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.
Study Background and Disease Burden
Tobacco smoking remains a leading cause of preventable morbidity and mortality worldwide. Individuals with major depressive disorder (MDD) smoke at disproportionately higher rates than the general population, contributing to excess cardiovascular and oncologic disease burden. Smoking cessation is thus a critical clinical goal in this vulnerable group, yet pharmacologic treatment efficacy and safety may differ due to the neuropsychiatric vulnerability inherent in MDD.
Previous concerns about neuropsychiatric side effects of smoking cessation medications, especially varenicline and bupropion, have tempered enthusiasm for their use in depressed populations. Furthermore, the relative efficacy of these therapies for smokers with current versus past MDD had not been systematically compared, creating clinical uncertainty.
Study Design
This study represents a secondary analysis of a large, double-blind, randomized, placebo-controlled trial evaluating four interventions over 12 weeks plus follow-up: varenicline, bupropion, nicotine replacement therapy (NRT; nicotine patch), and placebo. The analysis included 6,653 adults aged 18 to 75, stratified into three cohorts: past MDD (N=2,174), current MDD (N=451), and no psychiatric diagnosis (N=4,028).
All participants received brief smoking cessation counseling alongside pharmacotherapy. The primary efficacy endpoint was biochemically confirmed continuous abstinence from smoking during weeks 9-12. The primary safety outcome was the incidence of moderate to severe neuropsychiatric adverse events (NPSAEs), encompassing symptoms such as anxiety, depression, suicidal ideation, and other psychiatric complications.
Key Findings
Safety Profile: The overall risk of neuropsychiatric adverse events did not significantly differ between varenicline, bupropion, NRT, and placebo within each cohort (past-MDD, current-MDD, and nonpsychiatric). However, both past and current MDD cohorts had a statistically higher baseline risk of NPSAEs compared to the nonpsychiatric cohort (p < 0.001), underscoring the intrinsic vulnerability of individuals with MDD to psychiatric adverse events when attempting cessation.
Efficacy in Past MDD: Among participants with a history of MDD but not currently depressed, all three active interventions demonstrated significantly higher odds of continuous abstinence compared to placebo: varenicline (OR=3.0, 95% CI=2.0–4.5), bupropion (OR=2.1, 95% CI=1.6–2.7), and NRT (OR=2.1, 95% CI=1.4–3.2). This suggests that in individuals with remitted depression, standard cessation pharmacotherapies retain robust efficacy.
Efficacy in Current MDD: In those with active depression during cessation treatment, varenicline significantly increased odds of abstinence compared to placebo (OR=2.67, 95% CI=1.2–6.15) and NRT (OR=2.93, 95% CI=1.2–7.2). In contrast, bupropion and NRT did not demonstrate superiority over placebo in this group, delineating varenicline as the most efficacious option among current MDD smokers.
Psychiatric Symptom Impact: Notably, varenicline use was associated with reductions in anxiety and depressive symptoms during quit attempts among participants with current MDD, suggesting potential psychotropic benefits alongside smoking cessation.
Expert Commentary
This large, methodologically rigorous secondary analysis addresses a critical clinical question concerning smoking cessation pharmacotherapy in depressed populations. The findings support varenicline as the preferred first-line agent for smokers with both active and past MDD given its superior efficacy and comparable neuropsychiatric safety profile. The data alleviate prior concerns about varenicline-associated psychiatric risks in depression, consistent with accumulating evidence from other trials and regulatory reviews.
Limitations include the secondary nature of the analysis and relatively smaller sample size in the current MDD subgroup, which may affect the precision of estimates. Also, the trial included brief counseling which might have modulated outcomes. However, the biochemical verification of abstinence and DSM-based ascertainment of MDD strengthen internal validity.
Guidelines from the U.S. Public Health Service and Psychiatric associations increasingly advocate tailored cessation approaches in mental illness. This study provides impactful evidence endorsing varenicline plus counseling for smokers with MDD to improve quit rates without excess neuropsychiatric harm.
Conclusion
In summary, varenicline emerges as the most effective and safe pharmacologic option for smoking cessation in individuals with current or past major depressive disorder, achieving superior abstinence rates and reduced psychiatric symptoms during quit attempts. Bupropion and nicotine patch demonstrate moderate efficacy in those with past but not current MDD. Clinicians should consider varenicline plus counseling as front-line treatment in this high-risk population, while maintaining vigilance for neuropsychiatric symptoms inherent to MDD. Further pragmatic research may optimize integration of psychiatric care and cessation strategies to address this persistent public health challenge.
References
Kypriotakis G, Cinciripini PM, Green CE, Lawrence D, Anthenelli RM, Minnix JA, Beneventi D, Morris C, Karam-Hage M, Blalock JA. Effects of Varenicline, Bupropion, Nicotine Patch, and Placebo on Treating Smoking Among Persons With Current or Past Major Depressive Disorder: Secondary Analysis of a Double-Blind, Randomized, Placebo-Controlled Trial. Am J Psychiatry. 2025 Feb 1;182(2):174-186. doi: 10.1176/appi.ajp.20230855. Epub 2024 Dec 11. PMID: 39659160.
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Prochaska JJ. Smoking and mental illness — breaking the link. N Engl J Med. 2011 May 5;364(18):1681-1683.
anthenelli RM, Benowitz NL, West R, et al. Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES): a double-blind, randomised, placebo-controlled clinical trial. Lancet. 2016 May 7;387(10037):2507-2520.
