a double-blind placebo and bupropion-controlled study Schizophr Res 2013146376ndash8
34 Garza D Murphy M Tseng LJ Riordan HJ Chatterjee A A double-blind randomized placebo-controlled pilot study of neuropsychiatric adverse events in abstinent smokers treated with varenicline or placebo Biol Psychiatry 2011691075ndash82
35 Gonzales D Rennard SI Nides M Oncken C Azoulay S Billing CB et al Varenicline an alpha4beta2 nicotinic acetylcholine receptor partial agonist vs sustained-release bupropion and placebo for smoking cessation a randomized controlled trial JAMA 200629647ndash55
36 Hughes JR Rennard SI Fingar JR Talbot SK Callas PW Fagerstrom KO Efficacy of varenicline to prompt quit attempts in smokers not currently trying to quit a randomized placebo-controlled trial Nicotine Tob Res 201113955ndash64
37 Jorenby DE Hays JT Rigotti NA Azoulay S Watsky EJ Williams KE et al Efficacy of varenicline an alpha4beta2 nicotinic acetylcholine receptor partial agonist vs placebo or sustained-release bupropion for smoking cessation a randomized controlled trial JAMA 200629656ndash63
38 Litten RZ Ryan ML Fertig JB Falk DE Johnson B Dunn KE et al A double-blind placebo-controlled trial assessing the efficacy of varenicline tartrate for alcohol dependence J Addict Med 20137277ndash86
39 McClure EA Vandrey RG Johnson MW Stitzer ML Effects of varenicline on abstinence and smoking reward following a programmed lapse Nicotine Tob Res 201315139ndash48
40 McKee SA Harrison EL OrsquoMalley SS Krishnan-Sarin S Shi J Tetrault JM et al Varenicline reduces alcohol self-administration in heavy-drinking smokers Biol Psychiatry 200966185ndash90
41 Meszaros ZS Abdul-Malak Y Dimmock JA Wang D Ajagbe TO Batki SL Varenicline treatment of concurrent alcohol and nicotine dependence in schizophrenia a randomized placebo-controlled pilot trial J Clin Psychopharmacol 201333243ndash7
42 Mitchell JM Teague CH Kayser AS Bartlett SE Fields HL Varenicline decreases alcohol consumption in heavy-drinking smokers Psychopharmacology (Berl) 2012223299ndash306
43 Nakamura M Oshima A Fujimoto Y Maruyama N Ishibashi T Reeves KR Efficacy and tolerability of varenicline an alpha4beta2 nicotinic acetylcholine receptor partial agonist in a 12-week randomized placebo-controlled dose-response study with 40-week follow-up for smoking cessation in Japanese smokers Clin Ther 2007291040ndash56
44 Niaura R Hays JT Jorenby DE Leone FT Pappas JE Reeves KR et al The efficacy and safety of varenicline for smoking cessation using a flexible dosing strategy in adult smokers a randomized controlled trial Curr Med Res Opin 2008241931ndash41
45 Nides M Oncken C Gonzales D Rennard S Watsky EJ Anziano R et al Smoking cessation with varenicline a selective alpha4beta2 nicotinic receptor partial agonist results from a 7-week randomized placebo- and bupropion-controlled trial with 1-year follow-up Arch Intern Med 20061661561ndash8
46 Oncken C Gonzales D Nides M Rennard S Watsky E Billing CB et al Efficacy and safety of the novel selective nicotinic acetylcholine receptor partial agonist varenicline for smoking cessation Arch Intern Med 20061661571ndash7
47 Plebani JG Lynch KG Yu Q Pettinati HM OrsquoBrien CP Kampman KM Results of an initial clinical trial of varenicline for the treatment of cocaine dependence Drug Alcohol Depend 2012121163ndash6
48 Plebani JG Lynch KG Rennert L Pettinati HM OrsquoBrien CP Kampman KM Results from a pilot clinical trial of varenicline for the treatment of alcohol dependence Drug Alcohol Depend 2013133754ndash8
49 Poling J Rounsaville B Gonsai K Severino K Sofuoglu M The safety and efficacy of varenicline in cocaine using smokers maintained on methadone a pilot study Am J Addict 201019401ndash8
50 Rennard S Hughes J Cinciripini PM Kralikova E Raupach T Arteaga C et al A randomized placebo-controlled trial of varenicline for smoking cessation allowing flexible quit dates Nicotine Tob Res 201214343ndash50
51 Rigotti NA Pipe AL Benowitz NL Arteaga C Garza D Tonstad S Efficacy and safety of varenicline for smoking cessation in patients with cardiovascular disease a randomized trial Circulation 2010121221ndash9
52 Shim JC Jung DU Jung SS Seo YS Cho DM Lee JH et al Adjunctive varenicline treatment with antipsychotic medications for cognitive impairments in people with schizophrenia a randomized double-blind placebo-controlled trial Neuropsychopharmacology 201237660ndash8
53 Stein MD Caviness CM Kurth ME Audet D Olson J Anderson BJ Varenicline for smoking cessation among methadone-maintained smokers a randomized clinical trial Drug Alcohol Depend 2013133486ndash93
54 Steinberg MB Randall J Greenhaus S Schmelzer AC Richardson DL Carson JL Tobacco dependence treatment for hospitalized smokers a randomized controlled pilot trial using varenicline Addic Behav 2011361127ndash32
55 Tashkin DP Rennard S Hays JT Ma W Lawrence D Lee TC Effects of varenicline on smoking cessation in patients with mild to moderate COPD a randomized controlled trial Chest 2011139591ndash9
56 Tonnesen P Mikkelsen K Varenicline to stop long-term nicotine replacement use a double-blind randomized placebo-controlled trial Nicotine Tob Res 201315419ndash27
57 Tonstad S Tonnesen P Hajek P Williams KE Billing CB Reeves KR et al Effect of maintenance therapy with varenicline on smoking cessation a randomized controlled trial JAMA 200629664ndash71
58 Tsai ST Cho HJ Cheng HS Kim CH Hsueh KC Billing CB Jr et al A randomized placebo-controlled trial of varenicline a selective alpha4beta2 nicotinic acetylcholine receptor partial agonist as a new therapy for smoking cessation in Asian smokers Clin Ther 2007291027ndash39
59 Wang C Xiao D Chan KPW Pothirat C Garza D Davies S Varenicline for smoking cessation A placebo-controlled randomized study Respirology 200914384ndash92
60 Weiner E Buchholz A Coffay A Liu F McMahon RP Buchanan RW et al Varenicline for smoking cessation in people with schizophrenia a double blind randomized pilot study Schizophr Res 201112994ndash5
RESEARCH
11thethinspbmj | BMJ 2015350h1109 | doi 101136bmjh1109
61 Williams K Reeves K Billing C Pennington A Gong J A double-blind study evaluating the long-term safety of varenicline for smoking cessation Curr Med Res Opin 200723793ndash801
62 Williams JM Anthenelli RM Morris CD Treadow J Thompson JR Yunis C et al A randomized double-blind placebo-controlled study evaluating the safety and efficacy of varenicline for smoking cessation in patients with schizophrenia or schizoaffective disorder J Clin Psychiatry 201273654ndash60
63 Wong J Abrishami A Yang Y Zaki A Friedman Z Selby P et al A perioperative smoking cessation intervention with varenicline a double-blind randomized placebo-controlled trial Anesthesiology 2012117755ndash64
64 Zesiewicz TA Greenstein PE Sullivan KL Wecker L Miller A Jahan I et al A randomized trial of varenicline (Chantix) for the treatment of spinocerebellar ataxia type 3 Neurology 201278545ndash50
65 Zhao Q Schwam E Fullerton T OrsquoGorman M Burstein AH Pharmacokinetics safety and tolerability following multiple oral doses of varenicline under various titration schedules in elderly nonsmokers J Clin Pharmacol 201151492ndash501
66 Chengappa KN Perkins KA Brar JS Schlicht PJ Turkin SR Hetrick ML et al Varenicline for smoking cessation in bipolar disorder a randomized double-blind placebo-controlled study J Clin Psychiatry 201475765ndash72
67 Gonzales D Hajek P Pliamm L Nackaerts K Tseng LJ McRae TD et al Retreatment with varenicline for smoking cessation in smokers who have previously taken varenicline a randomized placebo-controlled trial Clin Pharmacol Ther 201496390ndash6
68 Kishi T Iwata N Varenicline for smoking cessation in people with schizophrenia systematic review and meta-analysis Eur Arch Psychiatry Clin Neurosci 2014 Oct 5 [Epub ahead of print]
69 Hong LE Thaker GK McMahon RP Summerfelt A Rachbeisel J Fuller RL et al Effects of moderate-dose treatment with varenicline on neurobiological and cognitive biomarkers in smokers and nonsmokers with schizophrenia or schizoaffective disorder Arch Gen Psychiatry 2011681195ndash206
70 Huang Y Li W Yang L Jiang Y Wu Y Long-term efficacy and safety of varenicline for smoking cessation a systematic review and
meta-analysis of randomized controlled trials J Public Health 201220355ndash65
71 Singh S Loke YK Spangler JG Furberg CD Risk of serious adverse cardiovascular events associated with varenicline a systematic review and meta-analysis CMAJ 20111831359ndash66
72 Prochaska JJ Hilton JF Risk of cardiovascular serious adverse events associated with varenicline use for tobacco cessation systematic review and meta-analysis BMJ 2012344e2856
73 Mocking RJ Patrick Pflanz C Pringle A Parsons E McTavish SF Cowen PJ et al Effects of short-term varenicline administration on emotional and cognitive processing in healthy non-smoking adults a randomized double-blind study Neuropsychopharmacology 201338476ndash84
74 Taylor G McNeill A Girling A Farley A Lindson-Hawley N Aveyard P Change in mental health after smoking cessation systematic review and meta-analysis BMJ 2014348g1151
75 Smoking cessation services in primary care pharmacies local authorities and workplaces particularly for manual working groups pregnant women and hard to reach communities NICE public health guidance 10 National Institute for Health and Care Excellence 2008
copy BMJ Publishing Group Ltd 2015
Appendix 1 Search strategy to identify relevant articles in MedlineAppendix 2 Further characteristics of included ran-domised controlled trialsAppendix 3 Forest plots for secondary outcomesAppendix 4 Subgroup analysesAppendix 5 Funnel plots Appendix 6 Summary of Peto odds ratios risk differ-ences and 95 confidence intervals for neuropsychiat-ric events
RESEARCH
7thethinspbmj | BMJ 2015350h1109 | doi 101136bmjh1109
This discrepancy with our findings could be explained by the small sample size of their study (288 from four randomised controlled trials versus 10 347 from 35 ran-domised controlled trials in our analysis)
Gibbons and Mann used pooled data from 17 ran-domised controlled trials sponsored by Pfizer to exam-ine neuropsychiatric adverse events associated with varenicline10 Our study included industry and non- industry sponsored trials and more than twice the num-ber of trials that they included Their findings of no increased risk of suicidal events depression and agita-tion are consistent with our study Although the authors did not include references to the published literature for their included studies (which made cross referenc-ing difficult) it is likely that we included most of their studies in our analysis
Another meta-analysis examined the long term effi-cacy and safety of varenicline in trials with a minimum follow-up period of 12 months70 A meta-analysis of the main psychiatric related adverse effects (which com-bined depressed mood other mood disorders bipolar disorder delirium suicidal and self injurious behaviours adjustment disorders and abnormal think-ing into a single outcome) did not show a ldquosignificant increase of psychiatric side effects for varenicline com-pared with placebordquo70 This meta-analysis however included only three trials and the combined psychiat-ric outcome was non-specific The authors reported an increased risk of insomnia (relative risk 165 95 confi-dence interval 129 to 211) abnormal dreams (278 207 to 373) and sleep disturbance (209 162 to 269) but no
increased risk of irritability (114 075 to 173) which is consistent with our findings70
A previous Cochrane review examined the efficacy and tolerability of nicotine receptor partial agonists including varenicline16 Trials were excluded if partici-pants used smokeless tobacco or if there was less than six months of follow-up In addition to the efficacy out-comes meta-analyses were performed for the most commonly reported adverse events nausea insomnia abnormal dreams and headache Findings were consis-tent with our study for insomnia (relative risk 162 95 confidence interval 140 to 188) and abnormal dreams (291 234 to 362)16 The Cochrane review did not report any treatment emergent deaths Although we used a broader definition of deaths in our analysis by includ-ing all deaths irrespective of whether or not we thought they were related to treatment we did not find an increased risk of death in the varenicline group
strengths and limitationsTo the best of our knowledge this is the most compre-hensive published systematic review (and meta-analy-sis) of neuropsychiatric effects associated with use of varenicline Compared with the previous Cochrane review16 our analysis included 16 additional trials for the meta-analysis of the risk of insomnia events and 23 addi-tional trials for the pooled analysis of abnormal dreams
The choice of summary statistics for meta-analyses of rare events caused controversy (about whether the Peto odds ratio should be reported instead of risk differ-ences) when it led to conflicting findings from two sys-tematic reviews examining the risk of cardiovascular side effects associated with varenicline use71 72 We pres-ent results using both measures a relative measure (Peto odds ratio and sensitivity analyses with fixed and random effects odds ratios) as well as an absolute mea-sure (risk difference) Findings were consistent for all examined outcomes
