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Articles   |    
Varenicline, Smoking Cessation, and Neuropsychiatric Adverse Events
Robert D. Gibbons, Ph.D.; J. John Mann, M.D.
Am J Psychiatry 2013;170:1460-1467. doi:10.1176/appi.ajp.2013.12121599
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Dr. Gibbons has served as an expert witness for Pfizer in a case related to varenicline and neuropsychiatric adverse events, for the U.S. Department of Justice and for Wyeth on cases related to antidepressants and suicide, and for Pfizer on cases related to gabapentin and suicide. Dr. Mann has received research support from GlaxoSmithKline and Novartis and receives royalties for the Columbia Suicide Severity Rating Scale from the Foundation for Mental Health. Data for the randomized controlled trials were supplied by Pfizer. Pfizer had no involvement in the analysis of these data or the writing of the paper. Pfizer reviewed the final manuscript to ensure accuracy of the study descriptions and ensure against inadvertent disclosure of confidential information or unprotected inventions. Pfizer did not provide any comments except minor corrections in Table 1.

Supported by NIMH grants MH062185 (to Dr. Mann) and MH8012201 (to Dr. Gibbons).

From the Center for Health Statistics and the Departments of Medicine, Health Studies, and Psychiatry, University of Chicago, Chicago; the Department of Molecular Imaging and Neuropathology, New York State Psychiatric Institute; and the Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York.

Address correspondence to Dr. Gibbons (rdg@uchicago.edu).

Copyright © 2013 by the American Psychiatric Association

Received December 20, 2012; Revised April 09, 2013; Accepted May 29, 2013.


Objective  In 2009, the U.S. Food and Drug Administration issued a black box warning for varenicline regarding neuropsychiatric events. The authors used data from randomized controlled trials and from a large Department of Defense (DOD) observational study to assess the efficacy and safety of varenicline.

Method  The authors reanalyzed data from the 17 placebo-controlled randomized controlled trials (N=8,027) of varenicline conducted by Pfizer, using complete intent-to-treat person-level longitudinal data to assess smoking abstinence and reports of suicidal thoughts and behavior, depression, aggression/agitation, and nausea and to compare effects in patients with (N=1,004) and without (N=7,023) psychiatric disorders. The authors also analyzed a large DOD data set to compare acute (30-day and 60-day) rates of neuropsychiatric adverse events in patients receiving varenicline or nicotine replacement therapy (N=35,800) and to assess reports of anxiety, mood, and psychotic symptoms and disorders, other mental disorders, and suicide attempt.

Results  In the randomized controlled trials, varenicline increased the risk of nausea (odds ratio=3.69, 95% CI=3.03–4.48) but not rates of suicidal events, depression, or aggression/agitation. It significantly increased the abstinence rate, by 124% compared with placebo and 22% compared with bupropion. Having a current or past psychiatric illness increased the risk of neuropsychiatric events equally in treated and placebo patients. In the DOD study, after propensity score matching, the overall rate of neuropsychiatric disorders was significantly lower for varenicline than for nicotine replacement therapy (2.28% compared with 3.16%).

Conclusions  This analysis revealed no evidence that varenicline is associated with adverse neuropsychiatric events. The evidence supports the superior efficacy of varenicline relative to both placebo and bupropion, indicating considerable benefit without evidence of risk of serious neuropsychiatric adverse events, in individuals with and without a recent history of a psychiatric disorder.

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FIGURE 1. Observed and Estimated Probabilities of Smoking in Patients Receiving Varenicline or Placebo

FIGURE 2. Observed and Estimated Probabilities of Smoking in Patients Receiving Varenicline or Bupropion
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TABLE 1.Summary of Randomized Double-Blind Placebo-Controlled Trials
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TABLE 2.Frequency Distributions for Variables Used in Propensity Score Matching in a U.S. Department of Defense Observational Study
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TABLE 3.Neuropsychiatric Events Before and After Propensity Score Matching in a U.S. Department of Defense Observational Study
Table Footer Note

a Fisher’s exact test.

Table Footer Note

b McNemar’s exact test.



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