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Cited by 1,177Smoking Behavior and CessationSubstance Abuse Treatment and OutcomesNicotinic Acetylcholine Receptors Study

Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES): a double-blind, randomised, placebo-controlled clinical trial.

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Anthenelli, Robert M, Benowitz, Neal L, West, Robert, St Aubin, Lisa, McRae, Thomas, Lawrence, David, Ascher, John, Russ, Cristina +2 more·2016·The Lancet
DOI 10.1016/s0140-6736(16)30272-0
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Abstract

Background Substantial concerns have been raised about the neuropsychiatric safety of the smoking cessation medications varenicline and bupropion. Their efficacy relative to nicotine patch largely relies on indirect comparisons, and there is limited information on safety and efficacy in smokers with psychiatric disorders. We compared the relative neuropsychiatric safety risk and efficacy of varenicline and bupropion with nicotine patch and placebo in smokers with and without psychiatric disorders.Methods We did a randomised, double-blind, triple-dummy, placebo-controlled and active-controlled (nicotine patch; 21 mg per day with taper) trial of varenicline (1 mg twice a day) and bupropion (150 mg twice a day) for 12 weeks with 12-week non-treatment follow-up done at 140 centres (clinical trial centres, academic centres, and outpatient clinics) in 16 countries between Nov 30, 2011, and Jan 13, 2015. Participants were motivated-to-quit smokers with and without psychiatric disorders who received brief cessation counselling at each visit. Randomisation was computer generated (1:1:1:1 ratio). Participants, investigators, and research personnel were masked to treatment assignments. The primary endpoint was the incidence of a composite measure of moderate and severe neuropsychiatric adverse events. The main efficacy endpoint was biochemically confirmed continuous abstinence for weeks 9-12. All participants randomly assigned were included in the efficacy analysis and those who received treatment were included in the safety analysis. The trial is registered at ClinicalTrials.gov (number NCT01456936) and is now closed.Findings 8144 participants were randomly assigned, 4116 to the psychiatric cohort (4074 included in the safety analysis) and 4028 to the non-psychiatric cohort (3984 included in the safety analysis). In the non-psychiatric cohort, 13 (1·3%) of 990 participants reported moderate and severe neuropsychiatric adverse events in the varenicline group, 22 (2·2%) of 989 in the bupropion group, 25 (2·5%) of 1006 in the nicotine patch group, and 24 (2·4%) of 999 in the placebo group. The varenicline-placebo and bupropion-placebo risk differences (RDs) for moderate and severe neuropsychiatric adverse events were -1·28 (95% CI -2·40 to -0·15) and -0·08 (-1·37 to 1·21), respectively; the RDs for comparisons with nicotine patch were -1·07 (-2·21 to 0·08) and 0·13 (-1·19 to 1·45), respectively. In the psychiatric cohort, moderate and severe neuropsychiatric adverse events were reported in 67 (6·5%) of 1026 participants in the varenicline group, 68 (6·7%) of 1017 in the bupropion group, 53 (5·2%) of 1016 in the nicotine patch group, and 50 (4·9%) of 1015 in the placebo group. The varenicline-placebo and bupropion-placebo RDs were 1·59 (95% CI -0·42 to 3·59) and 1·78 (-0·24 to 3·81), respectively; the RDs versus nicotine patch were 1·22 (-0·81 to 3·25) and 1·42 (-0·63 to 3·46), respectively. Varenicline-treated participants achieved higher abstinence rates than those on placebo (odds ratio [OR] 3·61, 95% CI 3·07 to 4·24), nicotine patch (1·68, 1·46 to 1·93), and bupropion (1·75, 1·52 to 2·01). Those on bupropion and nicotine patch achieved higher abstinence rates than those on placebo (OR 2·07 [1·75 to 2·45] and 2·15 [1·82 to 2·54], respectively). Across cohorts, the most frequent adverse events by treatment group were nausea (varenicline, 25% [511 of 2016 participants]), insomnia (bupropion, 12% [245 of 2006 participants]), abnormal dreams (nicotine patch, 12% [251 of 2022 participants]), and headache (placebo, 10% [199 of 2014 participants]). Efficacy treatment comparison did not differ by cohort.Interpretation The study did not show a significant increase in neuropsychiatric adverse events attributable to varenicline or bupropion relative to nicotine patch or placebo. Varenicline was more effective than placebo, nicotine patch, and bupropion in helping smokers achieve abstinence, whereas bupropion and nicotine patch were more effective than placebo.Funding Pfizer and GlaxoSmithKline.

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  • In the EAGLES trial (n=8144) 21.8% of smokers randomized to varenicline quit smoking at 6 months compared with 15.7% randomized to NRT (OR 1.52 [95% 1.29 to 1.78]) and 16.2% randomized to bupropion (OR 1.45 [95% CI, 1.24 to 1.70]).

    “In the EAGLES trial (n=8144) 21.8% of smokers randomized to varenicline quit smoking at 6 months compared with 15.7% randomized to NRT (OR 1.52 [95% 1.29 to 1.78]) and 16.2% randomized to bupropion (OR 1.45 [95% CI, 1.24 to 1.70]).”

    From Interventions for Tobacco Cessation in Adults, Including Pregnant Persons (2021) · cites this paper as [119]

    The Results (page unavailable) report that 8,144 smokers were randomized and that varenicline produced higher continuous abstinence through weeks 9–24 than nicotine patch or bupropion. The Discussion (page unavailable) gives 1.52 as this study’s estimate for the comparison with nicotine replacement. The accessible text does not show the quoted abstinence percentages, confidence intervals, or the 1.45 odds ratio, so those exact figures cannot be verified from our copy. (LLM, conf=0.83)

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  • Evidence now suggests that varenicline does not cause psychological disturbance.