Many study authors did not specify the actual dates that adverse events were reported so we included all reported events this decision would have increased the likelihood of obtaining reports of rare adverse events We contacted authors for all of our included trials to check the data extracted on adverse events and for study protocols and other information to adequately assess the risk of bias in the studies We had a high response rate (75)
There are some limitations Firstly in this analysis we used study level data instead of individual level data so we were unable to determine whether differences in the adverse events were because of greater quit rates in the varenicline group relative to placebo Secondly because of the small number of suicides and attempted suicide reported (n=6) we cannot rule out major beneficial or adverse effects of varenicline for this outcome (Peto odds ratio 167 95 confidence interval 033 to 857) Thirdly there was potential for heterogeneity in the reporting of adverse events Authors used a range of methods to record adverse events including self report open ended questions structured questionnaires side effect check-lists and case reports coded to the Medical Dictionary for
Jorenby 2006 Hughes 2011 Zhao 2011 Brandon 2011 Ebbert 2011 Steinberg 2011 Bolliger 2011 Tashkin 2011 Williams 2012 Rennard 2012 Mitchell 2012 Wong 2012 McClure 2013 Stein 2013 Cinciripini 2013 Meszaros 2013 Anthenelli 2013 Evins 2014 Chengappa 2014 Gonzales 2014Overall I2=0 P=0995
-000 (-001 to 001)-001 (-003 to 002)000 (-015 to 015)000 (-004 to 004)000 (-005 to 005)000 (-005 to 005)001 (-001 to 002)000 (-001 to 001)-001 (-010 to 008)-001 (-003 to 001)-003 (-012 to 005)000 (-001 to 001)000 (-005 to 005)001 (-004 to 005)-001 (-004 to 002)000 (-061 to 061)-001 (-003 to 000)001 (-008 to 010)003 (-008 to 014)000 (-001 to 001)-000 (-001 to 000)
1551222
11112
1016224lt11121
10100
-05 0 05
Study
Favourstreatment
Favoursplacebo
Odds ratio(95 CI)
Odds ratio(95 CI)
Weight()
03430107014046038040
23900248584
1486033
0151041
111108625
0256240231
0249152799
Treatment
13401111010054038039
01981251343
2165131
0135042033
110625
3269247129
0245182191
ControlNo of eventstotal
fig 3 | forest plot of risk of suicidal ideation events (mantel-Haenszel risk difference) associated with varenicline use in 20 placebo controlled randomised trials
RESEARCH
8 doi 101136bmjh1109 | BMJ 2015350h1109 | thethinspbmj
Regulatory Activities (MedDRA wwwmeddraorg) All of the industry sponsored trials coded adverse events using MedDRA Fourthly we excluded two studies69 73 from the review as the maximum dose of varenicline used in these studies was only 1 mg once a daymdashthat is half of the rec-ommended maximum dose Hong and colleagues exam-ined varenicline treatment in 20 smokers and 15 non-smokers with schizophrenia or schizoaffective disor-der and found no evidence that varenicline worsened psychiatric symptoms in these patients69 Mocking and colleagues studied the effects of varenicline on emotional and cognitive processing in 21 healthy adult non-smokers and concluded that it did not cause problems in emo-tional processing or impulsivity providing less support for a possible depressogenic effect of varenicline73 Fur-thermore a secondary analysis which included all doses of varenicline in the original trials and these two excluded randomised controlled trials produced similar findings to our main analysis (see appendix 6)
We tried to minimise reporting bias by including all events (such as deaths) reported regardless of whether or
not we considered them to be related to treatment It is still possible however that reporting bias could have occurred as for certain trials where the corresponding authors did not respond to our requests for additional information we could not determine whether a lack of reporting of deaths in the published paper was synonymous with no deaths It was difficult to interpret the funnel plots to assess whether publication bias might be present as most trials were efficacy trials and were not performed solely to deter-mine the incidence of psychiatric adverse events
Additionally smoking cessation has been shown to have a positive impact on mental health outcomes with a reduction in depression and anxiety compared with those who continue to smoke74 Patients prescribed varenicline were reported to have an approximately threefold increased chance of quitting smoking com-pared with those given placebo (odds ratio 288 95 confidence interval 240 to 347)4 this could explain the reduction in anxiety observed in this meta-analysis
Lastly half of the trials were sponsored by Pfizer the manufacturers of varenicline Although previous research with nicotine replacement therapy has shown that industry sponsored trials were more likely than other trials to report outcomes that were favourable to the study sponsor14 we did not find any evidence for differences in depression and suicidal ideation for industry versus non industry sponsored trials (P=0386 and P=0380 respectively for interaction) In addition all of the industry sponsored trials were assessed over-all as having a low risk of bias
Conclusions and clinical implicationsBased on this comprehensive systematic review of pub-lished randomised controlled trials there is no evi-dence of an increased risk of depression suicidal behaviour (that is suicide or attempted suicide sui-cidal ideation) and death from any cause associated with treatment with varenicline Varenicline users however have an increased risk of abnormal dreams insomnia and sleep disturbances which are consistent with findings from other studies and previously docu-mented commonly reported side effects of varenicline (wwwchantixcom) We reported our findings using two summary statistics (a relative measure and an abso-lute measure) and observed consistency with both methods This meta-analysis adds to previous research (observational and experimental) that found no evi-dence for increased suicidal behaviour or depression with varenicline the most effective drug for smoking cessation4 The dangers of smoking are well docu-mented and the health benefits of stopping smoking are well known Our analysis suggests that the benefits of varenicline for smoking cessation outweigh the as yet unproved risks of suicidal behaviour In the UK vareni-cline is recommended alongside bupropion and nico-tine replacement therapy as first line treatment for smoking cessation75 Therefore the reduction in vareni-cline prescribing in the UK should be as much a cause for concern to clinicians regulatory agencies and policy makers as the unfounded fears regarding vareni-clinersquos association with suicidal behaviour
Nides 2006 Tonstad 2006 Jorenby 2006 Onken 2006 Gonzales 2006 Williams 2007 Tsai 2007 Niaura 2008 Rigotti 2010 Fagerstrom 2010 Hughes 2011 Garza 2011 Ebbert 2011 Steinberg 2011 Bolliger 2011 Tashkin 2011 Williams 2012 Rennard 2012 Wong 2012 Zesiewicz 2012 McClure 2013 Stein 2013 Litten 2013 Cinciripini 2013 Meszaros 2013 Anthenelli 2013 Evins 2014 Chengappa 2014 Gonzales 2014 Faessel 2009 Brandon 2011Overall I2=0 P=0631
193 (020 to 1870)088 (044 to 178)
419 (095 to 1855)070 (018 to 267)057 (017 to 186)148 (051 to 428)050 (005 to 488)148 (025 to 864)164 (041 to 661)043 (010 to 191)053 (005 to 514)
100 (006 to 1619)014 (000 to 682)097 (013 to 719)102 (030 to 340)122 (037 to 402)066 (013 to 326)020 (004 to 090)089 (089 to 642)012 (012 to 208)078 (078 to 185)066 (066 to 185)123 (123 to 378)051 (020 to 130)
100 (005 to 1991)140 (067 to 292)
118 (007 to 1932)381 (099 to 1467)234 (053 to 1040)
ExcludedExcluded
096 (075 to 122)
1123345123311lt1144232186571
1113300
100
0001 001 01 1 10 100 1000
Study
Favourstreatment
Favoursplacebo
Odds ratio(95 CI)
Odds ratio(95 CI)
Weight()
212515602634362534349
1225111263157535322131107155038240
83906248484
44862151
091741
1711179768615
17256140831
5249014046
1635356
Treatment
112317604134041217344412621242155335052182111155138239
41985251343
51652135
292042733
610114106
1513269
147229
224507
0541394487
ControlNo of eventstotal
fig 4 | forest plot of risk of depression events (Peto odds ratio) associated with varenicline use in 31 placebo controlled randomised trials
RESEARCH
9thethinspbmj | BMJ 2015350h1109 | doi 101136bmjh1109
We are grateful to the corresponding authors of the trials and Cristina Russ of Pfizer (for the Pfizer sponsored trials) for their support with providing access to the data on psychiatric adverse events and death used in this studyContributors KHT DG and RMM conceived the study KHT conducted the literature search KHT and DWK screened the abstracts with assistance from DG KHT DG and RMM were responsible for data extraction and the risk of bias assessment KHT did the statistical analysis with support from JPH KHT wrote the paper with contributions from all authors All authors have approved the final draft of the manuscript KHT is study guarantor had full access to all of the data (including statistical reports and tables) and can take responsibility for the integrity of the data and the accuracy of the data analysisFunding KHT is currently funded by a clinical lectureship from the National Institute for Health Research Part of this work was undertaken while KHT was on a National Institute for Health Research doctoral research fellowship (DRF-2010-03-138) DWK is funded by a Wellcome Trust four year studentship (WT099874MA) DG is an NIHR senior investigator The views expressed in this publication are those of the authors and not necessarily those of the NHS the National Institute for Health Research or the Department of HealthCompeting interests All authors have completed the Unified Competing Interest form at wwwicmjeorgcoi_disclosurepdf (available on request from the corresponding author) and declare RMM had specified relationship with the MHRA in the past (was a member of the MHRArsquos Independent Scientific Advisory Committee for CPRD research and received expenses and a small fee for meeting attendance and preparation for meetings) DG had specified relationship with the MHRA in the past (was a member of the MHRArsquos Pharmacovigilance Expert Advisory Group and received travel expenses and a small fee for meeting attendance and preparation for meetings)Ethics approval Not requiredData sharing No additional data are availableTransparency declaration KHT affirms that this manuscript is an honest accurate and transparent account of the study being reported that no important aspects of the study have been omitted and that any discrepancies from the study as planned (and if relevant registered) have been explainedThis is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 40) license which permits others to distribute remix adapt build upon this work non-commercially and license their derivative works on different terms provided the original work is properly cited and the use is non-commercial See httpcreativecommonsorglicensesby-nc401 Peto R Darby S Deo H Silcocks P Whitley E Doll R Smoking
smoking cessation and lung cancer in the UK since 1950 combination of national statistics with two case-control studies BMJ 2000321323ndash9
2 Jha P Peto R Global effects of smoking of quitting and of taxing tobacco N Engl J Med 201437060ndash8
3 Allender S Balakrishnan R Scarborough P Webster P Rayner M The burden of smoking-related ill health in the UK Tob Control 200918262ndash67
4 Cahill K Stevens S Perera R Lancaster T Pharmacological interventions for smoking cessation an overview and network meta-analysis Cochrane Database Syst Rev 20135CD009329
5 Medicines and Healthcare Products Regulatory Agency Varenicline adverse psychiatric reactions including depression Drug Safety Update 200822ndash3
6 US Food and Drug Administration Information for healthcare professionals varenicline (marketed as Chantix) and bupropion (marketed as Zyban Wellbutrin and generics) FDA Drug Safety Newsletter 2009
7 Gunnell D Irvine D Wise L Davies C Martin RM Varenicline and suicidal behaviour a cohort study based on data from the General Practice Research Database BMJ 2009339b3805
8 Meyer TE Taylor LG Xie S Graham DJ Mosholder AD Williams JR et al Neuropsychiatric events in varenicline and nicotine replacement patch users in the Military Health System Addiction 2013108203ndash10
9 Thomas KH Martin RM Davies N Metcalfe C Windmeijer F Gunnell D Smoking cessation treatment and the risk of depression suicide and self-harm in the Clinical Practice Research Datalink prospective cohort study BMJ 2013347f5704
10 Gibbons RD Mann JJ Varenicline smoking cessation and neuropsychiatric adverse events Am J Psychiatry 20131701460ndash7
11 Walker AM Confounding by indication Epidemiology 19967335ndash612 Miller M Hemenway D Bell NS Yore MM Amoroso PJ Cigarette
smoking and suicide a prospective study of 300000 male active-duty Army soldiers Am J Epidemiol 20001511060ndash3
Nides 2006 Tonstad 2006 Jorenby 2006 Onken 2006 Gonzales 2006 Williams 2007 Tsai 2007 Niaura 2008 Faessel 2009 Rigotti 2010 Fagerstrom 2010 Hughes 2011 Garza 2011 Brandon 2011 Ebbert 2011 Steinberg 2011 Bolliger 2011 Tashkin 2011 Williams 2012 Rennard 2012 Wong 2012 Zesiewicz 2012 McClure 2013 Stein 2013 Litten 2013 Cinciripini 2013 Meszaros 2013 Anthenelli 2013 Evins 2014 Chengappa 2014 Gonzales 2014Overall I2=0 P=0783
