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Neuropsychiatric Safety and Efficacy of Varenicline, Bupropion, and Nicotine Patch in Smokers With Psychotic, Anxiety, and Mood Disorders in the EAGLES Trial

Evins, A. Eden, MD, MPH*; Benowitz, Neal L., MD; West, Robert, PhD; Russ, Cristina, MD§; McRae, Thomas, MD, MS§; Lawrence, David, PhD§; Krishen, Alok, MS∥¶; St Aubin, Lisa, DVM§; Maravic, Melissa Culhane, PhD, MPH#; Anthenelli, Robert M., MD**

Journal of Clinical Psychopharmacology: March/April 2019 - Volume 39 - Issue 2 - p 108–116
doi: 10.1097/JCP.0000000000001015
Original Contributions

Background Neuropsychiatric safety and relative efficacy of varenicline, bupropion, and transdermal nicotine patch (NRT) in those with psychiatric disorders are of interest.

Methods We performed secondary analyses of safety and efficacy outcomes by psychiatric diagnosis in EAGLES (Evaluating Adverse Events in a Global Smoking Cessation Study), a 12-week, randomized, double-blind, triple-dummy, placebo- and active (NRT)–controlled trial of varenicline and bupropion with 12-week follow-up, in a subset population, n = 4092, with a primary psychotic (n = 390), anxiety (n = 792), or mood (n = 2910) disorder. Primary end-point parameters were incidence of prespecified moderate and severe neuropsychiatric adverse events (NPSAEs) and weeks 9 to 12 continuous abstinence rates (9–12CAR).

Results The observed NPSAE incidence across treatments was 5.1% to 6.3% in those with a psychotic disorder, 4.6% to 8.0% in those with an anxiety disorder, and 4.6% to 6.8% in those with a mood disorder. Neither varenicline nor bupropion was associated with significantly increased NPSAEs relative to NRT or placebo in the psychiatric cohort or any psychiatric diagnostic subcohort. There was a significant effect of treatment on 9–12CAR (P < 0.0001) and no significant treatment-by-diagnostic subcohort interaction (P = 0.24). Abstinence rates with varenicline were superior to bupropion, NRT, and placebo, and abstinence with bupropion and NRT was superior to placebo. Within-diagnostic subcohort comparisons of treatment efficacy yielded estimated odds ratios for 9–12CAR versus placebo of greater than 3.00 for varenicline, greater than 1.90 for bupropion, and greater than 1.80 for NRT for all diagnostic groups.

Conclusions Varenicline, bupropion, and nicotine patch are well tolerated and effective in adults with psychotic, anxiety, and mood disorders. The relative effectiveness of varenicline, bupropion, and NRT versus placebo did not vary across psychiatric diagnoses.

From the *Department of Psychiatry, Harvard Medical School and Massachusetts General Hospital Boston, MA;

Department of Medicine, University of California, San Francisco, CA;

Department of Behavioural Science and Health, University College London, London, United Kingdom;

§Pfizer, New York, New York;

PAREXEL International on behalf of GSK, Research Triangle Park, NC;

Division of Biostatistics, Harvard Medical School and Massachusetts General Hospital;

#Department of Psychiatry, Massachusetts General Hospital, Boston, MA; and

**Department of Psychiatry, University of California, San Diego, CA.

Received December 21, 2017; accepted after revision December 5, 2018.

Reprints: A. Eden Evins, MD, MPH, Massachusetts General Hospital Center for Addiction Medicine, 101 Merrimac St, Suite 320, Boston, MA 02114 (e-mail:

Portions of this manuscript were presented at the Society for Research on Nicotine and Tobacco Annual Meeting 2016, Chicago, IL; and the Society for Research on Nicotine and Tobacco International Meeting 2017, Florence, Italy.

The EAGLES study was funded by Pfizer and GlaxoSmithKline.

Trial registration identifier: NCT01456936.

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