Review of pharmacotherapy for smoking cessation in patients with schizophrenia.

Smoking cessation is a chronic issue surrounding individuals with schizophrenia. It is estimated that up to 90% of patients diagnosed with schizophrenia smoke cigarettes. The purpose of this article is to provide a nonsystematic review of the efficacy of smoking cessation interventions as well as to explore the potential neuropsychiatric adverse effects of these agents in patients with schizophrenia. Eighteen studies were found and included in the review. Overall, nicotine replacement therapy, bupropion, and varenicline have all proven their effectiveness at either promoting smoking abstinence or a significant reduction in cigarette use.

Introduction

Cigarette smoking is an epidemic that plagues the United States despite massive efforts to educate the public on its many dangers. It is estimated that one out of every six adults in the United States currently smokes.1 Cigarette smoking is especially a concern among those diagnosed with mental illness with the prevalence being one in every five adults.2 It is estimated that up to 90% of patients diagnosed with schizophrenia smoke cigarettes.3 The purpose of this article is to provide a nonsystematic review of the efficacy of smoking cessation interventions as well as to explore the potential neuropsychiatric adverse effects of these agents in patients with schizophrenia.

Research has proposed that decreased nicotinic acetylcholine receptors (nAChRs) in certain brain regions may play a role in the pathogenesis of schizophrenia.3 Nicotine functions in the brain by binding to nAChRs, stimulating the release of dopamine from neurons, which is thought to be reduced in patients with schizophrenia. Therefore, it is hypothesized that individuals with schizophrenia use nicotine as a way to self-medicate, potentially reducing the cognitive and negative symptoms of the disease.4,5

Another barrier faced by individuals with schizophrenia is the low success rate of smoking cessation attempts and overall decreased motivation to quit.6 A study published in 2009 by Moss and colleagues7 demonstrated that individuals with schizophrenia who were unsuccessful at quitting smoking had significant deficits in prefrontal cortex–related neuropsychological testing. This suggests that it may be more difficult for an individual with schizophrenia to achieve smoking cessation due to the structural and physiological abnormalities noted above as well as other factors such as affordability, access to care, and lifestyle.

It is estimated that patients with schizophrenia have a 20% reduction in life expectancy compared to the general population.8 This reduction in life span is mostly attributed to respiratory and cardiovascular causes of death, both of which are perpetuated by cigarette use.8 Patients with schizophrenia have an increased risk of developing comorbidities, such as diabetes, hypertension, myocardial infarction, hyperlipidemia, and stroke over the general population.9,10 All of these factors put patients with schizophrenia at an increased risk of death and complications, which is why an effective smoking cessation therapy is important.

Current pharmacotherapies that are Food and Drug Administration approved for smoking cessation are nicotine replacement therapy (transdermal patches, lozenges, gum, inhalers, nasal sprays), bupropion, and varenicline. Nicotine replacement therapy (NRT) functions as a direct agonist at nAChRs, providing the nicotine that is lost from a reduction in smoking.11 Bupropion functions as a dopamine and norepinephrine reuptake inhibitor whereas varenicline is a partial nicotine agonist. The mechanism of bupropion for smoking cessation is not fully understood but is thought to be related to its ability to decrease dopamine and noradrenaline response to cessation of smoking, therefore decreasing nicotine withdrawal.12 Varenicline functions at the nAChRs by preventing nicotine from binding to the receptor while still stimulating the receptor enough to get some release of dopamine at the presynaptic terminal.13 These mechanisms allow for the addictive properties of smoking to have less of an effect over time, thus lessening the symptoms of nicotine craving and withdrawal. Many small studies have been conducted to determine the efficacy of these pharmacotherapies in schizophrenia because the mental health population has been excluded in the larger studies.

Methods

A literature search was conducted with the use of PubMed (limited to clinical trials) using medical subject headings (MeSH) and free text keywords: smoking cessation, bupropion, varenicline, nicotine replacement therapy, schizophrenia, psychotic, nicotine patch, and combinations of these phrases (MeSH terms used: smoking cessation AND schizophrenia AND nicotine replacement therapy, smoking cessation AND schizophrenia AND bupropion, smoking cessation AND schizophrenia AND varenicline, smoking cessation AND psychotic, schizophrenia AND varenicline, schizophrenia AND nicotine patch, schizophrenia AND bupropion). A total of 137 studies were found in the overall search criteria, and 18 studies were included. The remaining 119 studies were excluded (24 were duplicates, and the content of 94 studies was not pertinent). Scopus was utilized to confirm search results. Articles were included without regard to country of origin or study sample size. Patient age was not a specific exclusion criteria. Articles chosen included the mention of Diagnostic and Statistical Manual of Mental Disorders, 4th edition criteria for diagnosis of schizophrenia or schizoaffective disorder, similar outcome measures (ie, exhaled carbon monoxide [CO], serum, and urine cotinine), analysis of adverse events, exacerbation of positive and negative symptoms of schizophrenia, and other neuropsychiatric side effects.