001 (-002 to 003)-000 (-002 to 001)001 (-000 to 003)-001 (-005 to 003)-001 (-003 to 001)-002 (-002 to 006)001 (-004 to 002)001 (-002 to 003)000 (-019 to 019)001 (-001 to 002)-001 (-004 to 001)-001 (-004 to 002)000 (-005 to 005)000 (-004 to 004)-003 (-010 to 004)-000 (-010 to 010)000 (-002 to 002)000 (-002 to 003)-002 (-011 to 007)-002 (-005 to 001)-000 (-003 to 003)-022 (-052 to 008)-006 (-027 to 015)-006 (-021 to 010)001 (-006 to 008)-006 (-015 to 002)000 (-050 to 050)002 (-002 to 006)000 (-006 to 007)019 (001 to 037)001 (-001 to 003)-000 (-001 to 001)
313737433lt1752111165153lt11122lt16115
100
-05 0 05
Study
Favourstreatment
Favoursplacebo
Odds ratio(95 CI)
Odds ratio(95 CI)
Weight()
212515602634362534349
1225111263157014
535322131107155046038240
83906248484
44862151
091741
1711179768615
17256140831
52491635356
Treatment
112317604134041217344412621242155
07335052182111155054138239
41985251343
51652135
292042733
610114106
1513269
147229
22451394487
ControlNo of eventstotal
fig 5 | forest plot of risk of depression events (mantel-Haenszel risk difference) associated with varenicline use in 31 placebo controlled randomised trials
table 5 | Comparison of Peto fixed effects and random effects odds ratios (Or) for insomnia sleep disorders and abnormal dreams in people treated with varenicline
neuropsychiatric adverse event
no of eventsno treatedOdds ratio (95 Ci)
test for heterogeneity ()varenicline group Placebo group
insomniaPeto OR 6795621 3794762 156 (136 to 178) 0Fixed effects OR 6795621 3794762 156 (135 to 179) 0Random effects OR 6795621 3794762 156 (135 to 179) 0sleep disordersPeto OR 2115081 1234284 163 (129 to 207) 0Fixed effects OR 2115081 1234284 157 (122 to 203) 0Random effects OR 2115081 1234284 157 (122 to 203) 0abnormal dreams Peto OR 6035606 2244741 238 (205 to 277) 223Fixed effects OR 6035606 2244741 237 (199 to 282) 316Random effects OR 6035606 2244741 236 (187 to 298) 316All Plt0001
RESEARCH
10 doi 101136bmjh1109 | BMJ 2015350h1109 | thethinspbmj
13 Miller M Hemenway D Rimm E Cigarettes and suicide a prospective study of 50000 men Am J Public Health 200090768ndash73
14 Etter JF Burri M Stapleton J The impact of pharmaceutical company funding on results of randomized trials of nicotine replacement therapy for smoking cessation a meta-analysis Addiction 2007102815ndash22
15 Prescribing and Primary Care team Health and Social Care Information Centre Prescription cost analysis England 2013 Health and Social Care Information Centre 2014
16 Cahill K Stead LF Lancaster T Nicotine receptor partial agonists for smoking cessation Cochrane Database Syst Rev 20124CD006103
17 Higgins JPT Altman DG Assessing risk of bias in included studies Cochrane handbook for systematic reviews of interventions John Wiley 2008187ndash241
18 Harris R Bradburn M Deeks J Harbord R Altman D Sterne J metan fixed- and random-effects meta-analysis Stata J 200883ndash28
19 Bradburn MJ Deeks JJ Berlin JA Russell Localio A Much ado about nothing a comparison of the performance of meta-analytical methods with rare events Stat Med 20072653ndash77
20 Higgins JP Thompson SG Deeks JJ Altman DG Measuring inconsistency in meta-analyses BMJ 2003327557ndash60
21 Higgins JPT Deeks JJ Altman DG Special topics in statistics Cochrane handbook for systematic reviews of interventions John Wiley 2008481ndash529
22 Sterne JAC Harbord RM Funnel plots in meta-analysis Stata J 20044127ndash41
23 Harbord RM Harris RJ Sterne JAC Updated tests for small-study effects in meta-analyses Stata J 20099197ndash210
24 Anthenelli RM Morris C Ramey TS Dubrava SJ Tsilkos K Russ C et al Effects of varenicline on smoking cessation in adults with stably treated current or past major depression a randomized trial Ann Intern Med 2013159390ndash400
25 Bolliger CT Issa JS Posadas-Valay R Safwat T Abreu P Correia EA et al Effects of varenicline in adult smokers a multinational 24-week randomized double-blind placebo-controlled study Clin Ther 201133465ndash77
26 Brandon TH Drobes DJ Unrod M Heckman BW Oliver JA Roetzheim RC et al Varenicline effects on craving cue reactivity and smoking reward Psychopharmacology (Berl) 2011218391ndash403
27 Burstein AH Fullerton T Clark DJ Faessel HM Pharmacokinetics safety and tolerability after single and multiple oral doses of varenicline in elderly smokers J Clin Pharmacol 2006461234ndash40
28 Cinciripini PM Robinson JD Karam-Hage M Minnix JA Lam C Versace F et al Effects of varenicline and bupropion sustained-release use plus intensive smoking cessation counseling on prolonged abstinence from smoking and on depression negative affect and other symptoms of nicotine withdrawal JAMA Psychiatry 201370522ndash33
29 Ebbert JO Croghan IT Severson HH Schroeder DR Hays JT A pilot study of the efficacy of varenicline for the treatment of smokeless tobacco users in Midwestern United States Nicotine Tob Res 201113820ndash6
30 Evins AE Cather C Pratt SA Pachas GN Hoeppner SS Goff DC et al Maintenance treatment with varenicline for smoking cessation in patients with schizophrenia and bipolar disorder a randomized clinical trial JAMA 2014311145ndash54
31 Faessel H Ravva P Williams K Pharmacokinetics safety and tolerability of varenicline in healthy adolescent smokers a multicenter randomized double-blind placebo-controlled parallel-group study Clin Ther 200931177ndash89
32 Fagerstrom K Gilljam H Metcalfe M Tonstad S Messig M Stopping smokeless tobacco with varenicline randomised double blind placebo controlled trial BMJ 2010341c6549
33 Fatemi SH Yousefi MK Kneeland RE Liesch SB Folsom TD Thuras PD Antismoking and potential antipsychotic effects of varenicline in subjects with schizophrenia or schizoaffective disorder a double-blind placebo and bupropion-controlled study Schizophr Res 2013146376ndash8
34 Garza D Murphy M Tseng LJ Riordan HJ Chatterjee A A double-blind randomized placebo-controlled pilot study of neuropsychiatric adverse events in abstinent smokers treated with varenicline or placebo Biol Psychiatry 2011691075ndash82
35 Gonzales D Rennard SI Nides M Oncken C Azoulay S Billing CB et al Varenicline an alpha4beta2 nicotinic acetylcholine receptor partial agonist vs sustained-release bupropion and placebo for smoking cessation a randomized controlled trial JAMA 200629647ndash55
36 Hughes JR Rennard SI Fingar JR Talbot SK Callas PW Fagerstrom KO Efficacy of varenicline to prompt quit attempts in smokers not currently trying to quit a randomized placebo-controlled trial Nicotine Tob Res 201113955ndash64
37 Jorenby DE Hays JT Rigotti NA Azoulay S Watsky EJ Williams KE et al Efficacy of varenicline an alpha4beta2 nicotinic acetylcholine receptor partial agonist vs placebo or sustained-release bupropion for smoking cessation a randomized controlled trial JAMA 200629656ndash63
38 Litten RZ Ryan ML Fertig JB Falk DE Johnson B Dunn KE et al A double-blind placebo-controlled trial assessing the efficacy of varenicline tartrate for alcohol dependence J Addict Med 20137277ndash86
39 McClure EA Vandrey RG Johnson MW Stitzer ML Effects of varenicline on abstinence and smoking reward following a programmed lapse Nicotine Tob Res 201315139ndash48
40 McKee SA Harrison EL OrsquoMalley SS Krishnan-Sarin S Shi J Tetrault JM et al Varenicline reduces alcohol self-administration in heavy-drinking smokers Biol Psychiatry 200966185ndash90
41 Meszaros ZS Abdul-Malak Y Dimmock JA Wang D Ajagbe TO Batki SL Varenicline treatment of concurrent alcohol and nicotine dependence in schizophrenia a randomized placebo-controlled pilot trial J Clin Psychopharmacol 201333243ndash7
42 Mitchell JM Teague CH Kayser AS Bartlett SE Fields HL Varenicline decreases alcohol consumption in heavy-drinking smokers Psychopharmacology (Berl) 2012223299ndash306
43 Nakamura M Oshima A Fujimoto Y Maruyama N Ishibashi T Reeves KR Efficacy and tolerability of varenicline an alpha4beta2 nicotinic acetylcholine receptor partial agonist in a 12-week randomized placebo-controlled dose-response study with 40-week follow-up for smoking cessation in Japanese smokers Clin Ther 2007291040ndash56
44 Niaura R Hays JT Jorenby DE Leone FT Pappas JE Reeves KR et al The efficacy and safety of varenicline for smoking cessation using a flexible dosing strategy in adult smokers a randomized controlled trial Curr Med Res Opin 2008241931ndash41
45 Nides M Oncken C Gonzales D Rennard S Watsky EJ Anziano R et al Smoking cessation with varenicline a selective alpha4beta2 nicotinic receptor partial agonist results from a 7-week randomized placebo- and bupropion-controlled trial with 1-year follow-up Arch Intern Med 20061661561ndash8
46 Oncken C Gonzales D Nides M Rennard S Watsky E Billing CB et al Efficacy and safety of the novel selective nicotinic acetylcholine receptor partial agonist varenicline for smoking cessation Arch Intern Med 20061661571ndash7
47 Plebani JG Lynch KG Yu Q Pettinati HM OrsquoBrien CP Kampman KM Results of an initial clinical trial of varenicline for the treatment of cocaine dependence Drug Alcohol Depend 2012121163ndash6
48 Plebani JG Lynch KG Rennert L Pettinati HM OrsquoBrien CP Kampman KM Results from a pilot clinical trial of varenicline for the treatment of alcohol dependence Drug Alcohol Depend 2013133754ndash8
49 Poling J Rounsaville B Gonsai K Severino K Sofuoglu M The safety and efficacy of varenicline in cocaine using smokers maintained on methadone a pilot study Am J Addict 201019401ndash8
50 Rennard S Hughes J Cinciripini PM Kralikova E Raupach T Arteaga C et al A randomized placebo-controlled trial of varenicline for smoking cessation allowing flexible quit dates Nicotine Tob Res 201214343ndash50
51 Rigotti NA Pipe AL Benowitz NL Arteaga C Garza D Tonstad S Efficacy and safety of varenicline for smoking cessation in patients with cardiovascular disease a randomized trial Circulation 2010121221ndash9
52 Shim JC Jung DU Jung SS Seo YS Cho DM Lee JH et al Adjunctive varenicline treatment with antipsychotic medications for cognitive impairments in people with schizophrenia a randomized double-blind placebo-controlled trial Neuropsychopharmacology 201237660ndash8
53 Stein MD Caviness CM Kurth ME Audet D Olson J Anderson BJ Varenicline for smoking cessation among methadone-maintained smokers a randomized clinical trial Drug Alcohol Depend 2013133486ndash93
54 Steinberg MB Randall J Greenhaus S Schmelzer AC Richardson DL Carson JL Tobacco dependence treatment for hospitalized smokers a randomized controlled pilot trial using varenicline Addic Behav 2011361127ndash32
55 Tashkin DP Rennard S Hays JT Ma W Lawrence D Lee TC Effects of varenicline on smoking cessation in patients with mild to moderate COPD a randomized controlled trial Chest 2011139591ndash9
56 Tonnesen P Mikkelsen K Varenicline to stop long-term nicotine replacement use a double-blind randomized placebo-controlled trial Nicotine Tob Res 201315419ndash27
57 Tonstad S Tonnesen P Hajek P Williams KE Billing CB Reeves KR et al Effect of maintenance therapy with varenicline on smoking cessation a randomized controlled trial JAMA 200629664ndash71
58 Tsai ST Cho HJ Cheng HS Kim CH Hsueh KC Billing CB Jr et al A randomized placebo-controlled trial of varenicline a selective alpha4beta2 nicotinic acetylcholine receptor partial agonist as a new therapy for smoking cessation in Asian smokers Clin Ther 2007291027ndash39
59 Wang C Xiao D Chan KPW Pothirat C Garza D Davies S Varenicline for smoking cessation A placebo-controlled randomized study Respirology 200914384ndash92
60 Weiner E Buchholz A Coffay A Liu F McMahon RP Buchanan RW et al Varenicline for smoking cessation in people with schizophrenia a double blind randomized pilot study Schizophr Res 201112994ndash5
RESEARCH
11thethinspbmj | BMJ 2015350h1109 | doi 101136bmjh1109
61 Williams K Reeves K Billing C Pennington A Gong J A double-blind study evaluating the long-term safety of varenicline for smoking cessation Curr Med Res Opin 200723793ndash801
62 Williams JM Anthenelli RM Morris CD Treadow J Thompson JR Yunis C et al A randomized double-blind placebo-controlled study evaluating the safety and efficacy of varenicline for smoking cessation in patients with schizophrenia or schizoaffective disorder J Clin Psychiatry 201273654ndash60
63 Wong J Abrishami A Yang Y Zaki A Friedman Z Selby P et al A perioperative smoking cessation intervention with varenicline a double-blind randomized placebo-controlled trial Anesthesiology 2012117755ndash64
64 Zesiewicz TA Greenstein PE Sullivan KL Wecker L Miller A Jahan I et al A randomized trial of varenicline (Chantix) for the treatment of spinocerebellar ataxia type 3 Neurology 201278545ndash50
65 Zhao Q Schwam E Fullerton T OrsquoGorman M Burstein AH Pharmacokinetics safety and tolerability following multiple oral doses of varenicline under various titration schedules in elderly nonsmokers J Clin Pharmacol 201151492ndash501
66 Chengappa KN Perkins KA Brar JS Schlicht PJ Turkin SR Hetrick ML et al Varenicline for smoking cessation in bipolar disorder a randomized double-blind placebo-controlled study J Clin Psychiatry 201475765ndash72
67 Gonzales D Hajek P Pliamm L Nackaerts K Tseng LJ McRae TD et al Retreatment with varenicline for smoking cessation in smokers who have previously taken varenicline a randomized placebo-controlled trial Clin Pharmacol Ther 201496390ndash6
