Among smokers with major depressive disorder (MDD), varenicline was associated with improved smoking abstinence compared with placebo, according to authors of a study published in Addiction.

Given that up to 30% of individuals with depression are daily smokers, there is a clear need for effective smoking cessation interventions in the setting of depression.

The randomized, placebo-controlled trial ( ID: NCT02378714) was conducted at Northwestern University and the University of Pennsylvania (UPenn) between 2015 and 2020. The investigators recruited patients (N=300) with a diagnosis of MDD without psychotic features who smoked daily and were interested in quitting.

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Participants were randomly assigned to receive varenicline or placebo as well as behavioral activation for smoking cessation (BASC) or standard behavioral treatment (ST) for 12 weeks up to week 14 after a 2-week pre-quit period (varenicline plus BASC [n=83], varenicline plus ST [n=81], placebo plus BASC [n=68], or placebo plus ST [n=68]). Both behavioral interventions consisted of 8 sessions lasting 45 minutes each, with each session delivered weekly for 4 weeks then every other week for 8 weeks (with the exceptions of sessions 1 and 3, treatment was delivered by phone). The BASC intervention focused on reducing environmental and perceived stress due to smoking cessation. The primary outcome was 7-day smoking abstinence at 27 weeks, defined as carbon monoxide (CO) breath levels of 6 parts per million or less.

Mean age of the participants was 50.0 (SD, 12.6) years, 55.0% were women, 52.3% were Black, 44.3% had other psychiatric comorbidities in addition to MDD, and 27.3% used antidepressants. The participants smoked an average of 15.2 (SD, 7.9) cigarettes per day, and they had been smoking for an average of 31.2 (SD, 14.0) years.

Adherence was similar between treatment arms, and 63% of participants overall were adherent to behavioral treatment. The participants attended a mean of 5.3 to 6.3 behavioral sessions (χ2, 7.23; P =.065). Medication adherence rates ranged from 35.3% to 51.5% (χ2, 4.82; P =.185).

In the intention-to-treat population, abstinence at 14 weeks (confirmed by CO breath levels) among participants recruited at Northwestern was 30% of those in the varenicline group and 15.5% of participants in the placebo group. Among participants recruited at UPenn, abstinence at 14 weeks was observed in 30.3% of the varenicline group and 2.8% of the placebo group. This indicated that varenicline was more strongly associated with 14-week abstinence at UPenn (rate ratio [RR], 10.78; 95% CI, 3.11-37.40) than at Northwestern (RR, 1.93; 95% CI, 1.05-3.56).

At week 27, the abstinence rates were 16.2% for varenicline and 7.5% for placebo (RR, 2.16; 95% CI, 1.08-4.30). The hierarchical hypothesis testing analysis of BASC-by-varenicline-by-site at week 24 indicated that only varenicline had a significant main effect (c2, 4.84; P =.028).

The most common adverse events were anxiety, agitation, sleep problems, and abdominal pain. Placebo recipients reported more sleep problems at week 6 (P =.035) and more anxiety (P =.023) and dry mouth (P =.009) at week 14 compared with the varenicline recipients.

The study authors concluded, “[W]e found strong evidence that varenicline improved both short- and long-term abstinence rates relative to placebo among racially and socioeconomically diverse adults with varied motivation to quit and varied psychiatric presentations.” They noted, “However, we found no evidence that BASC was more effective than ST in increasing cessation.”

Disclosures: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.


Hitsman B, Papandonatos GD, Gollan JK, et al. Efficacy and safety of combination behavioral activation for smoking cessation and varenicline for treating tobacco dependence among individuals with current or past major depressive disorder: a 2×2 factorial, randomized, placebo-controlled trial. Addiction. Published online April 17, 2023. doi:10.1111/add.16209

This article originally appeared on Psychiatry Advisor