Highlight
This comprehensive secondary analysis of a randomized trial highlights four main findings: (1) Varenicline demonstrates superior efficacy over placebo, bupropion, and nicotine patch for smoking cessation in individuals with past or current major depressive disorder (MDD). (2) Bupropion and nicotine replacement therapy (NRT) are effective in those with past but not current MDD. (3) All examined pharmacotherapies have a similar safety profile with no significant increase in moderate to severe neuropsychiatric adverse events across MDD or non-psychiatric populations. (4) Among smokers with current MDD, varenicline may additionally reduce anxiety and depressive symptoms during cessation efforts.