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Evidence-Based Reviews

How to treat nicotine dependence in smokers with schizophrenia

Improve patients’ health, help them kick addiction with this practical approach.

Vol. 6, No. 7 / July 2007

Mr. V, age 49, has stable but symptomatic schizophrenia and a 33-year cigarette smoking history. He is very concerned because his primary care physician told him he has 2 serious smoking-related health problems: diabetes and hypertension. He tried a smoking cessation program for the general public, but it was a poor fit because of his schizophrenia symptoms.

Despite adhering to his medications (ziprasidone, 20 mg hs; perphenazine, 8 mg hs; lorazepam, 1 mg hs; zonisamide, 200 mg/d, and benztropine mesylate, 2 mg hs), Mr. V has residual auditory hallucinations, paranoid ideation, and impaired concentration and attention. He smokes approximately 1.5 packs per day, particularly when very ill, to alleviate chronic boredom, and to diminish distress from the hallucinations. All of his friends smoke, and they do not support his attempts to quit.

Successfully treating nicotine dependence can seem a formidable challenge in patients with schizophrenia:

  • 72% to 90% smoke cigarettes, compared with 21% of the general population1 (Box).2-12
  • They tend to smoke heavily, spending about one-third of their incomes on cigarettes.13
  • Their negative symptoms (such as apathy), positive symptoms (such as disorganized thinking), and cognitive impairment can reduce motivation to quit and adhere to a smoking cessation strategy.
  • Sociologic and physiologic aspects of schizophrenia reinforce their smoking habit (Table 1).9,12,14-17

Even so, smokers with schizophrenia can be highly motivated and persistent in attempting to quit.18 Promising results have been reported in trials when psychopharmacologic treatments are combined with cognitive and behavioral interventions.


Obstacles to smoking cessation for schizophrenia patients

Smokers with schizophrenia are more nicotine-dependent, more likely to become medically ill, and less likely to receive help in quitting, compared with the general population. They:

  • begin smoking at a higher rate before diagnosis or treatment for schizophrenia, compared with persons who do not go on to develop the disorder2
  • smoke each cigarette more intensely, extracting more nicotine per cigarette3-5
  • have higher rates of smoking-related illness and medical morbidity6
  • are much less likely to receive physician advice to quit smoking.7

Many persons with severe mental illness are misinformed about the risks and benefits of smoking vs nicotine dependence treatment.8 They often fear and overestimate the medical risks of nicotine replacement therapies.9 Many believe smoking relieves depression and anxiety,10 whereas nicotine actually is anxiogenic. Nicotine may improve some aspects of cognitive dysfunction in schizophrenia, which could be a disincentive for patients to quit smoking.11,12

This article reviews these empiric studies and suggests practical ways for clinicians to create smoking cessation and relapse prevention plans for individuals with schizophrenia.

Table 1

Why up to 90% of schizophrenia patients smoke cigarettes

Sociologic barriers to quitting

  • Their social groups often include a high percentage of heavy smokers
  • Some fear NRT is ‘unhealthy,’ causes cardiac arrest, or increases nicotine cravings9 (see Table 2, for an accurate NRT side effect profile)
  • They are unlikely to achieve sustained abstinence from a single cessation attempt

Physiologic reinforcers and disease factors

  • Nicotine may modulate schizophrenia’s cognitive dysfunction, including sensory gating (a measure of ability to filter out irrelevant environmental stimuli) and attention12,14
  • Nicotine may increase disease-associated reduction in nicotinic acetylcholine receptor activity15,16
  • Smoking (but not nicotine) reduces antipsychotic blood levels by increasing metabolism and may reduce side effects of antipsychotic medications17
  • Schizophrenia’s cognitive impairment can make smoking cessation strategies difficult to follow

Clinical trials of smoking cessation

Inadequate interventions. Conventional regimens—consisting of 8 to 12 weeks with sustained-release bupropion or nicotine replacement therapy (NRT) added to supportive or cognitive-behavioral therapy (CBT)19—are well-tolerated by patients with schizophrenia but only modestly effective. CBT alone (or with placebo) has not been effective for smoking cessation in schizophrenia. In clinical trials, abstinence rates have been:

  • 4% to 19% after 3 to 6 months with bupropion or NRT and CBT
  • ≤6% with placebo and CBT.20-23

Multifaceted interventions. High-dose NRT patch treatment (2 patches at a time) has not consistently shown additional benefits compared with single-patch treatment.24,25 However, combining short-acting NRT (gum, lozenge, inhaler, or nasal spray) with a long-acting NRT preparation (transdermal patch) is well-tolerated and has been shown to improve sustained abstinence rates26 (Table 2).

In a double-blind, placebo-controlled trial,27 51 smokers with schizophrenia were randomly assigned to receive combination NRT (21-mg NRT patch plus ≤18 mg/d NRT polacrilex gum prn) added to bupropion SR, 150 mg bid, or placebo. Smoking cessation—defined as quitting on the assigned date and maintaining continuous abstinence for 4 weeks (measured by expired air carbon monoxide <9 ppm and self-report of abstinence at weekly visits)—was achieved by:

  • 52% of those receiving bupropion and dual NRT
  • 19% who received placebo and the 2 forms of NRT.

Preventing relapse. Relapse is common among all smokers but especially in those with schizophrenia. In clinical trials, 70% to 83% of smokers with schizophrenia who attained abstinence relapsed to smoking within 6 to 12 months of stopping nicotine dependence treatment.21,22,27,28

In one clinical trial, >50% of patients achieved 4 weeks of continuous abstinence on a regimen of bupropion SR, 150 mg bid; nicotine patch (21 mg/d); and as-needed nicotine gum (≤18 mg/d). However:

  • 31% relapsed to smoking while NRT was being tapered from ~40 to 20 mg/d
  • 77% relapsed after nicotine dependence treatment was discontinued.27

Longer use of pharmacotherapy may be needed to prevent relapse to smoking in the schizophrenia population. In a recent open case series, 17 of 42 smokers with schizophrenia were able to quit for at least 2 weeks with a combination of bupropion SR, 150 mg bid, and dual NRT. Among those who quit, 13 (76%) remained abstinent for 12 additional months when offered continued pharmacotherapy and tapering CBT (AE Evins, under review).

Table 2

Suggested pharmacologic approaches for smoking cessation in patients with schizophrenia



Specific instructions

Potential side effects

Bupropion SR

150 mg bid

Consider maintenance treatment if patient attains abstinence and tolerates medication well

Insomnia, anxiety, irritability (usually mild, time-limited); contraindicated in patients with a seizure disorder or who are at high risk for seizures; take care when prescribing in combination with clozapine


0.5 mg once daily for 3 days; 0.5 mg bid for 4 days; 1 mg bid ongoing

No published data in smokers with schizophrenia; several trials are underway

Nausea, headache (nausea can be managed in some patients with dose reduction)

NRT patch

21 mg/d to start

Consider combination treatment with short-acting preparation; consider maintenance treatment if patient attains abstinence and tolerates medication well

Rash, skin irritation, hypersensitivity reaction

Short-acting NRT (gum, lozenge, inhaler, spray)

≤20 mg/d as needed for craving, in 2-mg or 4-mg increments

Instruct in correct use, particularly with gum; for patients who attain abstinence, consider maintenance of as-needed short-acting NRT


NRT: nicotine replacement therapy

CASE CONTINUED: Treating nicotine dependence

Mr. V cut down to 10 cigarettes a day during a 4-week motivational enhancement/psychoeducation intervention for smokers with major mental illness.29 He then enrolled in a 12-week study in which subjects received high-dose dual NRT and bupropion SR or placebo.

Mr. V was reluctant to use the NRT patch because he believed rumors that it could cause a heart attack, especially if he smoked while using a patch. He did try the patch, however, after his clinicians informed him it would increase his chances of quitting.