Results

Nicotine Replacement Therapy

Chou and colleagues14 conducted a study to determine the effectiveness of nicotine patch therapy for smoking cessation in patients with schizophrenia. After 8 weeks, it was found that nicotine dependence, the number of cigarettes smoked per day, and exhaled CO levels were all lower to a point of statistical significance as compared to placebo.14 Exhaled CO is easy to measure in a primary care setting and is a good indication of recent smoking activity based on its 5-hour half-life.15 Continued abstinence was found at the 3-month follow up.14 Dale Horst and colleagues16 investigated the long-term effects of NRT with analyses at 3 months and 9 months. They found that 100% of patients on extended placebo therapy relapsed as compared to the 33% that were on active treatment. More recently, the varying doses of transdermal nicotine patches and their effect on smoking cessation were investigated in patients with schizophrenia.17 It was found that there was no significant difference in a high-dose patch (31.2 mg) compared to the lower-dose (20.8 mg) patch and the effect on cessation.17 There were no serious adverse events with this therapy that were attributed to the use of the transdermal nicotine patches other than dermal irritation.14,16,17 More detailed results can be found in Table 1.

TABLE 1

Comparison of outcomes of nicotine replacement therapy, bupropion therapy, and varenicline therapy versus placebo trials conducted in individuals with schizophrenia

Bupropion

Bupropion has been studied extensively as an agent for smoking cessation. Studies18-24 of the efficacy of bupropion on smoking cessation in patients with schizophrenia have produced conflicting data. George and colleagues18 found a statistically significant decrease in overall smoking activity and reported 3 quitters with undetectable carbon monoxide levels as reflected in Table 1. Levels of plasma cotinine, a major metabolite of nicotine with a 16-hour half-life, were also assessed in a subset of patients from the same study.18 Although not statistically significant, reduced cotinine levels were found in the bupropion group when compared to the placebo group.18 A follow-up trial19 of 17 individuals with schizophrenia showed that if individuals reduced their smoking activity during active treatment, then they would continue to do so after 2 years. A study by Evins and colleagues24 showed a small (–4.2) decrease in positive schizophrenia and depressive symptoms on the Brief Psychiatric Rating Scale. Three studies19,22,23 found no significance in sustained abstinence after cessation of treatment whereas 1 study24 found significance in maintained abstinence at 24 weeks. Bupropion is classified as an antidepressant agent and possesses the warning for increased risk of suicidality.25 Yet many studies20-22 have been conducted with bupropion in patients with schizophrenia with minimal neuropsychiatric side effects observed. Overall, bupropion has shown that it can be an effective smoking cessation tool in patients with schizophrenia, but more studies will need to be conducted to see if long-term bupropion is efficacious for sustained abstinence.

Varenicline

A small pilot study (n = 8) by Weiner and colleagues26 showed that varenicline helped patients with sustained abstinence as measured by CO levels versus placebo. A larger study by Smith and colleagues27 showed varenicline decreased the number of cigarettes smoked, CO levels, plasma nicotine and cotinine levels, and brief urges to smoke. Other data showed varenicline reduced the average number of cigarettes smoked per day over placebo28 and a statistically significant longer length of smoking abstinence.29 Varenicline for smoking cessation in individuals with schizophrenia has shown no difference between treatment and placebo groups for exacerbations or worsening symptoms of schizophrenia.26-31 A study conducted by Williams and colleagues31 showed a slightly higher increase in suicidality with the placebo group (7%) compared to the varenicline group (6%) with neuropsychiatric events being slightly higher with varenicline, none of which were statistically significant. A study conducted by Meszaros and colleagues28 2 years later also noted that depression and anxiety were worsened in the placebo group compared to the varenicline group. Altogether, varenicline has been shown to be an effective treatment option with limited adverse neuropsychiatric side effects.