68 Kishi T Iwata N Varenicline for smoking cessation in people with schizophrenia systematic review and meta-analysis Eur Arch Psychiatry Clin Neurosci 2014 Oct 5 [Epub ahead of print]
69 Hong LE Thaker GK McMahon RP Summerfelt A Rachbeisel J Fuller RL et al Effects of moderate-dose treatment with varenicline on neurobiological and cognitive biomarkers in smokers and nonsmokers with schizophrenia or schizoaffective disorder Arch Gen Psychiatry 2011681195ndash206
70 Huang Y Li W Yang L Jiang Y Wu Y Long-term efficacy and safety of varenicline for smoking cessation a systematic review and
meta-analysis of randomized controlled trials J Public Health 201220355ndash65
71 Singh S Loke YK Spangler JG Furberg CD Risk of serious adverse cardiovascular events associated with varenicline a systematic review and meta-analysis CMAJ 20111831359ndash66
72 Prochaska JJ Hilton JF Risk of cardiovascular serious adverse events associated with varenicline use for tobacco cessation systematic review and meta-analysis BMJ 2012344e2856
73 Mocking RJ Patrick Pflanz C Pringle A Parsons E McTavish SF Cowen PJ et al Effects of short-term varenicline administration on emotional and cognitive processing in healthy non-smoking adults a randomized double-blind study Neuropsychopharmacology 201338476ndash84
74 Taylor G McNeill A Girling A Farley A Lindson-Hawley N Aveyard P Change in mental health after smoking cessation systematic review and meta-analysis BMJ 2014348g1151
75 Smoking cessation services in primary care pharmacies local authorities and workplaces particularly for manual working groups pregnant women and hard to reach communities NICE public health guidance 10 National Institute for Health and Care Excellence 2008
copy BMJ Publishing Group Ltd 2015
Appendix 1 Search strategy to identify relevant articles in MedlineAppendix 2 Further characteristics of included ran-domised controlled trialsAppendix 3 Forest plots for secondary outcomesAppendix 4 Subgroup analysesAppendix 5 Funnel plots Appendix 6 Summary of Peto odds ratios risk differ-ences and 95 confidence intervals for neuropsychiat-ric events
RESEARCH
8 doi 101136bmjh1109 | BMJ 2015350h1109 | thethinspbmj
Regulatory Activities (MedDRA wwwmeddraorg) All of the industry sponsored trials coded adverse events using MedDRA Fourthly we excluded two studies69 73 from the review as the maximum dose of varenicline used in these studies was only 1 mg once a daymdashthat is half of the rec-ommended maximum dose Hong and colleagues exam-ined varenicline treatment in 20 smokers and 15 non-smokers with schizophrenia or schizoaffective disor-der and found no evidence that varenicline worsened psychiatric symptoms in these patients69 Mocking and colleagues studied the effects of varenicline on emotional and cognitive processing in 21 healthy adult non-smokers and concluded that it did not cause problems in emo-tional processing or impulsivity providing less support for a possible depressogenic effect of varenicline73 Fur-thermore a secondary analysis which included all doses of varenicline in the original trials and these two excluded randomised controlled trials produced similar findings to our main analysis (see appendix 6)
We tried to minimise reporting bias by including all events (such as deaths) reported regardless of whether or
not we considered them to be related to treatment It is still possible however that reporting bias could have occurred as for certain trials where the corresponding authors did not respond to our requests for additional information we could not determine whether a lack of reporting of deaths in the published paper was synonymous with no deaths It was difficult to interpret the funnel plots to assess whether publication bias might be present as most trials were efficacy trials and were not performed solely to deter-mine the incidence of psychiatric adverse events
Additionally smoking cessation has been shown to have a positive impact on mental health outcomes with a reduction in depression and anxiety compared with those who continue to smoke74 Patients prescribed varenicline were reported to have an approximately threefold increased chance of quitting smoking com-pared with those given placebo (odds ratio 288 95 confidence interval 240 to 347)4 this could explain the reduction in anxiety observed in this meta-analysis
Lastly half of the trials were sponsored by Pfizer the manufacturers of varenicline Although previous research with nicotine replacement therapy has shown that industry sponsored trials were more likely than other trials to report outcomes that were favourable to the study sponsor14 we did not find any evidence for differences in depression and suicidal ideation for industry versus non industry sponsored trials (P=0386 and P=0380 respectively for interaction) In addition all of the industry sponsored trials were assessed over-all as having a low risk of bias
Conclusions and clinical implicationsBased on this comprehensive systematic review of pub-lished randomised controlled trials there is no evi-dence of an increased risk of depression suicidal behaviour (that is suicide or attempted suicide sui-cidal ideation) and death from any cause associated with treatment with varenicline Varenicline users however have an increased risk of abnormal dreams insomnia and sleep disturbances which are consistent with findings from other studies and previously docu-mented commonly reported side effects of varenicline (wwwchantixcom) We reported our findings using two summary statistics (a relative measure and an abso-lute measure) and observed consistency with both methods This meta-analysis adds to previous research (observational and experimental) that found no evi-dence for increased suicidal behaviour or depression with varenicline the most effective drug for smoking cessation4 The dangers of smoking are well docu-mented and the health benefits of stopping smoking are well known Our analysis suggests that the benefits of varenicline for smoking cessation outweigh the as yet unproved risks of suicidal behaviour In the UK vareni-cline is recommended alongside bupropion and nico-tine replacement therapy as first line treatment for smoking cessation75 Therefore the reduction in vareni-cline prescribing in the UK should be as much a cause for concern to clinicians regulatory agencies and policy makers as the unfounded fears regarding vareni-clinersquos association with suicidal behaviour
Nides 2006 Tonstad 2006 Jorenby 2006 Onken 2006 Gonzales 2006 Williams 2007 Tsai 2007 Niaura 2008 Rigotti 2010 Fagerstrom 2010 Hughes 2011 Garza 2011 Ebbert 2011 Steinberg 2011 Bolliger 2011 Tashkin 2011 Williams 2012 Rennard 2012 Wong 2012 Zesiewicz 2012 McClure 2013 Stein 2013 Litten 2013 Cinciripini 2013 Meszaros 2013 Anthenelli 2013 Evins 2014 Chengappa 2014 Gonzales 2014 Faessel 2009 Brandon 2011Overall I2=0 P=0631
193 (020 to 1870)088 (044 to 178)
419 (095 to 1855)070 (018 to 267)057 (017 to 186)148 (051 to 428)050 (005 to 488)148 (025 to 864)164 (041 to 661)043 (010 to 191)053 (005 to 514)
100 (006 to 1619)014 (000 to 682)097 (013 to 719)102 (030 to 340)122 (037 to 402)066 (013 to 326)020 (004 to 090)089 (089 to 642)012 (012 to 208)078 (078 to 185)066 (066 to 185)123 (123 to 378)051 (020 to 130)
100 (005 to 1991)140 (067 to 292)
118 (007 to 1932)381 (099 to 1467)234 (053 to 1040)
ExcludedExcluded
096 (075 to 122)
1123345123311lt1144232186571
1113300
100
0001 001 01 1 10 100 1000
Study
Favourstreatment
Favoursplacebo
Odds ratio(95 CI)
Odds ratio(95 CI)
Weight()
212515602634362534349
1225111263157535322131107155038240
83906248484
44862151
091741
1711179768615
17256140831
5249014046
1635356
Treatment
112317604134041217344412621242155335052182111155138239
41985251343
51652135
292042733
610114106
1513269
147229
224507
0541394487
ControlNo of eventstotal
fig 4 | forest plot of risk of depression events (Peto odds ratio) associated with varenicline use in 31 placebo controlled randomised trials
RESEARCH
9thethinspbmj | BMJ 2015350h1109 | doi 101136bmjh1109
We are grateful to the corresponding authors of the trials and Cristina Russ of Pfizer (for the Pfizer sponsored trials) for their support with providing access to the data on psychiatric adverse events and death used in this studyContributors KHT DG and RMM conceived the study KHT conducted the literature search KHT and DWK screened the abstracts with assistance from DG KHT DG and RMM were responsible for data extraction and the risk of bias assessment KHT did the statistical analysis with support from JPH KHT wrote the paper with contributions from all authors All authors have approved the final draft of the manuscript KHT is study guarantor had full access to all of the data (including statistical reports and tables) and can take responsibility for the integrity of the data and the accuracy of the data analysisFunding KHT is currently funded by a clinical lectureship from the National Institute for Health Research Part of this work was undertaken while KHT was on a National Institute for Health Research doctoral research fellowship (DRF-2010-03-138) DWK is funded by a Wellcome Trust four year studentship (WT099874MA) DG is an NIHR senior investigator The views expressed in this publication are those of the authors and not necessarily those of the NHS the National Institute for Health Research or the Department of HealthCompeting interests All authors have completed the Unified Competing Interest form at wwwicmjeorgcoi_disclosurepdf (available on request from the corresponding author) and declare RMM had specified relationship with the MHRA in the past (was a member of the MHRArsquos Independent Scientific Advisory Committee for CPRD research and received expenses and a small fee for meeting attendance and preparation for meetings) DG had specified relationship with the MHRA in the past (was a member of the MHRArsquos Pharmacovigilance Expert Advisory Group and received travel expenses and a small fee for meeting attendance and preparation for meetings)Ethics approval Not requiredData sharing No additional data are availableTransparency declaration KHT affirms that this manuscript is an honest accurate and transparent account of the study being reported that no important aspects of the study have been omitted and that any discrepancies from the study as planned (and if relevant registered) have been explainedThis is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 40) license which permits others to distribute remix adapt build upon this work non-commercially and license their derivative works on different terms provided the original work is properly cited and the use is non-commercial See httpcreativecommonsorglicensesby-nc401 Peto R Darby S Deo H Silcocks P Whitley E Doll R Smoking
smoking cessation and lung cancer in the UK since 1950 combination of national statistics with two case-control studies BMJ 2000321323ndash9
2 Jha P Peto R Global effects of smoking of quitting and of taxing tobacco N Engl J Med 201437060ndash8
3 Allender S Balakrishnan R Scarborough P Webster P Rayner M The burden of smoking-related ill health in the UK Tob Control 200918262ndash67
4 Cahill K Stevens S Perera R Lancaster T Pharmacological interventions for smoking cessation an overview and network meta-analysis Cochrane Database Syst Rev 20135CD009329
5 Medicines and Healthcare Products Regulatory Agency Varenicline adverse psychiatric reactions including depression Drug Safety Update 200822ndash3
6 US Food and Drug Administration Information for healthcare professionals varenicline (marketed as Chantix) and bupropion (marketed as Zyban Wellbutrin and generics) FDA Drug Safety Newsletter 2009
7 Gunnell D Irvine D Wise L Davies C Martin RM Varenicline and suicidal behaviour a cohort study based on data from the General Practice Research Database BMJ 2009339b3805
8 Meyer TE Taylor LG Xie S Graham DJ Mosholder AD Williams JR et al Neuropsychiatric events in varenicline and nicotine replacement patch users in the Military Health System Addiction 2013108203ndash10
9 Thomas KH Martin RM Davies N Metcalfe C Windmeijer F Gunnell D Smoking cessation treatment and the risk of depression suicide and self-harm in the Clinical Practice Research Datalink prospective cohort study BMJ 2013347f5704
10 Gibbons RD Mann JJ Varenicline smoking cessation and neuropsychiatric adverse events Am J Psychiatry 20131701460ndash7
11 Walker AM Confounding by indication Epidemiology 19967335ndash612 Miller M Hemenway D Bell NS Yore MM Amoroso PJ Cigarette
smoking and suicide a prospective study of 300000 male active-duty Army soldiers Am J Epidemiol 20001511060ndash3
Nides 2006 Tonstad 2006 Jorenby 2006 Onken 2006 Gonzales 2006 Williams 2007 Tsai 2007 Niaura 2008 Faessel 2009 Rigotti 2010 Fagerstrom 2010 Hughes 2011 Garza 2011 Brandon 2011 Ebbert 2011 Steinberg 2011 Bolliger 2011 Tashkin 2011 Williams 2012 Rennard 2012 Wong 2012 Zesiewicz 2012 McClure 2013 Stein 2013 Litten 2013 Cinciripini 2013 Meszaros 2013 Anthenelli 2013 Evins 2014 Chengappa 2014 Gonzales 2014Overall I2=0 P=0783
