A Double-Blind Randomized Placebo-Controlled Pilot Study of Neuropsychiatric Adverse Events in Abstinent Smokers Treated with Varenicline or Placebo

Published:February 08, 2011DOI:


      Varenicline is an α4β2 partial nicotinic agonist approved for smoking cessation. There have been spontaneous postmarketing reports of neuropsychiatric adverse events (NPAEs) in smokers without a history of psychiatric illness quitting with varenicline.


      One hundred ten smokers without history of psychiatric illness (screened by Structured Clinical Interview for DSM-IV) were randomized to 12 weeks of varenicline 1 mg twice daily (n = 55) or placebo. Adverse events were solicited systematically. Depressive symptoms, anxiety, aggression, and irritability were measured at baseline and weekly using the Montgomery-Åsberg Depression Rating Scale (MADRS), the Hamilton Anxiety Scale (HAM-A), and the Overt Aggression Scale—Modified (OAS-M). The Profile of Mood States (POMS) was administered daily. Mixed-model analysis of repeated measures was conducted to compare mean changes in scores between groups across study periods.


      Participants' mean baseline characteristics were 33 years of age, 22 cigarettes/day and Fagerström Test for Nicotine Dependence score > 7. Reported NPAEs were similar between groups. No suicidal events were reported. There were no significant differences between groups for the MADRS (treatment difference vs. placebo = .03, 95% confidence interval [CI] −.68–.73; NS), HAM-A (treatment difference [TD] = .14, 95% CI −.62–.90; NS), OAS-M Aggression subscale (TD = .5, 95% CI −1.18–2.18; NS), OAS-M Irritability subscale (TD = .08, 95% CI −.17–.34; NS), and the POMS total scores (TD = .5, 95% CI −.52–1.53; NS).


      There were no significant differences between groups on measures of depressive symptoms, anxiety, or aggression/hostility. Systematically solicited NPAEs were similar between the varenicline and placebo groups.

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      • Varenicline and the Evaluation of Neuropsychiatric Adverse Events in Smokers
        Biological PsychiatryVol. 69Issue 11
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          Varenicline, a selective partial agonist of α4β2 subunits of nicotinic acetylcholine receptors, has been shown to be efficacious relative to placebo as summarized in a meta-analysis of clinical trials of smokers without significant psychiatric comorbidities (1). In these studies, neuropsychiatric adverse events (NPAEs) on varenicline were infrequent and comparable to placebo. In the postmarketing period, however, various NPAEs have been reported to occur in individuals taking varenicline.
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