Update on Varenicline for Smoking Cessation in Patients With Bipolar Disorder

BIPOLAR UPDATE

Some reports suggest that 70% of patients with bipolar disorder smoke.¹ Mental health clinicians are uniquely positioned to treat these patients’ tobacco use disorder (TUD), but the tendency is to avoid prioritizing management of TUD and assume that someone else should do it, such as the primary care clinician.² This update will hopefully provide information to help psychopharmacology prescribers feel more comfortable owning the treatment of this comorbidity in their patients with bipolar disorder.³

For patients who have other substance use disorders (SUDs), here is some good news about the benefits of smoking cessation: Results from a large cohort study of 2652 adults found that patients trying to remain abstinent from other SUDs who quit smoking during that time have odds of recovery at 1 year from the other SUDs that are 30% to 43% higher than those who do not quit.⁴

The most effective medication by far for smoking cessation and for cessation of other forms of tobacco, such as chewing tobacco, is varenicline. For many—if not most—patients, it should be the first-line pharmacotherapy.³ The EAGLES study—a randomized, double-blind, placebo-controlled trial with 8144 participants—compared varenicline, bupropion, and nicotine replacement therapy (NRT). The results confirmed the findings of many smaller studies by finding varenicline treatment to have the best outcome, defined as abstinence at weeks 9 to 12.⁵ The investigators further studied the effect of the medication among smokers with additional psychiatric diagnoses. They divided the participants into 2 cohorts of 4000 participants each—one with and the other without psychiatric disorders. The psychiatric disorder breakdown was 70% unipolar and bipolar mood disorders, 20% anxiety disorders, and 10% psychotic disorders. The study results found that varenicline performed best among the 4 treatments in both groups. In the nonpsychiatric cohort, abstinence rates were 38% for varenicline, 26% for the other active treatments, and 14% for placebo. In the psychiatric disorder cohort, abstinence occurred in 29% of participants on varenicline, 19% to 20% on the other medications, and 11% on placebo.

A later publication reported the subgroup results in patients with bipolar disorder.⁶ Again, there was superior efficacy with varenicline compared with the other treatments. However, patients with bipolar disorder who smoke were and are notoriously difficult to treat: The continuous abstinence rate for smokers with bipolar disorder on varenicline was significantly lower compared with the varenicline-treated patients with TUD and no psychiatric comorbidity (13% vs 23%).

The safety results may surprise some clinicians and patients. There were no differences in moderate to severe neuropsychiatric adverse effects (eg, depression, suicidality, aggression) between varenicline and placebo in either cohort of patients. Also, there was no increase in any serious cardiovascular adverse events during treatment vs placebo.⁷ Due to the EAGLES findings, the US Food and Drug Administration removed the initial black box package insert warning regarding behavioral and cardiovascular adverse effects. Notably, neuropsychiatric adverse events do occur, but they are not more common if the patient is on varenicline. The effects are proposed to be due to nicotine withdrawal.

There seem to be no significant drug interactions with any bipolar disorder medications.

If smoking cessation fails on varenicline, findings from controlled studies have shown augmentations with NRT or bupropion can add efficacy.^8,9 Bupropion, however, is probably not a good choice for a patient with bipolar disorder. The preferred augmentation would be NRT with patch and oral agents, followed by slow taper; this strategy may blunt the nicotine withdrawal and thereby increase success rates.

One relatively minor adverse effect of varenicline, which can be significant in some patients, is insomnia. Nightmares and disturbed awakenings associated with posttraumatic stress disorder (PTSD) may increase in patients who take varenicline. Before initiating varenicline, clinicians and patients should try to manage sleep disturbance associated with PTSD using prazosin. Findings from 7 of 10 placebo-controlled studies to date have found efficacy for prazosin.¹⁰ Prazosin may need to be increased if nightmares resume or increase after starting varenicline.

Dr Osser is associate professor of psychiatry at Harvard Medical School and lead psychiatrist in the Bipolar Disorders Telehealth Program at the US Department of Veterans Affairs National TeleMental Health Center in Brockton, Massachusetts.

References

1. George TP, Wu BS, Weinberger AH. A review of smoking cessation in bipolar disorder: implications for future research. J Dual Diagn. 2012;8(2):126-130.

2. Kleinman RA, Barnett BS. Smoking cessation as a priority for psychiatrists. JAMA Psychiatry. 2024;81(10):951-952.

3. Mohammad A, Giakoumatos CI, Mekdessi N, Osser DN. A review of evidence and an algorithm for use of psychopharmacology in the treatment of tobacco use disorder in behavioral health settings. J Clin Psychopharmacol. 2025;45(6):600-608.

4. Parks MJ, Blanco C, Creamer MR, et al. Cigarette smoking during recovery from substance use disorders. JAMA Psychiatry. 2025;82(10):1002-1008.

5. 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;387(10037):2507-2520.

6. Heffner JL, Evins AE, Russ C, et al. Safety and efficacy of first-line smoking cessation pharmacotherapies in bipolar disorders: subgroup analysis of a randomized clinical trial. J Affect Disord. 2019;256:267-277.

7. Benowitz NL, Pipe A, West R, et al. Cardiovascular safety of varenicline, bupropion, and nicotine patch in smokers: a randomized clinical trial. JAMA Intern Med. 2018;178(5):622-631.

8. Rose JE, Behm FM. Combination treatment with varenicline and bupropion in an adaptive smoking cessation paradigm. Am J Psychiatry. 2014;171(11):1199-1205.

9. Koegelenberg CFN, Noor F, Bateman ED, et al. Efficacy of varenicline combined with nicotine replacement therapy vs varenicline alone for smoking cessation: a randomized clinical trial. JAMA. 2014;312(2):155-161.

10. Bajor LA, Balsara C, Osser DN. Posttraumatic stress disorder psychopharmacology algorithm update-2024-2025. Psychiatry Clin Psychopharmacol. 2025;35(suppl 1):S135-S140.