001 (-002 to 003)-000 (-002 to 001)001 (-000 to 003)-001 (-005 to 003)-001 (-003 to 001)-002 (-002 to 006)001 (-004 to 002)001 (-002 to 003)000 (-019 to 019)001 (-001 to 002)-001 (-004 to 001)-001 (-004 to 002)000 (-005 to 005)000 (-004 to 004)-003 (-010 to 004)-000 (-010 to 010)000 (-002 to 002)000 (-002 to 003)-002 (-011 to 007)-002 (-005 to 001)-000 (-003 to 003)-022 (-052 to 008)-006 (-027 to 015)-006 (-021 to 010)001 (-006 to 008)-006 (-015 to 002)000 (-050 to 050)002 (-002 to 006)000 (-006 to 007)019 (001 to 037)001 (-001 to 003)-000 (-001 to 001)
313737433lt1752111165153lt11122lt16115
100
-05 0 05
Study
Favourstreatment
Favoursplacebo
Odds ratio(95 CI)
Odds ratio(95 CI)
Weight()
212515602634362534349
1225111263157014
535322131107155046038240
83906248484
44862151
091741
1711179768615
17256140831
52491635356
Treatment
112317604134041217344412621242155
07335052182111155054138239
41985251343
51652135
292042733
610114106
1513269
147229
22451394487
ControlNo of eventstotal
fig 5 | forest plot of risk of depression events (mantel-Haenszel risk difference) associated with varenicline use in 31 placebo controlled randomised trials
table 5 | Comparison of Peto fixed effects and random effects odds ratios (Or) for insomnia sleep disorders and abnormal dreams in people treated with varenicline
neuropsychiatric adverse event
no of eventsno treatedOdds ratio (95 Ci)
test for heterogeneity ()varenicline group Placebo group
insomniaPeto OR 6795621 3794762 156 (136 to 178) 0Fixed effects OR 6795621 3794762 156 (135 to 179) 0Random effects OR 6795621 3794762 156 (135 to 179) 0sleep disordersPeto OR 2115081 1234284 163 (129 to 207) 0Fixed effects OR 2115081 1234284 157 (122 to 203) 0Random effects OR 2115081 1234284 157 (122 to 203) 0abnormal dreams Peto OR 6035606 2244741 238 (205 to 277) 223Fixed effects OR 6035606 2244741 237 (199 to 282) 316Random effects OR 6035606 2244741 236 (187 to 298) 316All Plt0001
RESEARCH
10 doi 101136bmjh1109 | BMJ 2015350h1109 | thethinspbmj
13 Miller M Hemenway D Rimm E Cigarettes and suicide a prospective study of 50000 men Am J Public Health 200090768ndash73
14 Etter JF Burri M Stapleton J The impact of pharmaceutical company funding on results of randomized trials of nicotine replacement therapy for smoking cessation a meta-analysis Addiction 2007102815ndash22
15 Prescribing and Primary Care team Health and Social Care Information Centre Prescription cost analysis England 2013 Health and Social Care Information Centre 2014
16 Cahill K Stead LF Lancaster T Nicotine receptor partial agonists for smoking cessation Cochrane Database Syst Rev 20124CD006103
17 Higgins JPT Altman DG Assessing risk of bias in included studies Cochrane handbook for systematic reviews of interventions John Wiley 2008187ndash241
18 Harris R Bradburn M Deeks J Harbord R Altman D Sterne J metan fixed- and random-effects meta-analysis Stata J 200883ndash28
19 Bradburn MJ Deeks JJ Berlin JA Russell Localio A Much ado about nothing a comparison of the performance of meta-analytical methods with rare events Stat Med 20072653ndash77
20 Higgins JP Thompson SG Deeks JJ Altman DG Measuring inconsistency in meta-analyses BMJ 2003327557ndash60
21 Higgins JPT Deeks JJ Altman DG Special topics in statistics Cochrane handbook for systematic reviews of interventions John Wiley 2008481ndash529
22 Sterne JAC Harbord RM Funnel plots in meta-analysis Stata J 20044127ndash41
23 Harbord RM Harris RJ Sterne JAC Updated tests for small-study effects in meta-analyses Stata J 20099197ndash210
24 Anthenelli RM Morris C Ramey TS Dubrava SJ Tsilkos K Russ C et al Effects of varenicline on smoking cessation in adults with stably treated current or past major depression a randomized trial Ann Intern Med 2013159390ndash400
25 Bolliger CT Issa JS Posadas-Valay R Safwat T Abreu P Correia EA et al Effects of varenicline in adult smokers a multinational 24-week randomized double-blind placebo-controlled study Clin Ther 201133465ndash77
26 Brandon TH Drobes DJ Unrod M Heckman BW Oliver JA Roetzheim RC et al Varenicline effects on craving cue reactivity and smoking reward Psychopharmacology (Berl) 2011218391ndash403
27 Burstein AH Fullerton T Clark DJ Faessel HM Pharmacokinetics safety and tolerability after single and multiple oral doses of varenicline in elderly smokers J Clin Pharmacol 2006461234ndash40
28 Cinciripini PM Robinson JD Karam-Hage M Minnix JA Lam C Versace F et al Effects of varenicline and bupropion sustained-release use plus intensive smoking cessation counseling on prolonged abstinence from smoking and on depression negative affect and other symptoms of nicotine withdrawal JAMA Psychiatry 201370522ndash33
29 Ebbert JO Croghan IT Severson HH Schroeder DR Hays JT A pilot study of the efficacy of varenicline for the treatment of smokeless tobacco users in Midwestern United States Nicotine Tob Res 201113820ndash6
30 Evins AE Cather C Pratt SA Pachas GN Hoeppner SS Goff DC et al Maintenance treatment with varenicline for smoking cessation in patients with schizophrenia and bipolar disorder a randomized clinical trial JAMA 2014311145ndash54
31 Faessel H Ravva P Williams K Pharmacokinetics safety and tolerability of varenicline in healthy adolescent smokers a multicenter randomized double-blind placebo-controlled parallel-group study Clin Ther 200931177ndash89
32 Fagerstrom K Gilljam H Metcalfe M Tonstad S Messig M Stopping smokeless tobacco with varenicline randomised double blind placebo controlled trial BMJ 2010341c6549
33 Fatemi SH Yousefi MK Kneeland RE Liesch SB Folsom TD Thuras PD Antismoking and potential antipsychotic effects of varenicline in subjects with schizophrenia or schizoaffective disorder a double-blind placebo and bupropion-controlled study Schizophr Res 2013146376ndash8
34 Garza D Murphy M Tseng LJ Riordan HJ Chatterjee A A double-blind randomized placebo-controlled pilot study of neuropsychiatric adverse events in abstinent smokers treated with varenicline or placebo Biol Psychiatry 2011691075ndash82
35 Gonzales D Rennard SI Nides M Oncken C Azoulay S Billing CB et al Varenicline an alpha4beta2 nicotinic acetylcholine receptor partial agonist vs sustained-release bupropion and placebo for smoking cessation a randomized controlled trial JAMA 200629647ndash55
36 Hughes JR Rennard SI Fingar JR Talbot SK Callas PW Fagerstrom KO Efficacy of varenicline to prompt quit attempts in smokers not currently trying to quit a randomized placebo-controlled trial Nicotine Tob Res 201113955ndash64
37 Jorenby DE Hays JT Rigotti NA Azoulay S Watsky EJ Williams KE et al Efficacy of varenicline an alpha4beta2 nicotinic acetylcholine receptor partial agonist vs placebo or sustained-release bupropion for smoking cessation a randomized controlled trial JAMA 200629656ndash63
38 Litten RZ Ryan ML Fertig JB Falk DE Johnson B Dunn KE et al A double-blind placebo-controlled trial assessing the efficacy of varenicline tartrate for alcohol dependence J Addict Med 20137277ndash86
39 McClure EA Vandrey RG Johnson MW Stitzer ML Effects of varenicline on abstinence and smoking reward following a programmed lapse Nicotine Tob Res 201315139ndash48
40 McKee SA Harrison EL OrsquoMalley SS Krishnan-Sarin S Shi J Tetrault JM et al Varenicline reduces alcohol self-administration in heavy-drinking smokers Biol Psychiatry 200966185ndash90
41 Meszaros ZS Abdul-Malak Y Dimmock JA Wang D Ajagbe TO Batki SL Varenicline treatment of concurrent alcohol and nicotine dependence in schizophrenia a randomized placebo-controlled pilot trial J Clin Psychopharmacol 201333243ndash7
42 Mitchell JM Teague CH Kayser AS Bartlett SE Fields HL Varenicline decreases alcohol consumption in heavy-drinking smokers Psychopharmacology (Berl) 2012223299ndash306
43 Nakamura M Oshima A Fujimoto Y Maruyama N Ishibashi T Reeves KR Efficacy and tolerability of varenicline an alpha4beta2 nicotinic acetylcholine receptor partial agonist in a 12-week randomized placebo-controlled dose-response study with 40-week follow-up for smoking cessation in Japanese smokers Clin Ther 2007291040ndash56
44 Niaura R Hays JT Jorenby DE Leone FT Pappas JE Reeves KR et al The efficacy and safety of varenicline for smoking cessation using a flexible dosing strategy in adult smokers a randomized controlled trial Curr Med Res Opin 2008241931ndash41
45 Nides M Oncken C Gonzales D Rennard S Watsky EJ Anziano R et al Smoking cessation with varenicline a selective alpha4beta2 nicotinic receptor partial agonist results from a 7-week randomized placebo- and bupropion-controlled trial with 1-year follow-up Arch Intern Med 20061661561ndash8
46 Oncken C Gonzales D Nides M Rennard S Watsky E Billing CB et al Efficacy and safety of the novel selective nicotinic acetylcholine receptor partial agonist varenicline for smoking cessation Arch Intern Med 20061661571ndash7
47 Plebani JG Lynch KG Yu Q Pettinati HM OrsquoBrien CP Kampman KM Results of an initial clinical trial of varenicline for the treatment of cocaine dependence Drug Alcohol Depend 2012121163ndash6
48 Plebani JG Lynch KG Rennert L Pettinati HM OrsquoBrien CP Kampman KM Results from a pilot clinical trial of varenicline for the treatment of alcohol dependence Drug Alcohol Depend 2013133754ndash8
49 Poling J Rounsaville B Gonsai K Severino K Sofuoglu M The safety and efficacy of varenicline in cocaine using smokers maintained on methadone a pilot study Am J Addict 201019401ndash8
50 Rennard S Hughes J Cinciripini PM Kralikova E Raupach T Arteaga C et al A randomized placebo-controlled trial of varenicline for smoking cessation allowing flexible quit dates Nicotine Tob Res 201214343ndash50
51 Rigotti NA Pipe AL Benowitz NL Arteaga C Garza D Tonstad S Efficacy and safety of varenicline for smoking cessation in patients with cardiovascular disease a randomized trial Circulation 2010121221ndash9
52 Shim JC Jung DU Jung SS Seo YS Cho DM Lee JH et al Adjunctive varenicline treatment with antipsychotic medications for cognitive impairments in people with schizophrenia a randomized double-blind placebo-controlled trial Neuropsychopharmacology 201237660ndash8
53 Stein MD Caviness CM Kurth ME Audet D Olson J Anderson BJ Varenicline for smoking cessation among methadone-maintained smokers a randomized clinical trial Drug Alcohol Depend 2013133486ndash93
54 Steinberg MB Randall J Greenhaus S Schmelzer AC Richardson DL Carson JL Tobacco dependence treatment for hospitalized smokers a randomized controlled pilot trial using varenicline Addic Behav 2011361127ndash32
55 Tashkin DP Rennard S Hays JT Ma W Lawrence D Lee TC Effects of varenicline on smoking cessation in patients with mild to moderate COPD a randomized controlled trial Chest 2011139591ndash9
56 Tonnesen P Mikkelsen K Varenicline to stop long-term nicotine replacement use a double-blind randomized placebo-controlled trial Nicotine Tob Res 201315419ndash27
57 Tonstad S Tonnesen P Hajek P Williams KE Billing CB Reeves KR et al Effect of maintenance therapy with varenicline on smoking cessation a randomized controlled trial JAMA 200629664ndash71
58 Tsai ST Cho HJ Cheng HS Kim CH Hsueh KC Billing CB Jr et al A randomized placebo-controlled trial of varenicline a selective alpha4beta2 nicotinic acetylcholine receptor partial agonist as a new therapy for smoking cessation in Asian smokers Clin Ther 2007291027ndash39
59 Wang C Xiao D Chan KPW Pothirat C Garza D Davies S Varenicline for smoking cessation A placebo-controlled randomized study Respirology 200914384ndash92
60 Weiner E Buchholz A Coffay A Liu F McMahon RP Buchanan RW et al Varenicline for smoking cessation in people with schizophrenia a double blind randomized pilot study Schizophr Res 201112994ndash5
RESEARCH
11thethinspbmj | BMJ 2015350h1109 | doi 101136bmjh1109
61 Williams K Reeves K Billing C Pennington A Gong J A double-blind study evaluating the long-term safety of varenicline for smoking cessation Curr Med Res Opin 200723793ndash801
62 Williams JM Anthenelli RM Morris CD Treadow J Thompson JR Yunis C et al A randomized double-blind placebo-controlled study evaluating the safety and efficacy of varenicline for smoking cessation in patients with schizophrenia or schizoaffective disorder J Clin Psychiatry 201273654ndash60
63 Wong J Abrishami A Yang Y Zaki A Friedman Z Selby P et al A perioperative smoking cessation intervention with varenicline a double-blind randomized placebo-controlled trial Anesthesiology 2012117755ndash64
64 Zesiewicz TA Greenstein PE Sullivan KL Wecker L Miller A Jahan I et al A randomized trial of varenicline (Chantix) for the treatment of spinocerebellar ataxia type 3 Neurology 201278545ndash50
65 Zhao Q Schwam E Fullerton T OrsquoGorman M Burstein AH Pharmacokinetics safety and tolerability following multiple oral doses of varenicline under various titration schedules in elderly nonsmokers J Clin Pharmacol 201151492ndash501
66 Chengappa KN Perkins KA Brar JS Schlicht PJ Turkin SR Hetrick ML et al Varenicline for smoking cessation in bipolar disorder a randomized double-blind placebo-controlled study J Clin Psychiatry 201475765ndash72
67 Gonzales D Hajek P Pliamm L Nackaerts K Tseng LJ McRae TD et al Retreatment with varenicline for smoking cessation in smokers who have previously taken varenicline a randomized placebo-controlled trial Clin Pharmacol Ther 201496390ndash6
