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.

110 smokers without history of psychiatric illness (screened by Structured Clinical Interview for DSM) were randomized to 12 weeks of varenicline (n=55) (1mg bid) or placebo. Adverse events were solicited systematically. Depressive symptoms, anxiety symptoms, aggression and irritability were measured at baseline and weekly using the Montgomery-Asberg 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 the study period.

Smokers had a mean age of 33; smoked on average 22 cigarettes/day with mean Fagerstrom score for Nicotine Dependence >7 at baseline. 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 [TD] = 0.03, 95% CI: -0.68, 0.73; NS), HAM-A (TD = 0.14, 95% CI: -0.62, 0.90; NS), OAS-m irritability subscale (TD = 0.08, 95% CI: -0.17, 0.34; NS), OAS-m aggression subscale (TD = 0.5, 95% CI: -1.18, 2.18, NS) and the POMS total scores (TD = 0.5, 95% CI: -0.52, 1.53; NS).

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