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

References (38)

  • Chantix (varenicline) Tablets [U.S. Precribing Information]

  • S. Tonstad

    Psychiatric adverse events in randomized, double-blind, placebo-controlled clinical trials of varenicline: A pooled analysis

    Drug Saf

    (2010)
  • D. Gunnell et al.

    Varenicline and suicidal behaviour: A cohort study based on data from the General Practice Research Database

    BMJ

    (2009)
  • D.K. Hatsukami et al.

    Tobacco withdrawal symptoms: An experimental analysis

    Psychopharmacology (Berl)

    (1984)
  • J.R. Hughes

    Measurement of the effects of abstinence from tobacco: A qualitative review

    Psychol Addict Behav

    (2007)
  • J.R. Hughes

    Effects of abstinence from tobacco: Valid symptoms and time course

    Nicotine Tob Res

    (2007)
  • J.R. Hughes

    Effects of abstinence from tobacco: Etiology, animal models, epidemiology, and significance: A subjective review

    Nicotine Tob Res

    (2007)
  • J.R. Hughes et al.

    Signs and symptoms of tobacco withdrawal

    Arch Gen Psychiatry

    (1986)
  • D. Hemenway et al.

    Smoking and suicide among nurses

    Am J Public Health

    (1993)
  • Cited by (43)

    • The possible role of maternal bonding style and CHRNB2 gene polymorphisms in nicotine dependence and related depressive phenotype

      2015, Progress in Neuro-Psychopharmacology and Biological Psychiatry
      Citation Excerpt :

      Numerous neuropsychiatric adverse events during varenicline treatment have been reported, including suicidal ideation and depressed mood and in a currently published paper authors demonstrated that the second most frequent drug with reports on depression and suicide was the varenicline in the UK between 1998 and 2011 (Pirmoradi et al., 2008; Thomas et al., 2014; Tonstad et al., 2010). Other studies, however, did not find evidence for these neuropsychiatric side effects (Cinciripini et al., 2013; Garza et al., 2011; Thomas et al., 2013). Nevertheless, a recent study suggests that varenicline may have a protective effect on depressed mood (Cinciripini et al., 2013); furthermore, α4β2 nAChR as potential antidepressant targets have been implicated (Yu et al., 2014).

    • Nicotine receptor partial agonists for smoking cessation

      2023, Cochrane Database of Systematic Reviews
    View all citing articles on Scopus
    View full text