    “Although evidence now suggests that varenicline does not cause psychological disturbance [6, 42]”

    From intEgrating Smoking Cessation treatment As part of usual Psychological care for dEpression and anxiety (ESCAPE): A randomised and controlled, multi-centre, acceptability and feasibility trial with nested qualitative methods (2025) · cites this paper as [42]

    The Discussion (page not supplied) reports no significant increase in moderate-to-severe neuropsychiatric adverse events with varenicline versus nicotine patch or placebo, and no treatment-associated changes in mood or anxiety measures. But the Implications section (page not supplied) says a small increased risk remains possible in smokers with psychiatric disorders; the study therefore does not establish that varenicline causes no psychological disturbance. (LLM, conf=0.84)

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  • Adult smokers randomized to varenicline have a statistically significant higher likelihood of quitting smoking at 6 months compared with those randomized to NRT or bupropion.

    “Evidence from existing systematic reviews as well as the EAGLES trial indicate that adult smokers randomized to varenicline have a statistically significant higher likelihood of quitting smoking at 6 months compared with those randomized to NRT or bupropion.”

    From Interventions for Tobacco Cessation in Adults, Including Pregnant Persons (2021) · cites this paper as [119]

  • Recent studies have challenged concerns that smoking cessation treatments may be unsafe for people with psychotic disorders.

    “In the past, concerns have been raised that such treatments may be unsafe for people with psychotic disorders, however, recent studies have challenged these (Anthenelli et al., 2016).”

    From The impact of cigarette smoking on life expectancy in schizophrenia, schizoaffective disorder and bipolar affective disorder: An electronic case register cohort study (2021) · cites this paper as Anthenelli et al., 2016

  • Evidence from five large cohort studies did not find differences in stillbirth, birth outcomes, or any congenital anomaly for infants born to mothers with exposure to NRT, bupropion, or varenicline versus those who were unexposed to medications but whose mothers smoked.

    “Evidence from five large cohort studies did not find differences in stillbirth, birth outcomes, or any congenital anomaly for infants born to mothers with exposure to NRT, bupropion, or varenicline versus those who were unexposed to medications but whose mothers smoked.”

    From Interventions for Tobacco Cessation in Adults, Including Pregnant Persons (2021) · cites this paper as [110]

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Research works printed but not linked: 3

  1. [18]18. American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th edn, text revision. 2000. http://dsm. psychiatryonline.org/doi/abs/10.1176/appi.books.9780890420249. dsm-iv-tr (accessed Oct 8, 2015). · DOI
  2. [22]22. International Conference on Harmonisation. Guideline for good clinical practice E6(R1). 1996. http://www.ich.org/products/ guidelines/effi cacy/effi cacy-single/article/good-clinical-practice. html (accessed Oct 8, 2015).
  3. [23]23. First MB, Spitzer RL, Gibbon M, Williams JBW. Structured clinical interview for DSM-IV-TR axis I disorders, research version, patient edition (SCID-I/P). New York: Biometrics Research, New York State Psychiatric Institute; November, 2002.

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Authors
Anthenelli, R. M., Benowitz, N. L., West, R., St Aubin, L., McRae, T., Lawrence, D., Ascher, J., Russ, C., Krishen, A., & Evins, A. E.
Affiliations
  • University of California San Diego (US)
  • University of California, San Francisco (US)
  • University College London (GB)
  • Pfizer (United States) (US)
  • PAREXEL International (United States) (US)
  • Harvard University (US)
Corresponding author
Anthenelli, Robert M
ORCID
Venue
The Lancet
Publisher
Elsevier BV
Published
2016-06
Volume
387
Issue
10037
Pages
2507-2520
ISSN
  • 0099-5355 (ISSN-L)
  • 0140-6736
DOI
10.1016/s0140-6736(16)30272-0
OpenAlex
W2340896985
Semantic Scholar
5fa246846e932707d2f6b52df14ab7c9abab6f99
Cited by
1,177
References
28
Citations by year
2026: 60 · 2025: 69 · 2024: 94 · 2023: 104 · 2022: 92 · 2021: 124 · 2020: 260 · 2019: 127 · 2018: 114 · 2017: 96 · 2016: 35 · 2015: 1
FWCI
99.72
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • The Lancet (publishedVersion)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • UCL Discovery (University College London) (submittedVersion)
Funders
  • GlaxoSmithKline
  • Cancer Research UK (14135)
Topics
  • Health Sciences › Medicine › Physiology › Smoking Behavior and Cessation
  • Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
Keywords
lines, bupropion, nicotine patch, smoking cessation, neuropsychiatric adverse effects, mental illness, nicotine dependence, continuous abstinence, drug safety, nicotine replacement therapy, anxiety, psychosis, mood disorders, substance use disorders, bipolar disorder, postpartum depression, post-traumatic stress disorder, postpartum psychosis
MeSH terms
Varenicline, Smoking Prevention, Adolescent, Adult, Aged, Mental Disorders, Double-Blind Method, Female, Humans, Male, Middle Aged, Smoking, Smoking Cessation, Bupropion, Treatment Outcome, Nicotinic Agonists, Dopamine Uptake Inhibitors, Young Adult, Tobacco Use Cessation Devices

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