68 Kishi T Iwata N Varenicline for smoking cessation in people with schizophrenia systematic review and meta-analysis Eur Arch Psychiatry Clin Neurosci 2014 Oct 5 [Epub ahead of print]
69 Hong LE Thaker GK McMahon RP Summerfelt A Rachbeisel J Fuller RL et al Effects of moderate-dose treatment with varenicline on neurobiological and cognitive biomarkers in smokers and nonsmokers with schizophrenia or schizoaffective disorder Arch Gen Psychiatry 2011681195ndash206
70 Huang Y Li W Yang L Jiang Y Wu Y Long-term efficacy and safety of varenicline for smoking cessation a systematic review and
meta-analysis of randomized controlled trials J Public Health 201220355ndash65
71 Singh S Loke YK Spangler JG Furberg CD Risk of serious adverse cardiovascular events associated with varenicline a systematic review and meta-analysis CMAJ 20111831359ndash66
72 Prochaska JJ Hilton JF Risk of cardiovascular serious adverse events associated with varenicline use for tobacco cessation systematic review and meta-analysis BMJ 2012344e2856
73 Mocking RJ Patrick Pflanz C Pringle A Parsons E McTavish SF Cowen PJ et al Effects of short-term varenicline administration on emotional and cognitive processing in healthy non-smoking adults a randomized double-blind study Neuropsychopharmacology 201338476ndash84
74 Taylor G McNeill A Girling A Farley A Lindson-Hawley N Aveyard P Change in mental health after smoking cessation systematic review and meta-analysis BMJ 2014348g1151
75 Smoking cessation services in primary care pharmacies local authorities and workplaces particularly for manual working groups pregnant women and hard to reach communities NICE public health guidance 10 National Institute for Health and Care Excellence 2008
copy BMJ Publishing Group Ltd 2015
Appendix 1 Search strategy to identify relevant articles in MedlineAppendix 2 Further characteristics of included ran-domised controlled trialsAppendix 3 Forest plots for secondary outcomesAppendix 4 Subgroup analysesAppendix 5 Funnel plots Appendix 6 Summary of Peto odds ratios risk differ-ences and 95 confidence intervals for neuropsychiat-ric events
RESEARCH
9thethinspbmj | BMJ 2015350h1109 | doi 101136bmjh1109
We are grateful to the corresponding authors of the trials and Cristina Russ of Pfizer (for the Pfizer sponsored trials) for their support with providing access to the data on psychiatric adverse events and death used in this studyContributors KHT DG and RMM conceived the study KHT conducted the literature search KHT and DWK screened the abstracts with assistance from DG KHT DG and RMM were responsible for data extraction and the risk of bias assessment KHT did the statistical analysis with support from JPH KHT wrote the paper with contributions from all authors All authors have approved the final draft of the manuscript KHT is study guarantor had full access to all of the data (including statistical reports and tables) and can take responsibility for the integrity of the data and the accuracy of the data analysisFunding KHT is currently funded by a clinical lectureship from the National Institute for Health Research Part of this work was undertaken while KHT was on a National Institute for Health Research doctoral research fellowship (DRF-2010-03-138) DWK is funded by a Wellcome Trust four year studentship (WT099874MA) DG is an NIHR senior investigator The views expressed in this publication are those of the authors and not necessarily those of the NHS the National Institute for Health Research or the Department of HealthCompeting interests All authors have completed the Unified Competing Interest form at wwwicmjeorgcoi_disclosurepdf (available on request from the corresponding author) and declare RMM had specified relationship with the MHRA in the past (was a member of the MHRArsquos Independent Scientific Advisory Committee for CPRD research and received expenses and a small fee for meeting attendance and preparation for meetings) DG had specified relationship with the MHRA in the past (was a member of the MHRArsquos Pharmacovigilance Expert Advisory Group and received travel expenses and a small fee for meeting attendance and preparation for meetings)Ethics approval Not requiredData sharing No additional data are availableTransparency declaration KHT affirms that this manuscript is an honest accurate and transparent account of the study being reported that no important aspects of the study have been omitted and that any discrepancies from the study as planned (and if relevant registered) have been explainedThis is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 40) license which permits others to distribute remix adapt build upon this work non-commercially and license their derivative works on different terms provided the original work is properly cited and the use is non-commercial See httpcreativecommonsorglicensesby-nc401 Peto R Darby S Deo H Silcocks P Whitley E Doll R Smoking
smoking cessation and lung cancer in the UK since 1950 combination of national statistics with two case-control studies BMJ 2000321323ndash9
2 Jha P Peto R Global effects of smoking of quitting and of taxing tobacco N Engl J Med 201437060ndash8
3 Allender S Balakrishnan R Scarborough P Webster P Rayner M The burden of smoking-related ill health in the UK Tob Control 200918262ndash67
4 Cahill K Stevens S Perera R Lancaster T Pharmacological interventions for smoking cessation an overview and network meta-analysis Cochrane Database Syst Rev 20135CD009329
5 Medicines and Healthcare Products Regulatory Agency Varenicline adverse psychiatric reactions including depression Drug Safety Update 200822ndash3
6 US Food and Drug Administration Information for healthcare professionals varenicline (marketed as Chantix) and bupropion (marketed as Zyban Wellbutrin and generics) FDA Drug Safety Newsletter 2009
7 Gunnell D Irvine D Wise L Davies C Martin RM Varenicline and suicidal behaviour a cohort study based on data from the General Practice Research Database BMJ 2009339b3805
8 Meyer TE Taylor LG Xie S Graham DJ Mosholder AD Williams JR et al Neuropsychiatric events in varenicline and nicotine replacement patch users in the Military Health System Addiction 2013108203ndash10
9 Thomas KH Martin RM Davies N Metcalfe C Windmeijer F Gunnell D Smoking cessation treatment and the risk of depression suicide and self-harm in the Clinical Practice Research Datalink prospective cohort study BMJ 2013347f5704
10 Gibbons RD Mann JJ Varenicline smoking cessation and neuropsychiatric adverse events Am J Psychiatry 20131701460ndash7
11 Walker AM Confounding by indication Epidemiology 19967335ndash612 Miller M Hemenway D Bell NS Yore MM Amoroso PJ Cigarette
smoking and suicide a prospective study of 300000 male active-duty Army soldiers Am J Epidemiol 20001511060ndash3
Nides 2006 Tonstad 2006 Jorenby 2006 Onken 2006 Gonzales 2006 Williams 2007 Tsai 2007 Niaura 2008 Faessel 2009 Rigotti 2010 Fagerstrom 2010 Hughes 2011 Garza 2011 Brandon 2011 Ebbert 2011 Steinberg 2011 Bolliger 2011 Tashkin 2011 Williams 2012 Rennard 2012 Wong 2012 Zesiewicz 2012 McClure 2013 Stein 2013 Litten 2013 Cinciripini 2013 Meszaros 2013 Anthenelli 2013 Evins 2014 Chengappa 2014 Gonzales 2014Overall I2=0 P=0783
001 (-002 to 003)-000 (-002 to 001)001 (-000 to 003)-001 (-005 to 003)-001 (-003 to 001)-002 (-002 to 006)001 (-004 to 002)001 (-002 to 003)000 (-019 to 019)001 (-001 to 002)-001 (-004 to 001)-001 (-004 to 002)000 (-005 to 005)000 (-004 to 004)-003 (-010 to 004)-000 (-010 to 010)000 (-002 to 002)000 (-002 to 003)-002 (-011 to 007)-002 (-005 to 001)-000 (-003 to 003)-022 (-052 to 008)-006 (-027 to 015)-006 (-021 to 010)001 (-006 to 008)-006 (-015 to 002)000 (-050 to 050)002 (-002 to 006)000 (-006 to 007)019 (001 to 037)001 (-001 to 003)-000 (-001 to 001)
313737433lt1752111165153lt11122lt16115
100
-05 0 05
Study
Favourstreatment
Favoursplacebo
Odds ratio(95 CI)
Odds ratio(95 CI)
Weight()
212515602634362534349
1225111263157014
535322131107155046038240
83906248484
44862151
091741
1711179768615
17256140831
52491635356
Treatment
112317604134041217344412621242155
07335052182111155054138239
41985251343
51652135
292042733
610114106
1513269
147229
22451394487
ControlNo of eventstotal
fig 5 | forest plot of risk of depression events (mantel-Haenszel risk difference) associated with varenicline use in 31 placebo controlled randomised trials
table 5 | Comparison of Peto fixed effects and random effects odds ratios (Or) for insomnia sleep disorders and abnormal dreams in people treated with varenicline
neuropsychiatric adverse event
no of eventsno treatedOdds ratio (95 Ci)
test for heterogeneity ()varenicline group Placebo group
insomniaPeto OR 6795621 3794762 156 (136 to 178) 0Fixed effects OR 6795621 3794762 156 (135 to 179) 0Random effects OR 6795621 3794762 156 (135 to 179) 0sleep disordersPeto OR 2115081 1234284 163 (129 to 207) 0Fixed effects OR 2115081 1234284 157 (122 to 203) 0Random effects OR 2115081 1234284 157 (122 to 203) 0abnormal dreams Peto OR 6035606 2244741 238 (205 to 277) 223Fixed effects OR 6035606 2244741 237 (199 to 282) 316Random effects OR 6035606 2244741 236 (187 to 298) 316All Plt0001
RESEARCH
10 doi 101136bmjh1109 | BMJ 2015350h1109 | thethinspbmj
13 Miller M Hemenway D Rimm E Cigarettes and suicide a prospective study of 50000 men Am J Public Health 200090768ndash73
14 Etter JF Burri M Stapleton J The impact of pharmaceutical company funding on results of randomized trials of nicotine replacement therapy for smoking cessation a meta-analysis Addiction 2007102815ndash22
15 Prescribing and Primary Care team Health and Social Care Information Centre Prescription cost analysis England 2013 Health and Social Care Information Centre 2014
16 Cahill K Stead LF Lancaster T Nicotine receptor partial agonists for smoking cessation Cochrane Database Syst Rev 20124CD006103
17 Higgins JPT Altman DG Assessing risk of bias in included studies Cochrane handbook for systematic reviews of interventions John Wiley 2008187ndash241
18 Harris R Bradburn M Deeks J Harbord R Altman D Sterne J metan fixed- and random-effects meta-analysis Stata J 200883ndash28
19 Bradburn MJ Deeks JJ Berlin JA Russell Localio A Much ado about nothing a comparison of the performance of meta-analytical methods with rare events Stat Med 20072653ndash77
20 Higgins JP Thompson SG Deeks JJ Altman DG Measuring inconsistency in meta-analyses BMJ 2003327557ndash60
21 Higgins JPT Deeks JJ Altman DG Special topics in statistics Cochrane handbook for systematic reviews of interventions John Wiley 2008481ndash529
22 Sterne JAC Harbord RM Funnel plots in meta-analysis Stata J 20044127ndash41
23 Harbord RM Harris RJ Sterne JAC Updated tests for small-study effects in meta-analyses Stata J 20099197ndash210
24 Anthenelli RM Morris C Ramey TS Dubrava SJ Tsilkos K Russ C et al Effects of varenicline on smoking cessation in adults with stably treated current or past major depression a randomized trial Ann Intern Med 2013159390ndash400
25 Bolliger CT Issa JS Posadas-Valay R Safwat T Abreu P Correia EA et al Effects of varenicline in adult smokers a multinational 24-week randomized double-blind placebo-controlled study Clin Ther 201133465ndash77
26 Brandon TH Drobes DJ Unrod M Heckman BW Oliver JA Roetzheim RC et al Varenicline effects on craving cue reactivity and smoking reward Psychopharmacology (Berl) 2011218391ndash403
27 Burstein AH Fullerton T Clark DJ Faessel HM Pharmacokinetics safety and tolerability after single and multiple oral doses of varenicline in elderly smokers J Clin Pharmacol 2006461234ndash40
28 Cinciripini PM Robinson JD Karam-Hage M Minnix JA Lam C Versace F et al Effects of varenicline and bupropion sustained-release use plus intensive smoking cessation counseling on prolonged abstinence from smoking and on depression negative affect and other symptoms of nicotine withdrawal JAMA Psychiatry 201370522ndash33
29 Ebbert JO Croghan IT Severson HH Schroeder DR Hays JT A pilot study of the efficacy of varenicline for the treatment of smokeless tobacco users in Midwestern United States Nicotine Tob Res 201113820ndash6
30 Evins AE Cather C Pratt SA Pachas GN Hoeppner SS Goff DC et al Maintenance treatment with varenicline for smoking cessation in patients with schizophrenia and bipolar disorder a randomized clinical trial JAMA 2014311145ndash54
31 Faessel H Ravva P Williams K Pharmacokinetics safety and tolerability of varenicline in healthy adolescent smokers a multicenter randomized double-blind placebo-controlled parallel-group study Clin Ther 200931177ndash89
32 Fagerstrom K Gilljam H Metcalfe M Tonstad S Messig M Stopping smokeless tobacco with varenicline randomised double blind placebo controlled trial BMJ 2010341c6549
33 Fatemi SH Yousefi MK Kneeland RE Liesch SB Folsom TD Thuras PD Antismoking and potential antipsychotic effects of varenicline in subjects with schizophrenia or schizoaffective disorder a double-blind placebo and bupropion-controlled study Schizophr Res 2013146376ndash8
34 Garza D Murphy M Tseng LJ Riordan HJ Chatterjee A A double-blind randomized placebo-controlled pilot study of neuropsychiatric adverse events in abstinent smokers treated with varenicline or placebo Biol Psychiatry 2011691075ndash82
