Savvy Psychopharmacology

Smoking cessation: Varenicline and the risk of neuropsychiatric adverse events

Current Psychiatry. 2022 July;21(7):41-45 | doi: 10.12788/cp.0263

References

1. Chantix [package insert]. New York, NY: Pfizer Inc; 2019.
2. Sharma R, Alla K, Pfeffer D, et al. An appraisal of practice guidelines for smoking cessation in people with severe mental illness. Aust N Z J Psychiatry. 2017;51(11):1106-1120. doi:10.1177/0004867417726176
3. 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. doi:10.1016/s0140-6736(16)30272-0
4. Beard E, Jackson SE, Anthenelli RM, et al. Estimation of risk of neuropsychiatric adverse events from varenicline, bupropion and nicotine patch versus placebo: secondary analysis of results from the EAGLES trial using Bayes factors. Addiction. 2021;116(10):2816-2824. doi:10.1111/add.15440
5. Ayers CR, Heffner JL, Russ C, et al. Efficacy and safety of pharmacotherapies for smoking cessation in anxiety disorders: subgroup analysis of the randomized, active- and placebo-controlled EAGLES trial. Depress Anxiety. 2020;37(3)247-260. doi:10.1002/da.22982
6. Evins AE, Cather C, Pratt SA, et al. Maintenance treatment with varenicline for smoking cessation in patients with schizophrenia and bipolar disorder: a randomized clinical trial. JAMA. 2014;311(2):145-154. doi:10.1001/jama.2013.285113

Further analysis of EAGLES

Beard et al⁴ used Bayes factor testing for additional analysis of EAGLES data to determine whether the data were insensitive to neuropsychiatric effects secondary to a lack of statistical power. In the psychiatric cohort, the varenicline and bupropion groups exhibited suggestive but not conclusive data that there was no increase in NPSAEs compared to placebo (Bayes factor 0.52 and 0.71, respectively).⁴

Another EAGLES analysis by Ayers et al⁵ evaluated participants with anxiety disorders (N = 712), including PTSD (N = 192), generalized anxiety disorder (GAD) (N = 243), and panic disorder (N = 277).Of those with PTSD who received varenicline, there were no statistically significant differences in CAR from Week 9 to Week 12 vs placebo.⁵ However, there was a significant difference in individuals with GAD (OR 4.53; 95% CI, 1.20 to 17.10), and panic disorder (OR 8.49; 95% CI, 1.57 to 45.78).⁵ In contrast to CAR from Week 9 to Week 12, 7-day point prevalence abstinence at Week 12 for participants with PTSD was significant (OR 4.04; 95% CI, 1.39 to 11.74) when comparing varenicline to placebo. Within the anxiety disorder cohort, there were no significant differences in moderate to severe NPSAE rates based on treatment group. Calculated risk differences comparing varenicline to placebo were: PTSD group -7.73 (95% CI, -21.95 to 6.49), GAD group 2.80 (95% CI, -6.63 to 12.23), and panic disorder group -0.18 (95% CI, -9.57 to 9.21).⁵

Other studies

Evins et al⁶ conducted a randomized controlled trial to evaluate the safety of varenicline maintenance therapy in patients with schizophrenia or bipolar disorder. To be deemed clinically stable, participants in this study needed to be taking a stable dose of an antipsychotic or mood-stabilizing agent(s) for ≥30 days, compared to the 3-month requirement of the EAGLES trial.^3,6Participants received 12 weeks of open-label varenicline; those who achieved abstinence (N = 87) entered the relapse-prevention phase and were randomized to varenicline 1 mg twice a day or placebo for 40 weeks. Of those who entered relapse-prevention, 5 in the placebo group and 2 in the varenicline group were psychiatrically hospitalized (risk ratio 0.45; 95% CI, 0.04 to 2.9).⁶ These researchers concluded that varenicline maintenance therapy prolonged abstinence rates with no significant increase in neuropsychiatric events.⁶

Although treatment options for smoking cessation have advanced, individuals with SMI are still disproportionately affected by the negative outcomes of cigarette smoking. Current literature suggests that varenicline does not confer an appreciable risk of neuropsychiatric events in otherwise stable patients and is the preferred first-line treatment. However, there is a gap in understanding the impact of this medication on individuals with unstable psychiatric illness. Health care professionals should be encouraged to use varenicline with careful monitoring for appropriate patients with psychiatric disorders as a standard of care to help them quit smoking.

CASE CONTINUED

After consulting with the psychiatric pharmacist and discussing the risks and benefits of varenicline, Mr. T is started on the appropriate titration schedule (Table 1¹). A pharmacist provides varenicline education, including the possibility of psychiatric adverse effects, and tells Mr. T to report any worsening psychiatric symptoms. Mr. T is scheduled for frequent follow-up visits to monitor possible adverse effects and his tobacco use. He says he understands the potential adverse effects of varenicline and agrees to frequent follow-up appointments while taking it.

Related Resources

Leone FT, Zhang Y, Evers-Casey S, et al. Initiating pharmacologic treatment in tobacco-dependent adults. An official American Thoracic Society clinical practice guideline. Am J Respir Crit Care Med. 2020;202(2):e5-e31. doi:10.1164/rccm.202005.1982ST
Cieslak K, Freudenreich O. 4 Ways to help your patients with schizophrenia quit smoking. Current Psychiatry. 2018; 17(2):28,33.

Drug Brand Names

Bupropion • Wellbutrin
Varenicline • Chantix

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