Elsevier

Biological Psychiatry

Volume 69, Issue 11, 1 June 2011, Pages 1075-1082
Biological Psychiatry

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

https://doi.org/10.1016/j.biopsych.2010.12.005Get rights and content

Background

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.

Methods

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.

Results

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).

Conclusions

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.

Section snippets

Study Design and Participants

This randomized, double-blind, placebo-controlled pilot study enrolled smokers at a single United States Phase I investigational center from September 2008 to August 2009. The trial was conducted in accordance with the Declaration of Helsinki (22) and in compliance with the institutional review board for the study site (California IRB, Inc., Pasadena, California) and the International Conference on Harmonisation and Good Clinical Practice Guidelines (23).

Adult smokers (aged 18–75 years) who

Results

Overall, 857 smokers were screened for possible participation in this study, and 110 were randomized in a 1:1 ratio to the varenicline (n = 55) and placebo (n = 55) treatment groups (Figure S1 in Supplement 1). More varenicline participants than placebo participants discontinued treatment (16 vs. 6 participants, respectively). Most of the difference between treatment groups was seen in the category of “lost to follow-up.” Study sites were instructed to continue attempting to contact

Discussion

This study was an exploratory, unpowered, pilot study in a population of smokers with no history of preexisting psychiatric disorders, suicidal behaviors, or suicidal ideation who were highly nicotine-dependent (Fagerström Test for Nicotine Dependence score > 5).

The most common AE observed during the study in the varenicline group was nausea, consistent with other published studies of varenicline (1, 2, 3, 4). All NPAEs in this study were comparable between groups, with the exception of

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