First-line Pharmacotherapy for Smoking Cessation with Comorbid Psychiatric Conditions

First-line Pharmacotherapy for Smoking Cessation with Comorbid Psychiatric Conditions
Ashley Jensen, Pharm.D., New Ulm Medical Center

Background: According to the National Survey on Drug Use and Health (NSDUH) performed by Substance Abuse and Mental Health Services Administrations (SAMSHA), approximately one in four adults in the U.S. has some form of behavioral health condition, and these adults consume almost 40% of all cigarettes smoked by adults. There are several therapeutic options for smoking cessation including five nicotine replacement therapy (NRT) products, bupropion sustained release (SR), varenicline, or combination therapy. Previous concerns with possible neuropsychiatric effects of varenicline and black box warnings, led physicians and patients to be reluctant to use this medication. The 2018 American College of Cardiology (ACC) Expert Consensus on Tobacco Cessation Treatment recommends varenicline or combination NRT for first-line therapy over single NRT or bupropion, with only brief mention of considerations in psychiatric disease. Furthermore, the 2020 American Thoracic Society (ATS) Clinical Practice Guideline for tobacco dependence strongly recommends the use of varenicline over NRT or bupropion SR in patients with or without a comorbid psychiatric condition.

Evidence and Discussion: The Evaluating Adverse Events in a Global Smoking Cessation Study (EAGLES) was one of the largest trials assessing neuropsychiatric safety and efficacy of varenicline, bupropion, and NRT in smokers with and without psychiatric disorders. In this randomized, double-blind, triple-dummy, placebo-controlled and active-controlled trial, participants were randomized 1:1:1:1 to receive either varenicline, bupropion, nicotine patch, or placebo and divided into non-psychiatric or psychiatric cohorts. Of the participants (n=3984) in the non-psychiatric cohort, the difference in risk (RD) of the primary composite neuropsychiatric between the varenicline–placebo, varenicline-bupropion, and varenicline-nicotine patch for moderate and severe neuropsychiatric adverse events were -1.28 [95% CI -2.40 to -0.15], -1.19 [95% CI -2.30 to -0.09], and -1.07 [-2.21 to 0.08], respectively. In the psychiatric cohort (n=4074), the RD between the varenicline–placebo, varenicline-bupropion, and varenicline-nicotine patch for moderate and severe neuropsychiatric adverse events were 1.59 [95% CI -0.42 to 3.59), -0.20 [95% CI -2.34 to 1.95], and 1.22 [95% CI -0.81 to 3.25), respectively. This large multinational trial did not show a significant increase in rates of moderate-to-severe neuropsychiatric adverse events with either varenicline or bupropion relative to nicotine patch or placebo in those with or without psychiatric disorders. In addition, varenicline showed significantly higher abstinence rates compared to all other treatment regimens (P<0.001). The results of this trial did not support the concerns about psychiatric side effects previously voiced by the FDA in 2009, leading to the removal of the black box warning in 2016.

The updated 2020 ATS guidelines for smoking cessation further addressed whether or not patients with a history of mental health or substance use disorders should start with the optimal controller medication identified for patients without psychiatric conditions or use NRT. A systematic review was performed identifying two randomized clinical trials that directly compared varenicline with NRT patch. Both trials concluded that varenicline may result in a large benefit for abstinence and would likely result in little to no difference in serious adverse events (SAEs) in patients with substance use or psychiatric disorders. The systemic review suggested a slight yet trivial decrease in risk of SAEs with varenicline compared to a NRT patch (RR, 0.95 [95% CI 0.54 – 1.67]). The results from this systematic review drove the ATS guidelines to recommend using varenicline over a nicotine patch for tobacco-dependent adults with comorbid conditions, including substance use disorder, depression, anxiety, schizophrenia, and/or bipolar disorder, for whom treatment is being initiated.

Clinical Impact: ACC and ATS guidelines address limitations and misconceptions around treating vulnerable patients with behavioral health disorders for smoking cessation. With the evidence presented in both the ACC and ATS guidelines, it allows providers to be more confident in choosing the most appropriate and affordable therapy for smoking cessation.


  1. Substance Abuse and Mental Health Services Administration. The NSDUH Report Data Spotlight: Adults with Mental Illness or Substance Use Disorder Account for 40 Percent of All Cigarettes Smoked. U.S. Dept. of Health & Human Services, Substance Abuse & Mental Health Services Administration, Center for Behavioral Health Statistics and Quality. Published March 20, 2013. Accessed November 09, 2020.

  2. Anthenelli RM, Benowitz NL, West R, St. Aubin L, McRae T, Lawrence D, et al. Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES): a double-blind, randomized, placebo-controlled clinical trial. Lancet 2016;387:2507–2520. doi: 0.1016/S0140-6736.

  3. Barua SR, Rigotti NL, Benowitz NL, et al. 2018 ACC expert consensus decision pathway on tobacco cessation treatment. JACC. 2018;73(25):3332-3365. doi:10.1016/j.jacc.2018.10.027.

  4. Leone FT, Zhang Y, Evers-Casey S, et al. Initiating Pharmacological treatment in tobacco-dependent adults. Am J Respir Crit Care Med. 2020; 202(2):e5-e31. doi:10.1164/rccm.202005-1982ST.

  5. Rohsenow DJ, Tidey JW, Martin RA, et al. Varenicline versus nicotine patch with brief advice for smokers with substance use disorders with or without depression: effects on smoking, substance use and depressive symptoms. Addiction. 2017; 112:1808–1820. doi: 10.1111/add.13861.