35 Gonzales D Rennard SI Nides M Oncken C Azoulay S Billing CB et al Varenicline an alpha4beta2 nicotinic acetylcholine receptor partial agonist vs sustained-release bupropion and placebo for smoking cessation a randomized controlled trial JAMA 200629647ndash55
36 Hughes JR Rennard SI Fingar JR Talbot SK Callas PW Fagerstrom KO Efficacy of varenicline to prompt quit attempts in smokers not currently trying to quit a randomized placebo-controlled trial Nicotine Tob Res 201113955ndash64
37 Jorenby DE Hays JT Rigotti NA Azoulay S Watsky EJ Williams KE et al Efficacy of varenicline an alpha4beta2 nicotinic acetylcholine receptor partial agonist vs placebo or sustained-release bupropion for smoking cessation a randomized controlled trial JAMA 200629656ndash63
38 Litten RZ Ryan ML Fertig JB Falk DE Johnson B Dunn KE et al A double-blind placebo-controlled trial assessing the efficacy of varenicline tartrate for alcohol dependence J Addict Med 20137277ndash86
39 McClure EA Vandrey RG Johnson MW Stitzer ML Effects of varenicline on abstinence and smoking reward following a programmed lapse Nicotine Tob Res 201315139ndash48
40 McKee SA Harrison EL OrsquoMalley SS Krishnan-Sarin S Shi J Tetrault JM et al Varenicline reduces alcohol self-administration in heavy-drinking smokers Biol Psychiatry 200966185ndash90
41 Meszaros ZS Abdul-Malak Y Dimmock JA Wang D Ajagbe TO Batki SL Varenicline treatment of concurrent alcohol and nicotine dependence in schizophrenia a randomized placebo-controlled pilot trial J Clin Psychopharmacol 201333243ndash7
42 Mitchell JM Teague CH Kayser AS Bartlett SE Fields HL Varenicline decreases alcohol consumption in heavy-drinking smokers Psychopharmacology (Berl) 2012223299ndash306
43 Nakamura M Oshima A Fujimoto Y Maruyama N Ishibashi T Reeves KR Efficacy and tolerability of varenicline an alpha4beta2 nicotinic acetylcholine receptor partial agonist in a 12-week randomized placebo-controlled dose-response study with 40-week follow-up for smoking cessation in Japanese smokers Clin Ther 2007291040ndash56
44 Niaura R Hays JT Jorenby DE Leone FT Pappas JE Reeves KR et al The efficacy and safety of varenicline for smoking cessation using a flexible dosing strategy in adult smokers a randomized controlled trial Curr Med Res Opin 2008241931ndash41
45 Nides M Oncken C Gonzales D Rennard S Watsky EJ Anziano R et al Smoking cessation with varenicline a selective alpha4beta2 nicotinic receptor partial agonist results from a 7-week randomized placebo- and bupropion-controlled trial with 1-year follow-up Arch Intern Med 20061661561ndash8
46 Oncken C Gonzales D Nides M Rennard S Watsky E Billing CB et al Efficacy and safety of the novel selective nicotinic acetylcholine receptor partial agonist varenicline for smoking cessation Arch Intern Med 20061661571ndash7
47 Plebani JG Lynch KG Yu Q Pettinati HM OrsquoBrien CP Kampman KM Results of an initial clinical trial of varenicline for the treatment of cocaine dependence Drug Alcohol Depend 2012121163ndash6
48 Plebani JG Lynch KG Rennert L Pettinati HM OrsquoBrien CP Kampman KM Results from a pilot clinical trial of varenicline for the treatment of alcohol dependence Drug Alcohol Depend 2013133754ndash8
49 Poling J Rounsaville B Gonsai K Severino K Sofuoglu M The safety and efficacy of varenicline in cocaine using smokers maintained on methadone a pilot study Am J Addict 201019401ndash8
50 Rennard S Hughes J Cinciripini PM Kralikova E Raupach T Arteaga C et al A randomized placebo-controlled trial of varenicline for smoking cessation allowing flexible quit dates Nicotine Tob Res 201214343ndash50
51 Rigotti NA Pipe AL Benowitz NL Arteaga C Garza D Tonstad S Efficacy and safety of varenicline for smoking cessation in patients with cardiovascular disease a randomized trial Circulation 2010121221ndash9
52 Shim JC Jung DU Jung SS Seo YS Cho DM Lee JH et al Adjunctive varenicline treatment with antipsychotic medications for cognitive impairments in people with schizophrenia a randomized double-blind placebo-controlled trial Neuropsychopharmacology 201237660ndash8
53 Stein MD Caviness CM Kurth ME Audet D Olson J Anderson BJ Varenicline for smoking cessation among methadone-maintained smokers a randomized clinical trial Drug Alcohol Depend 2013133486ndash93
54 Steinberg MB Randall J Greenhaus S Schmelzer AC Richardson DL Carson JL Tobacco dependence treatment for hospitalized smokers a randomized controlled pilot trial using varenicline Addic Behav 2011361127ndash32
55 Tashkin DP Rennard S Hays JT Ma W Lawrence D Lee TC Effects of varenicline on smoking cessation in patients with mild to moderate COPD a randomized controlled trial Chest 2011139591ndash9
56 Tonnesen P Mikkelsen K Varenicline to stop long-term nicotine replacement use a double-blind randomized placebo-controlled trial Nicotine Tob Res 201315419ndash27
57 Tonstad S Tonnesen P Hajek P Williams KE Billing CB Reeves KR et al Effect of maintenance therapy with varenicline on smoking cessation a randomized controlled trial JAMA 200629664ndash71
58 Tsai ST Cho HJ Cheng HS Kim CH Hsueh KC Billing CB Jr et al A randomized placebo-controlled trial of varenicline a selective alpha4beta2 nicotinic acetylcholine receptor partial agonist as a new therapy for smoking cessation in Asian smokers Clin Ther 2007291027ndash39
59 Wang C Xiao D Chan KPW Pothirat C Garza D Davies S Varenicline for smoking cessation A placebo-controlled randomized study Respirology 200914384ndash92
60 Weiner E Buchholz A Coffay A Liu F McMahon RP Buchanan RW et al Varenicline for smoking cessation in people with schizophrenia a double blind randomized pilot study Schizophr Res 201112994ndash5
RESEARCH
11thethinspbmj | BMJ 2015350h1109 | doi 101136bmjh1109
61 Williams K Reeves K Billing C Pennington A Gong J A double-blind study evaluating the long-term safety of varenicline for smoking cessation Curr Med Res Opin 200723793ndash801
62 Williams JM Anthenelli RM Morris CD Treadow J Thompson JR Yunis C et al A randomized double-blind placebo-controlled study evaluating the safety and efficacy of varenicline for smoking cessation in patients with schizophrenia or schizoaffective disorder J Clin Psychiatry 201273654ndash60
63 Wong J Abrishami A Yang Y Zaki A Friedman Z Selby P et al A perioperative smoking cessation intervention with varenicline a double-blind randomized placebo-controlled trial Anesthesiology 2012117755ndash64
64 Zesiewicz TA Greenstein PE Sullivan KL Wecker L Miller A Jahan I et al A randomized trial of varenicline (Chantix) for the treatment of spinocerebellar ataxia type 3 Neurology 201278545ndash50
65 Zhao Q Schwam E Fullerton T OrsquoGorman M Burstein AH Pharmacokinetics safety and tolerability following multiple oral doses of varenicline under various titration schedules in elderly nonsmokers J Clin Pharmacol 201151492ndash501
66 Chengappa KN Perkins KA Brar JS Schlicht PJ Turkin SR Hetrick ML et al Varenicline for smoking cessation in bipolar disorder a randomized double-blind placebo-controlled study J Clin Psychiatry 201475765ndash72
67 Gonzales D Hajek P Pliamm L Nackaerts K Tseng LJ McRae TD et al Retreatment with varenicline for smoking cessation in smokers who have previously taken varenicline a randomized placebo-controlled trial Clin Pharmacol Ther 201496390ndash6
68 Kishi T Iwata N Varenicline for smoking cessation in people with schizophrenia systematic review and meta-analysis Eur Arch Psychiatry Clin Neurosci 2014 Oct 5 [Epub ahead of print]
69 Hong LE Thaker GK McMahon RP Summerfelt A Rachbeisel J Fuller RL et al Effects of moderate-dose treatment with varenicline on neurobiological and cognitive biomarkers in smokers and nonsmokers with schizophrenia or schizoaffective disorder Arch Gen Psychiatry 2011681195ndash206
70 Huang Y Li W Yang L Jiang Y Wu Y Long-term efficacy and safety of varenicline for smoking cessation a systematic review and
meta-analysis of randomized controlled trials J Public Health 201220355ndash65
71 Singh S Loke YK Spangler JG Furberg CD Risk of serious adverse cardiovascular events associated with varenicline a systematic review and meta-analysis CMAJ 20111831359ndash66
72 Prochaska JJ Hilton JF Risk of cardiovascular serious adverse events associated with varenicline use for tobacco cessation systematic review and meta-analysis BMJ 2012344e2856
73 Mocking RJ Patrick Pflanz C Pringle A Parsons E McTavish SF Cowen PJ et al Effects of short-term varenicline administration on emotional and cognitive processing in healthy non-smoking adults a randomized double-blind study Neuropsychopharmacology 201338476ndash84
74 Taylor G McNeill A Girling A Farley A Lindson-Hawley N Aveyard P Change in mental health after smoking cessation systematic review and meta-analysis BMJ 2014348g1151
75 Smoking cessation services in primary care pharmacies local authorities and workplaces particularly for manual working groups pregnant women and hard to reach communities NICE public health guidance 10 National Institute for Health and Care Excellence 2008
copy BMJ Publishing Group Ltd 2015
Appendix 1 Search strategy to identify relevant articles in MedlineAppendix 2 Further characteristics of included ran-domised controlled trialsAppendix 3 Forest plots for secondary outcomesAppendix 4 Subgroup analysesAppendix 5 Funnel plots Appendix 6 Summary of Peto odds ratios risk differ-ences and 95 confidence intervals for neuropsychiat-ric events
RESEARCH
10 doi 101136bmjh1109 | BMJ 2015350h1109 | thethinspbmj
13 Miller M Hemenway D Rimm E Cigarettes and suicide a prospective study of 50000 men Am J Public Health 200090768ndash73
14 Etter JF Burri M Stapleton J The impact of pharmaceutical company funding on results of randomized trials of nicotine replacement therapy for smoking cessation a meta-analysis Addiction 2007102815ndash22
15 Prescribing and Primary Care team Health and Social Care Information Centre Prescription cost analysis England 2013 Health and Social Care Information Centre 2014
16 Cahill K Stead LF Lancaster T Nicotine receptor partial agonists for smoking cessation Cochrane Database Syst Rev 20124CD006103
17 Higgins JPT Altman DG Assessing risk of bias in included studies Cochrane handbook for systematic reviews of interventions John Wiley 2008187ndash241
18 Harris R Bradburn M Deeks J Harbord R Altman D Sterne J metan fixed- and random-effects meta-analysis Stata J 200883ndash28
19 Bradburn MJ Deeks JJ Berlin JA Russell Localio A Much ado about nothing a comparison of the performance of meta-analytical methods with rare events Stat Med 20072653ndash77
20 Higgins JP Thompson SG Deeks JJ Altman DG Measuring inconsistency in meta-analyses BMJ 2003327557ndash60
21 Higgins JPT Deeks JJ Altman DG Special topics in statistics Cochrane handbook for systematic reviews of interventions John Wiley 2008481ndash529
22 Sterne JAC Harbord RM Funnel plots in meta-analysis Stata J 20044127ndash41
23 Harbord RM Harris RJ Sterne JAC Updated tests for small-study effects in meta-analyses Stata J 20099197ndash210
24 Anthenelli RM Morris C Ramey TS Dubrava SJ Tsilkos K Russ C et al Effects of varenicline on smoking cessation in adults with stably treated current or past major depression a randomized trial Ann Intern Med 2013159390ndash400
25 Bolliger CT Issa JS Posadas-Valay R Safwat T Abreu P Correia EA et al Effects of varenicline in adult smokers a multinational 24-week randomized double-blind placebo-controlled study Clin Ther 201133465ndash77
26 Brandon TH Drobes DJ Unrod M Heckman BW Oliver JA Roetzheim RC et al Varenicline effects on craving cue reactivity and smoking reward Psychopharmacology (Berl) 2011218391ndash403
27 Burstein AH Fullerton T Clark DJ Faessel HM Pharmacokinetics safety and tolerability after single and multiple oral doses of varenicline in elderly smokers J Clin Pharmacol 2006461234ndash40
28 Cinciripini PM Robinson JD Karam-Hage M Minnix JA Lam C Versace F et al Effects of varenicline and bupropion sustained-release use plus intensive smoking cessation counseling on prolonged abstinence from smoking and on depression negative affect and other symptoms of nicotine withdrawal JAMA Psychiatry 201370522ndash33
29 Ebbert JO Croghan IT Severson HH Schroeder DR Hays JT A pilot study of the efficacy of varenicline for the treatment of smokeless tobacco users in Midwestern United States Nicotine Tob Res 201113820ndash6
30 Evins AE Cather C Pratt SA Pachas GN Hoeppner SS Goff DC et al Maintenance treatment with varenicline for smoking cessation in patients with schizophrenia and bipolar disorder a randomized clinical trial JAMA 2014311145ndash54
31 Faessel H Ravva P Williams K Pharmacokinetics safety and tolerability of varenicline in healthy adolescent smokers a multicenter randomized double-blind placebo-controlled parallel-group study Clin Ther 200931177ndash89
32 Fagerstrom K Gilljam H Metcalfe M Tonstad S Messig M Stopping smokeless tobacco with varenicline randomised double blind placebo controlled trial BMJ 2010341c6549
33 Fatemi SH Yousefi MK Kneeland RE Liesch SB Folsom TD Thuras PD Antismoking and potential antipsychotic effects of varenicline in subjects with schizophrenia or schizoaffective disorder a double-blind placebo and bupropion-controlled study Schizophr Res 2013146376ndash8
34 Garza D Murphy M Tseng LJ Riordan HJ Chatterjee A A double-blind randomized placebo-controlled pilot study of neuropsychiatric adverse events in abstinent smokers treated with varenicline or placebo Biol Psychiatry 2011691075ndash82
