Varenicline (Chantix) was approved in 2006 to treat smoking addiction. Since its approval, the drug has been plagued by reports of worsening depression and increases in suicidality, prompting the FDA to issue an alert in 2008 noting “serious neuropsychiatric symptoms” associated with the drug. But a new study suggests that varenicline may be safe and effective in smokers with a history of depression. In a study sponsored by Pfizer, 525 adult smokers with stably treated current or past major depression and no recent cardiovascular events were randomized to varenicline 1 mg twice daily or placebo for 12 weeks with 40 weeks of nontreatment follow-up. The primary outcome was carbon monoxide-confirmed continuous absence rate (CAR) for weeks 9-12. Other outcomes included ratings of mood, anxiety, and suicidal ideation or behavior. About two-thirds of patients in both groups completed the study. Patients treated with varenicline had double the quit rate at weeks 9-12 (CAR 35.9% vs 15.6%; odds ratio, 3.35; 95% confidence interval [CI], 2.16-5.21; P < 0.001). The quit rates were also approximately double from weeks 9-24 and from weeks 9-52, with the CAR at week 52 for the varenicline group at 20.3% vs 10.4% for placebo. There were no clinically relevant differences between groups in suicidal ideation or behavior, or overall worsening depression or anxiety. About 27% of the treatment group experienced nausea as the most frequent adverse event. The authors conclude that varenicline increased smoking cessation in smokers with stably treated current or past depression without exacerbating depression or anxiety (Ann Intern Med 2013;159:390-400). n