As you have likely noted in your practice, smoking is very common among patients with mental illness. Studies have shown that nearly every psychiatric diagnosis is associated with an increased prevalence of smoking, and that there is a growing disparity in smoking rates between patients with mental illness and the general population (Dickerson F et al, Psychiatr Serv 2018;69(2):147–153). Smoking cessation rates are lower in patients with mental illness, so getting your patients to quit can be a challenge. But there is good news—studies show not only that nicotine replacement therapy, bupropion, and varenicline work for these patients, but that initial fears of them exacerbating psychiatric illness have been overblown (Evins AE et al, J Clin Psychopharmacol 2019;39(2):108–116).

Nicotine replacement therapy
Nicotine replacement therapy (NRT) supplies an alternative source of nicotine without harmful exposure to smoke. NRT comes in a daily long-acting transdermal patch as well as a variety of short-acting formulations. The patch delivers a constant level of nicotine throughout the day, reducing episodes of craving.

The starting dose will depend on the patient’s nicotine consumption. As a simple rule of thumb, since a single cigarette delivers about 1 mg of nicotine and there are 20 cigarettes in a pack, patients who smoke a single pack per day (ppd) should start with the 21 mg patch. You can start 2-ppd smokers on two 21 mg patches, and 0.5-ppd smokers should start at 14 mg.

Keep patients on this initial dose for four to six weeks and decrease by 7 mg every four weeks or so until the medication is completely tapered off. Some patients may require longer periods at each dose or may smoke a bit with the patch on. As long as they are smoking less than before, it makes sense to continue treatment as a harm reduction measure. Finally, be sure to have patients remove the patch before bed in order to minimize the possibility of nightmares.

Many patients experience breakthrough cravings while using the patch—if so, they should add one of the short-acting agents. Gum and lozenges are the most common, but there are a variety of formulations that are generally felt to be equivalent (Hajek P et al, Arch Intern Med 1999;159(17):2033–2038). One piece of gum delivers 2 or 4 mg of nicotine over 30 minutes.

Combining long- and short-acting formulations, so-called combination NRT (cNRT) is superior to either formulation alone (Lindson N et al, Cochrane Database Syst Rev 2019;4(4):CD013308), though light smokers could consider just going with the patch or the gum. cNRT can cause jitteriness, though it usually isn’t a problem as long as the patient only takes the short-acting formulation when experiencing cravings. Finally, vaping is not considered NRT, though it is inching closer (www.tinyurl.com/te3ejze; also see Q&A in this issue for more information about vaping).

Varenicline
Varenicline (Chantix) works as a partial agonist at nicotine receptors and, along with cNRT, is the most effective smoking cessation agent. To start, titrate the dose as follows: 0.5 mg daily for days one to three, 0.5 mg twice daily for days four to seven, then 1 mg twice daily for at least 11 more weeks (total of 12 weeks). If your patient has stopped smoking at the end of 12 weeks and is not craving cigarettes, varenicline can be discontinued without tapering. If the patient hasn’t achieved abstinence or is still experiencing cravings, varenicline can be continued at 1 mg twice daily for up to a year (Leone FT et al, Am J Respir Crit Care Med 2020;202(2):e5–e31).

Typically, patients are instructed to quit smoking on day eight. While this is the most studied approach, the manufacturer insert for Chantix indicates that patients can set a quit date as far out as five weeks after starting the medication or taper smoking over as long as three months (www.tinyurl.com/368va6sr). Even if patients are not ready to set a quit date, experts still recommend starting varenicline since most patients who take it are eventually able to quit (Leone et al, 2020). Although vivid dreams and nightmares aren’t very common on varenicline, tell patients about the possibility regardless.

Varenicline’s potential psychiatric side effects have been widely covered, but these worries were largely unfounded. A meta-analysis of 39 randomized controlled trials covering 10,761 patients found no difference between varenicline and placebo in rates of depression, suicidal ideation, or aggression (Thomas KH et al, BMJ 2015;350:h1109). This makes varenicline safe for patients with stable mental illness and a reasonable first-line treatment, although it is always wise to monitor for possible worsening of symptoms.

Bupropion
Bupropion (Zyban, Wellbutrin) works by inhibiting dopamine uptake in the mesolimbic dopamine system (reward center) of the brain. The manufacturer-recommended smoking cessation dosing is to start at 150 mg daily for three days then increase to 150 mg BID (or 300 mg of the XL formulation). It turns out that 150 mg daily is probably just as effective and causes fewer side effects (Hurt RD et al, N Engl J Med 1997;337(17):1195–1202). Like varenicline, bupropion can be stopped without tapering.

While superior to placebo, bupropion is not quite as effective as varenicline (Anthenelli RN et al, Lancet 2016;387(10037):2507–2520). It is also contraindicated in those with eating disorders or seizure histories because it lowers the seizure threshold. Bupropion may, however, be a particularly good choice for smokers with comorbid depression. It is also safe and effective for patients with schizophrenia (Tsoi DT et al, Cochrane Database Syst Rev 2013;2013(2):CD007253) and may have the lowest rate of mood flip among the antidepressants in patients with bipolar disorder who are already on a mood stabilizer (Leverich GS et al, Am J Psychiatry 2006;163(2):232–239). Varenicline and bupropion can be safely combined with NRT, which may help some patients—however, the combination might also increase side effects, and we have only mixed data on its efficacy (Baker TB et al, JAMA 2021;326(15):1485–1493).

Smoking and the P450 system
Smoking induces a number of P450 enzymes, but the clinically relevant one is CYP1A2, which metabolizes several antidepressants and antipsychotics. Smoking will decrease serum levels of medication, while quitting smoking will increase medication levels. The relevant antidepressants here are fluvoxamine, duloxetine, mirtazapine, and trazodone (Oliveira P et al, Ann Gen Psychiatry 2017;16:17). For antipsychotics, smoking can reduce serum levels of clozapine by 50% and olanzapine by 30% (Tsuda Y et al, BMJ Open 2014;4(3):e004216).

There is no standard protocol for how to adjust dosages in smokers vs ­nonsmokers. As always, dosing should follow the clinical picture—be vigilant for the emergence of side effects in patients who quit smoking and the waning of medication efficacy in patients who start smoking more. For clozapine, we recommend monitoring serum levels as well.

Note that P450 induction is due to polycyclic aromatic hydrocarbons (PAHs) in smoke, not nicotine itself. Therefore, NRT and other smokeless forms of tobacco do not induce medication metabolism. Aerosols from vaping can contain PAHs, though typically at lower amounts than cigarettes (Traboulsi H et al, Int J Mol Sci 2020;21(10):3495), so vaping’s effects on the P450 system can be unpredictable.

CATR Verdict: NRT, varenicline, and bupropion are safe and effective cessation agents for smokers with stable mental illness. For most patients, we recommend starting with cNRT or varenicline, since these are both more effective than bupropion. As always, consider comorbid conditions and potential medication interactions when choosing an agent.