35 Gonzales D Rennard SI Nides M Oncken C Azoulay S Billing CB et al Varenicline an alpha4beta2 nicotinic acetylcholine receptor partial agonist vs sustained-release bupropion and placebo for smoking cessation a randomized controlled trial JAMA 200629647ndash55
36 Hughes JR Rennard SI Fingar JR Talbot SK Callas PW Fagerstrom KO Efficacy of varenicline to prompt quit attempts in smokers not currently trying to quit a randomized placebo-controlled trial Nicotine Tob Res 201113955ndash64
37 Jorenby DE Hays JT Rigotti NA Azoulay S Watsky EJ Williams KE et al Efficacy of varenicline an alpha4beta2 nicotinic acetylcholine receptor partial agonist vs placebo or sustained-release bupropion for smoking cessation a randomized controlled trial JAMA 200629656ndash63
38 Litten RZ Ryan ML Fertig JB Falk DE Johnson B Dunn KE et al A double-blind placebo-controlled trial assessing the efficacy of varenicline tartrate for alcohol dependence J Addict Med 20137277ndash86
39 McClure EA Vandrey RG Johnson MW Stitzer ML Effects of varenicline on abstinence and smoking reward following a programmed lapse Nicotine Tob Res 201315139ndash48
40 McKee SA Harrison EL OrsquoMalley SS Krishnan-Sarin S Shi J Tetrault JM et al Varenicline reduces alcohol self-administration in heavy-drinking smokers Biol Psychiatry 200966185ndash90
41 Meszaros ZS Abdul-Malak Y Dimmock JA Wang D Ajagbe TO Batki SL Varenicline treatment of concurrent alcohol and nicotine dependence in schizophrenia a randomized placebo-controlled pilot trial J Clin Psychopharmacol 201333243ndash7
42 Mitchell JM Teague CH Kayser AS Bartlett SE Fields HL Varenicline decreases alcohol consumption in heavy-drinking smokers Psychopharmacology (Berl) 2012223299ndash306
43 Nakamura M Oshima A Fujimoto Y Maruyama N Ishibashi T Reeves KR Efficacy and tolerability of varenicline an alpha4beta2 nicotinic acetylcholine receptor partial agonist in a 12-week randomized placebo-controlled dose-response study with 40-week follow-up for smoking cessation in Japanese smokers Clin Ther 2007291040ndash56
44 Niaura R Hays JT Jorenby DE Leone FT Pappas JE Reeves KR et al The efficacy and safety of varenicline for smoking cessation using a flexible dosing strategy in adult smokers a randomized controlled trial Curr Med Res Opin 2008241931ndash41
45 Nides M Oncken C Gonzales D Rennard S Watsky EJ Anziano R et al Smoking cessation with varenicline a selective alpha4beta2 nicotinic receptor partial agonist results from a 7-week randomized placebo- and bupropion-controlled trial with 1-year follow-up Arch Intern Med 20061661561ndash8
46 Oncken C Gonzales D Nides M Rennard S Watsky E Billing CB et al Efficacy and safety of the novel selective nicotinic acetylcholine receptor partial agonist varenicline for smoking cessation Arch Intern Med 20061661571ndash7
47 Plebani JG Lynch KG Yu Q Pettinati HM OrsquoBrien CP Kampman KM Results of an initial clinical trial of varenicline for the treatment of cocaine dependence Drug Alcohol Depend 2012121163ndash6
48 Plebani JG Lynch KG Rennert L Pettinati HM OrsquoBrien CP Kampman KM Results from a pilot clinical trial of varenicline for the treatment of alcohol dependence Drug Alcohol Depend 2013133754ndash8
49 Poling J Rounsaville B Gonsai K Severino K Sofuoglu M The safety and efficacy of varenicline in cocaine using smokers maintained on methadone a pilot study Am J Addict 201019401ndash8
50 Rennard S Hughes J Cinciripini PM Kralikova E Raupach T Arteaga C et al A randomized placebo-controlled trial of varenicline for smoking cessation allowing flexible quit dates Nicotine Tob Res 201214343ndash50
51 Rigotti NA Pipe AL Benowitz NL Arteaga C Garza D Tonstad S Efficacy and safety of varenicline for smoking cessation in patients with cardiovascular disease a randomized trial Circulation 2010121221ndash9
52 Shim JC Jung DU Jung SS Seo YS Cho DM Lee JH et al Adjunctive varenicline treatment with antipsychotic medications for cognitive impairments in people with schizophrenia a randomized double-blind placebo-controlled trial Neuropsychopharmacology 201237660ndash8
53 Stein MD Caviness CM Kurth ME Audet D Olson J Anderson BJ Varenicline for smoking cessation among methadone-maintained smokers a randomized clinical trial Drug Alcohol Depend 2013133486ndash93
54 Steinberg MB Randall J Greenhaus S Schmelzer AC Richardson DL Carson JL Tobacco dependence treatment for hospitalized smokers a randomized controlled pilot trial using varenicline Addic Behav 2011361127ndash32
55 Tashkin DP Rennard S Hays JT Ma W Lawrence D Lee TC Effects of varenicline on smoking cessation in patients with mild to moderate COPD a randomized controlled trial Chest 2011139591ndash9
56 Tonnesen P Mikkelsen K Varenicline to stop long-term nicotine replacement use a double-blind randomized placebo-controlled trial Nicotine Tob Res 201315419ndash27
57 Tonstad S Tonnesen P Hajek P Williams KE Billing CB Reeves KR et al Effect of maintenance therapy with varenicline on smoking cessation a randomized controlled trial JAMA 200629664ndash71
58 Tsai ST Cho HJ Cheng HS Kim CH Hsueh KC Billing CB Jr et al A randomized placebo-controlled trial of varenicline a selective alpha4beta2 nicotinic acetylcholine receptor partial agonist as a new therapy for smoking cessation in Asian smokers Clin Ther 2007291027ndash39
59 Wang C Xiao D Chan KPW Pothirat C Garza D Davies S Varenicline for smoking cessation A placebo-controlled randomized study Respirology 200914384ndash92
60 Weiner E Buchholz A Coffay A Liu F McMahon RP Buchanan RW et al Varenicline for smoking cessation in people with schizophrenia a double blind randomized pilot study Schizophr Res 201112994ndash5
RESEARCH
11thethinspbmj | BMJ 2015350h1109 | doi 101136bmjh1109
61 Williams K Reeves K Billing C Pennington A Gong J A double-blind study evaluating the long-term safety of varenicline for smoking cessation Curr Med Res Opin 200723793ndash801
62 Williams JM Anthenelli RM Morris CD Treadow J Thompson JR Yunis C et al A randomized double-blind placebo-controlled study evaluating the safety and efficacy of varenicline for smoking cessation in patients with schizophrenia or schizoaffective disorder J Clin Psychiatry 201273654ndash60
63 Wong J Abrishami A Yang Y Zaki A Friedman Z Selby P et al A perioperative smoking cessation intervention with varenicline a double-blind randomized placebo-controlled trial Anesthesiology 2012117755ndash64
64 Zesiewicz TA Greenstein PE Sullivan KL Wecker L Miller A Jahan I et al A randomized trial of varenicline (Chantix) for the treatment of spinocerebellar ataxia type 3 Neurology 201278545ndash50
65 Zhao Q Schwam E Fullerton T OrsquoGorman M Burstein AH Pharmacokinetics safety and tolerability following multiple oral doses of varenicline under various titration schedules in elderly nonsmokers J Clin Pharmacol 201151492ndash501
66 Chengappa KN Perkins KA Brar JS Schlicht PJ Turkin SR Hetrick ML et al Varenicline for smoking cessation in bipolar disorder a randomized double-blind placebo-controlled study J Clin Psychiatry 201475765ndash72
67 Gonzales D Hajek P Pliamm L Nackaerts K Tseng LJ McRae TD et al Retreatment with varenicline for smoking cessation in smokers who have previously taken varenicline a randomized placebo-controlled trial Clin Pharmacol Ther 201496390ndash6
68 Kishi T Iwata N Varenicline for smoking cessation in people with schizophrenia systematic review and meta-analysis Eur Arch Psychiatry Clin Neurosci 2014 Oct 5 [Epub ahead of print]
69 Hong LE Thaker GK McMahon RP Summerfelt A Rachbeisel J Fuller RL et al Effects of moderate-dose treatment with varenicline on neurobiological and cognitive biomarkers in smokers and nonsmokers with schizophrenia or schizoaffective disorder Arch Gen Psychiatry 2011681195ndash206
70 Huang Y Li W Yang L Jiang Y Wu Y Long-term efficacy and safety of varenicline for smoking cessation a systematic review and
meta-analysis of randomized controlled trials J Public Health 201220355ndash65
71 Singh S Loke YK Spangler JG Furberg CD Risk of serious adverse cardiovascular events associated with varenicline a systematic review and meta-analysis CMAJ 20111831359ndash66
72 Prochaska JJ Hilton JF Risk of cardiovascular serious adverse events associated with varenicline use for tobacco cessation systematic review and meta-analysis BMJ 2012344e2856
73 Mocking RJ Patrick Pflanz C Pringle A Parsons E McTavish SF Cowen PJ et al Effects of short-term varenicline administration on emotional and cognitive processing in healthy non-smoking adults a randomized double-blind study Neuropsychopharmacology 201338476ndash84
74 Taylor G McNeill A Girling A Farley A Lindson-Hawley N Aveyard P Change in mental health after smoking cessation systematic review and meta-analysis BMJ 2014348g1151
75 Smoking cessation services in primary care pharmacies local authorities and workplaces particularly for manual working groups pregnant women and hard to reach communities NICE public health guidance 10 National Institute for Health and Care Excellence 2008
copy BMJ Publishing Group Ltd 2015
Appendix 1 Search strategy to identify relevant articles in MedlineAppendix 2 Further characteristics of included ran-domised controlled trialsAppendix 3 Forest plots for secondary outcomesAppendix 4 Subgroup analysesAppendix 5 Funnel plots Appendix 6 Summary of Peto odds ratios risk differ-ences and 95 confidence intervals for neuropsychiat-ric events
RESEARCH
11thethinspbmj | BMJ 2015350h1109 | doi 101136bmjh1109
61 Williams K Reeves K Billing C Pennington A Gong J A double-blind study evaluating the long-term safety of varenicline for smoking cessation Curr Med Res Opin 200723793ndash801
62 Williams JM Anthenelli RM Morris CD Treadow J Thompson JR Yunis C et al A randomized double-blind placebo-controlled study evaluating the safety and efficacy of varenicline for smoking cessation in patients with schizophrenia or schizoaffective disorder J Clin Psychiatry 201273654ndash60
63 Wong J Abrishami A Yang Y Zaki A Friedman Z Selby P et al A perioperative smoking cessation intervention with varenicline a double-blind randomized placebo-controlled trial Anesthesiology 2012117755ndash64
64 Zesiewicz TA Greenstein PE Sullivan KL Wecker L Miller A Jahan I et al A randomized trial of varenicline (Chantix) for the treatment of spinocerebellar ataxia type 3 Neurology 201278545ndash50
65 Zhao Q Schwam E Fullerton T OrsquoGorman M Burstein AH Pharmacokinetics safety and tolerability following multiple oral doses of varenicline under various titration schedules in elderly nonsmokers J Clin Pharmacol 201151492ndash501
66 Chengappa KN Perkins KA Brar JS Schlicht PJ Turkin SR Hetrick ML et al Varenicline for smoking cessation in bipolar disorder a randomized double-blind placebo-controlled study J Clin Psychiatry 201475765ndash72
67 Gonzales D Hajek P Pliamm L Nackaerts K Tseng LJ McRae TD et al Retreatment with varenicline for smoking cessation in smokers who have previously taken varenicline a randomized placebo-controlled trial Clin Pharmacol Ther 201496390ndash6
68 Kishi T Iwata N Varenicline for smoking cessation in people with schizophrenia systematic review and meta-analysis Eur Arch Psychiatry Clin Neurosci 2014 Oct 5 [Epub ahead of print]
69 Hong LE Thaker GK McMahon RP Summerfelt A Rachbeisel J Fuller RL et al Effects of moderate-dose treatment with varenicline on neurobiological and cognitive biomarkers in smokers and nonsmokers with schizophrenia or schizoaffective disorder Arch Gen Psychiatry 2011681195ndash206
70 Huang Y Li W Yang L Jiang Y Wu Y Long-term efficacy and safety of varenicline for smoking cessation a systematic review and
meta-analysis of randomized controlled trials J Public Health 201220355ndash65
71 Singh S Loke YK Spangler JG Furberg CD Risk of serious adverse cardiovascular events associated with varenicline a systematic review and meta-analysis CMAJ 20111831359ndash66
72 Prochaska JJ Hilton JF Risk of cardiovascular serious adverse events associated with varenicline use for tobacco cessation systematic review and meta-analysis BMJ 2012344e2856
73 Mocking RJ Patrick Pflanz C Pringle A Parsons E McTavish SF Cowen PJ et al Effects of short-term varenicline administration on emotional and cognitive processing in healthy non-smoking adults a randomized double-blind study Neuropsychopharmacology 201338476ndash84
74 Taylor G McNeill A Girling A Farley A Lindson-Hawley N Aveyard P Change in mental health after smoking cessation systematic review and meta-analysis BMJ 2014348g1151
75 Smoking cessation services in primary care pharmacies local authorities and workplaces particularly for manual working groups pregnant women and hard to reach communities NICE public health guidance 10 National Institute for Health and Care Excellence 2008
copy BMJ Publishing Group Ltd 2015
Appendix 1 Search strategy to identify relevant articles in MedlineAppendix 2 Further characteristics of included ran-domised controlled trialsAppendix 3 Forest plots for secondary outcomesAppendix 4 Subgroup analysesAppendix 5 Funnel plots Appendix 6 Summary of Peto odds ratios risk differ-ences and 95 confidence intervals for neuropsychiat-ric events