He received bupropion SR, 150 mg bid; NRT patch, 21 mg/d; and nicotine polacrilex gum, up to 18 mg/d as needed, and tolerated the regimen well. After 4 weeks, he quit smoking on the quit date. His blood pressure—monitored weekly for the first month then monthly thereafter—remained stable throughout the intervention.

Prescribing considerations

Metabolic changes. Smoking—but not NRT—induces hepatic clearance of many psychotropics, and smoking cessation can be associated with increased drug serum levels. Polycyclic aromatic hydrocarbons present in cigarette smoke—but not NRT—induce hepatic aryl hydrocarbon hydroxylases and cytochrome P (CYP)-450 isozymes, primarily CYP 1A1, 1A2, and 2E1, thereby increasing metabolic clearance of medications—such as clozapine—that are substrates for these enzymes.

Smoking cessation is associated with a 30% to 42% reduction in activity of CYP 1A2, and the half-life of this reduction is 27 to 54 hours. Thus, therapeutic drug monitoring and dose reduction of 10% over the first 4 days of tobacco abstinence is recommended to avoid toxicity. If the patient remains abstinent from tobacco, further reducing the antipsychotic dose may be warranted, based on individual assessment.

Weight gain. Patients who quit smoking gain an average of 3 to 5 kg.30

Nicotine withdrawal. Patients are used to thinking that nicotine is calming, whereas in reality nicotine and smoking are anxiogenic, and cigarette smoking alleviates the anxiety that comes from nicotine withdrawal.31 Educate patients about nicotine withdrawal symptoms, which easily can be confused with early signs of a psychotic relapse but are much more time-limited:

  • dysphoria and irritability
  • anxiety
  • insomnia
  • reduced heart rate
  • restlessness
  • difficulty concentrating.

Bupropion SR at 150 mg bid has been well-tolerated when added to antipsychotics and modestly effective for smoking cessation in this population. It has been associated with reduced negative symptoms and greater symptom stability during the cessation attempt—compared with placebo—and is well-tolerated when combined with NRT.20-22,27

NRT in a variety of delivery forms has been well tolerated and modestly effective for smoking cessation in schizophrenia.23,27,28 Combinations of short-acting NRT (gum, lozenge, inhaler, or nasal spray) with the long-acting NRT patch improve long-term abstinence rates in smokers in the general population26 and may improve abstinence rates in those with schizophrenia.27 Maintaining the pharmacotherapy used to achieve abstinence may also improve sustained abstinence rates.

Varenicline is a partial nicotinic receptor agonist approved for treating tobacco dependence. No reports have been published on its safety and efficacy for smoking cessation in persons with schizophrenia.

In our experience with open-label varenicline for nicotine dependence in schizophrenia, 8 of 9 patients quit smoking, reported reduced cravings, and remained clinically stable on the agent for 6 to 9 months. All had previously relapsed after discontinuing NRT, bupropion, or the combination.

Controlled trials are needed to discern this agent’s place in the treatment hierarchy for smokers with schizophrenia, and several such trials are underway.

10-step office-based approach

CBT alone is not effective for smoking cessation in the schizophrenia population,22,28 but pharmacologic interventions have not been shown to succeed without concurrent behavioral treatment.

The 10 behavioral treatments described below and the tools listed in Table 3 can be covered in 1 or 2 visits and individualized for a relatively brief, office-based approach. Using the complete list may be ideal, but you can deliver a reasonable behavioral intervention by choosing tasks tailored to each patient’s needs. After the initial session, review these interventions at follow-up appointments to reinforce skills.

1 Send a clear and simple message to your patients to quit smoking. If possible, provide a handout about health risks of smoking and benefits of quitting.

2 Elicit the patient’s reasons for wanting to quit, and help him or her list these reasons as specifically as possible, such as:

  • “I want to have more spending money.”
  • “I want to improve my health.”
  • “I want to make my sister proud.”

Copy this list on index cards for the patient, and encourage him or her to carry 1 and post others around the house.

3 Prescribe pharmacotherapy, as supported by clinical trial results. Explain the rationale for its use, and encourage adherence. Review proper techniques for using NRT patches and gum, lozenge, inhaler, or nasal spray.

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