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Review
. 2015 Mar 12:350:h1109.
doi: 10.1136/bmj.h1109.

Risk of neuropsychiatric adverse events associated with varenicline: systematic review and meta-analysis

Kyla H Thomas  1 , Richard M Martin  2 , Duleeka W Knipe  2 , Julian P T Higgins  2 , David Gunnell  2
Affiliations
Review

Risk of neuropsychiatric adverse events associated with varenicline: systematic review and meta-analysis

Kyla H Thomas et al. BMJ. .

Abstract

Objective: To determine the risk of neuropsychiatric adverse events associated with use of varenicline compared with placebo in randomised controlled trials.

Design: Systematic review and meta-analysis comparing study effects using two summary estimates in fixed effects models, risk differences, and Peto odds ratios.

Data sources: Medline, Embase, PsycINFO, the Cochrane Central Register of Controlled Trials (CENTRAL), and clinicaltrials.gov.

Eligibility criteria for selecting studies: Randomised controlled trials with a placebo comparison group that reported on neuropsychiatric adverse events (depression, suicidal ideation, suicide attempt, suicide, insomnia, sleep disorders, abnormal dreams, somnolence, fatigue, anxiety) and death. Studies that did not involve human participants, did not use the maximum recommended dose of varenicline (1 mg twice daily), and were cross over trials were excluded.

Results: In the 39 randomised controlled trials (10,761 participants), there was no evidence of an increased risk of suicide or attempted suicide (odds ratio 1.67, 95% confidence interval 0.33 to 8.57), suicidal ideation (0.58, 0.28 to 1.20), depression (0.96, 0.75 to 1.22), irritability (0.98, 0.81 to 1.17), aggression (0.91, 0.52 to 1.59), or death (1.05, 0.47 to 2.38) in the varenicline users compared with placebo users. Varenicline was associated with an increased risk of sleep disorders (1.63, 1.29 to 2.07), insomnia (1.56, 1.36 to 1.78), abnormal dreams (2.38, 2.05 to 2.77), and fatigue (1.28, 1.06 to 1.55) but a reduced risk of anxiety (0.75, 0.61 to 0.93). Similar findings were observed when risk differences were reported. There was no evidence for a variation in depression and suicidal ideation by age group, sex, ethnicity, smoking status, presence or absence of psychiatric illness, and type of study sponsor (that is, pharmaceutical industry or other).

Conclusions: This meta-analysis found no evidence of an increased risk of suicide or attempted suicide, suicidal ideation, depression, or death with varenicline. These findings provide some reassurance for users and prescribers regarding the neuropsychiatric safety of varenicline. There was evidence that varenicline was associated with a higher risk of sleep problems such as insomnia and abnormal dreams. These side effects, however, are already well recognised.

Systematic review registration: PROSPERO 2014:CRD42014009224.

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Conflict of interest statement

Competing interests: All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: RMM had specified relationship with the MHRA in the past (was a member of the MHRA’s 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 MHRA’s Pharmacovigilance Expert Advisory Group and received travel expenses and a small fee for meeting attendance and preparation for meetings).

Figures

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Fig 1 Flow chart showing selection of randomised controlled trials for inclusion in systematic review of varenicline
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Fig 2 Forest plot of risk of suicidal ideation events (Peto odds ratio) associated with varenicline use in 20 placebo controlled randomised trials
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Fig 3 Forest plot of risk of suicidal ideation events (Mantel-Haenszel risk difference) associated with varenicline use in 20 placebo controlled randomised trials
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Fig 4 Forest plot of risk of depression events (Peto odds ratio) associated with varenicline use in 31 placebo controlled randomised trials
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Fig 5 Forest plot of risk of depression events (Mantel-Haenszel risk difference) associated with varenicline use in 31 placebo controlled randomised trials
See this image and copyright information in PMC

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