Addressing Smoking: Is Varenicline the Answer?

March 4, 2021
David N. Osser, MD

Psychiatric Times, Vol 38, Issue 3, Volume 03,

Many patients with bipolar and other psychiatric disorders believe it is better to wait to address cigarette and other nicotine use. Here is why that is not necessarily the case.


Many patients with bipolar disorder (BD) have comorbid substance use disorders, including nicotine use. Some reports suggest 70% of patients with BD smoke.1 Importantly, data show that continuing to smoke reduces the chances of successfully addressing other substance use.2,3 The mechanisms of nicotine and other substances are similar, so it is necessary to stop all substances that are maintaining the pathological processes. Patients, and some clinicians, erroneously believe it is OK to wait to address cigarette and other nicotine use.

The most effective smoking cessation medication is varenicline. The EAGLES study, a randomized, double-blind, placebo-controlled trial (N=8144) compared varenicline, bupropion, and nicotine replacement therapy (NRT). The results confirmed many smaller studies that varenicline treatment had the best outcome (defined as abstinence at weeks 9-12).4 The investigators also studied the effects among various diagnoses by dividing patients into 2 equal cohorts—one with and the other without psychiatric disorders (70% unipolar and bipolar mood disorders, 20% anxiety disorders, and 10% psychotic disorders). The study found varenicline performed the best of the 4 treatments in both groups. In the nonpsychiatric cohort, abstinence rates were 38% for varenicline vs 26% on other active treatments and 14% on placebo. In the psychiatric cohort, abstinence occurred in 29% on varenicline, 19% to 20% on the other medications, and 11% on placebo.

The safety results may surprise some clinicians and patients. No differences were reported in moderate to severe neuropsychiatric adverse effects (eg, depression, suicidality, aggression) between varenicline and placebo in either cohort. In fact, as a result of the EAGLES findings, the US Food and Drug Administration removed the longstanding black box warning regarding such adverse effects. Interestingly, these neuropsychiatric adverse events can occur, but they are not more common if the patient is on varenicline. The effects are proposed to be due to nicotine withdrawal. These safety results are consistent with many other studies, and the call to “stop ringing the alarm bell” was in the literature even before EAGLES.5 Previous studies included patients with stabilized BD, and findings showed excellent efficacy and safety regarding precipitation of mood swings. There seem to be no significant drug interactions with any bipolar medications.

If smoking cessation fails on varenicline, controlled studies have shown augmentations with NRT or bupropion can add efficacy.6,7 Bupropion, however, is probably not a good choice for a patient with BD. The preferred augmentation would be NRT with patch and oral agents followed by slow taper; this strategy may blunt the nicotine withdrawal and increase success rates.

One minor adverse effect of varenicline is insomnia. Nightmares and disturbed awakenings associated with posttraumatic stress disorder (PTSD) may increase with varenicline. Before initiating varenicline, sleep disturbance associated with PTSD should be managed with prazosin. Five out of 8 placebo-controlled studies have found efficacy for prazosin. (Prazosin for PTSD in BD will be discussed in a future article; dosing and procedures with prazosin are best exemplified by Raskind et al.8 Prazosin may need to be increased if the nightmares resume or increase after starting varenicline.)

The hydrocarbons in cigarette smoke increase the activity of cytochrome P450 1A2, which metabolizes olanzapine and clozapine. Smoking cessation will, therefore, result in gradual deinduction of this enzyme, and plasma levels of these antipsychotics will increase over a week or 2.

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


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. Kandel ER, Kandel DB. A molecular basis for nicotine as a gateway drug. N Engl J Med. 2014;371(10):932-943.

3. Leão RM, Cruz FC, Vendruscolo LF, et al. Chronic nicotine activates stress/reward-related brain regions and facilitates the transition to compulsive alcohol drinking. J Neurosci. 2015;35(15):6241-6253.

4. 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.

5. Evins AE. Reassessing the safety of varenicline. Am J Psychiatry. 2013;170(12):1385-1387.

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

7. Koegelenberg CF, 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.

8. Raskind MA, Peterson K, Williams T, et al. A trial of prazosin for combat trauma PTSD with nightmares in active-duty soldiers returned from Iraq and Afghanistan. Am J Psychiatry. 2013;170(9):1003-1010.❒

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