Predictors of Neuropsychiatric Adverse Events with Smoking Cessation Medications in the Randomized Controlled EAGLES Trial

  • Robert M. AnthenelliEmail author
  • Michael Gaffney
  • Neal L. Benowitz
  • Robert West
  • Thomas McRae
  • Cristina Russ
  • David Lawrence
  • Lisa St. Aubin
  • Alok Krishen
  • A. Eden Evins



Pre-treatment factors that increase smokers’ risk of experiencing neuropsychiatric adverse events (NPSAEs) when quitting smoking are unknown.


To identify baseline smoker characteristics beyond the history of mental illness that predict which participants were more likely to experience moderate to severe NPSAEs in EAGLES.


A prospective correlational cohort study in the context of a multinational, multicenter, double-blind, randomized trial.


Smokers without (N = 3984; NPC)/with (N = 4050; PC) histories of, or current clinically stable, psychiatric disorders including mood (N = 2882; 71%), anxiety (N = 782; 19%), and psychotic (N = 386; 10%) disorders.


Bupropion, 150 mg twice daily, or varenicline, 1 mg twice daily, versus active control (nicotine patch, 21 mg/day with taper) and placebo for 12 weeks with 12-week non-treatment follow-up.

Main Measures

Primary safety outcome was the incidence of a composite measure of moderate/severe NPSAEs. Associations among baseline demographic/clinical characteristics and the primary safety endpoint were analyzed post hoc via generalized linear regression.

Key Results

The incidence of moderate to severe NPSAEs was higher among smokers in the PC (238/4050; 5.9%) than in the NPC (84/3984; 2.1%). Three baseline characteristics predicted increased risk for experiencing clinically significant NPSAEs when quitting regardless of carrying a psychiatric diagnosis: current symptoms of anxiety (for every ~ 4-unit increase in HADS anxiety score, the absolute risk of occurrence of the NPSAE endpoint increased by 1% in both PC and NPC); prior history of suicidal ideation and/or behavior (PC, 4.4% increase; P = 0.001; NPC, 4.1% increase; P = 0.02), and being of White race (versus Black: PC, 2.9% ± 0.9 [SE] increase; P = 0.002; and NPC, 3.4% ± 0.8 [SE] increase; P = 0.001). Among smokers with psychiatric disorders, younger age, female sex, history of substance use disorders, and proxy measures of nicotine dependence or psychiatric illness severity also predicted greater risk. There were no significant interactions between these characteristics and treatment. Smokers with unstable psychiatric disorders or with current, active substance abuse were excluded from the study.


Irrespective of cessation pharmacotherapy use, smokers attempting to quit were more likely to experience moderate to severe NPSAEs if they reported current anxiety or prior suicidal ideation at baseline and were White. In smokers with a psychiatric history, female sex, younger age, and greater severity of nicotine dependence were also predictive.

Trial Registration Identifier: NCT01456936


neuropsychiatric adverse event smoking cessation medication varenicline predictors 



Editorial support (in the form of creating tables and figures, formatting references, collating review comments, and proofing and formatting for submission) was provided by Anne Jakobsen, MSc, Engage Scientific, Horsham, UK.

Author Contribution

Sponsor employees, with input from academic authors, designed the study. The sponsors supported the conduct of the trial, monitored study sites, and collected and analyzed the data; all authors had full access to the data. The lead academic (corresponding) author (RMA) prepared the initial draft of the manuscript and had final responsibility for the decision to submit for publication.


Editorial support was funded by Pfizer. The EAGLES trial was funded by Pfizer and GlaxoSmithKline. EAGLES was a post-marketing requirement in the USA and Europe for Pfizer and GlaxoSmithKline.

Compliance with Ethical Standards

Upon request, and subject to certain criteria, conditions and exceptions (see for more information), Pfizer will provide access to individual de-identified participant data from Pfizer-sponsored global interventional clinical studies conducted for medicines, vaccines and medical devices (1) for indications that have been approved in the USA and/or EU or (2) in programs that have been terminated (i.e., development for all indications has been discontinued). Pfizer will also consider requests for the protocol, data dictionary, and statistical analysis plan. Data may be requested from Pfizer trials 24 months after study completion. The de-identified participant data will be made available to researchers whose proposals meet the research criteria and other conditions, and for which an exception does not apply, via a secure portal. To gain access, data requestors must enter into a data access agreement with Pfizer.

Conflict of Interest

RMA reports his university receiving grants from Alkermes and Pfizer and providing consulting and/or advisory board services to Arena Pharmaceuticals, Cerecor, Pfizer, and US WorldMeds. RMA’s writing of this manuscript was supported, in part, by National Institute on Alcohol Abuse and Alcoholism Grant no. U01 AA013641, and National Institute on Drug Abuse (NIDA) Grant no. UO1 DA041731, and NIDA/Veterans Affairs Cooperative Study no. 1033. NLB reports consulting and/or advisory board services to GlaxoSmithKline, Pfizer, and Achieve Life Sciences and is a paid expert witness in litigation against tobacco companies. RW reports grants from Johnson & Johnson and Pfizer and personal fees for consulting and/or advisory board services to GlaxoSmithKline, Johnson & Johnson, and Pfizer. RW’s writing of this manuscript was supported, in part, by Cancer Research United Kingdom. AEE reports grants from Forum Pharmaceuticals and Pfizer and personal fees for advisory board services from Pfizer, Reckitt Benckiser, and Alkermes. AEE’s writing of the manuscript was supported by a NIDA Career Award in Patient-Oriented Research, K24 DA030443. MG, TM, CR, DL, and LSA are employees and stockholders of Pfizer. AK is a PAREXEL employee working on behalf of GlaxoSmithKline.


The opinions expressed in this article are those of the authors and do not necessarily reflect the views of their employers.


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Copyright information

© Society of General Internal Medicine 2019

Authors and Affiliations

  • Robert M. Anthenelli
    • 1
    Email author
  • Michael Gaffney
    • 2
  • Neal L. Benowitz
    • 3
  • Robert West
    • 4
  • Thomas McRae
    • 2
  • Cristina Russ
    • 2
  • David Lawrence
    • 2
  • Lisa St. Aubin
    • 2
  • Alok Krishen
    • 5
  • A. Eden Evins
    • 6
  1. 1.Department of PsychiatryUniversity of California, San DiegoLa JollaUSA
  2. 2.PfizerNew YorkUSA
  3. 3.Department of MedicineUniversity of CaliforniaSan FranciscoUSA
  4. 4.University CollegeLondonUK
  5. 5.PAREXEL International on behalf of GlaxoSmithKlineResearch Triangle ParkUSA
  6. 6.Massachusetts General Hospital and Harvard Medical SchoolBostonUSA

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