Comparative and Combination Data

Two studies32,33 found that nicotine replacement therapy is more efficacious when combined with bupropion than when used alone (Table 2). The combination of these 2 agents had no significant effect on positive or negative symptoms of schizophrenia.33 When varenicline use was compared to bupropion, Fatemi and colleagues34 found that there were no significant differences between the groups other than the varenicline group was more effective at lowering the urge to smoke in patients with schizophrenia.

TABLE 2

Comparisons and combinations of smoking cessation pharmacotherapies conducted in individuals with schizophrenia

Added Effectiveness With Antipsychotics

Some smoking cessation data suggest that second-generation antipsychotics enhance the effectiveness of bupropion or NRT. A study by George and colleagues35 found that individuals taking atypical antipsychotics in combination with the nicotine transdermal patch had greater abstinence rates than those taking typical antipsychotics alone. Evins and colleagues23 noted that individuals taking atypical antipsychotics with bupropion had an overall reduction in expired air CO levels but not on abstinence rates versus those on typical antipsychotics alone. Two-year follow-up data published by Evins and colleagues19 found that 4 individuals who were able to maintain abstinence, 3 on clozapine and 1 on haloperidol.

Drug Interactions

Cigarette smoke can induce cytochrome P450 isoenzyme 1A2, which increases the metabolism of certain antipsychotics.3 For example, when patients decrease or stop smoking, serum levels of clozapine and olanzapine may increase.3 Patients should be monitored closely for side effects of antipsychotics as smoking cessation ensues.

Safety

While bupropion and varenicline have been studied extensively as agents for smoking cessation, both agents have been linked to neuropsychiatric events. Individuals with schizophrenia have been commonly excluded from most large clinical trials of smoking cessation.25,36 No studies included in this review resulted in significant neuropsychiatric adverse events related to smoking cessation treatment. The EAGLES trial was a large (n = 8114), double-blind, placebo-controlled trial in which the safety of NRT, varenicline, and bupropion were investigated in psychiatric versus nonpsychiatric patients.36 Psychiatric disease states included mood disorders (major depressive disorder, bipolar disorder), anxiety disorders (panic disorder, post-traumatic stress disorder, obsessive-compulsive disorder, social phobia and generalized anxiety disorder), psychotic disorders (schizophrenia and schizoaffective disorder, borderline personality disorder). Of these individuals included, 386 were characterized as having a psychotic diagnosis. The study showed no statistical differences in neuropsychiatric adverse events in patients receiving active treatment in comparison to placebo.37 In December 2016, the Food and Drug Administration removed the black box warning from the varenicline label about the risk of serious neuropsychiatric events and is updating the boxed warning on bupropion.38

Discussion

Nicotine replacement therapy, bupropion, and varenicline are all plausible options for smoking cessation in individuals with schizophrenia. All of these agents were well tolerated in regards to neuropsychiatric events. Data18,23,24,34 also show that bupropion and varenicline are effective in stabilizing the positive and negative symptoms that accompany schizophrenia. The relationship between bupropion or NRT and second-generation antipsychotics was also noted in which patients on both agents showed increased abstinence rates.35

In the combination and comparative studies,32-34,39 it was found that varenicline may be superior to bupropion, and that combination therapy is more effective than single-agent therapy. This consequently leads to the notion that smoking cessation therapy in patients with schizophrenia is multidimensional with the need for more than 1 cessation medication to achieve sustained abstinence.

Sustained abstinence needs to be further studied in patients with schizophrenia. Current studies have found that many individuals relapse back into their previous smoking habits after discontinuation of smoking cessation pharmacotherapy. Long-term studies with extended use of both bupropion and varenicline, with or without NRT, could be beneficial in uncovering an effective course of therapy for these individuals.

It is important to keep in mind that these studies were very small and excluded many patients with unstable disease or comorbid substance abuse. This limits the generalizability of these studies to those individuals whose schizophrenia is well controlled on antipsychotics and who furthermore do not suffer from substance abuse, such as illicit drug use.

Drug-drug interactions should be kept in mind when initiating or stopping smoking cessation medications in patients with schizophrenia. Bupropion is a strong inhibitor of cytochrome P450 isoenzyme 2D6 (CYP2D6) as well as an organic cation transporter-2.25 Serum levels of first-generation antipsychotics (eg, haloperidol) may be increased by concomitant bupropion use, and hence, these patients may require closer monitoring for side effects. Second-generation antipsychotics (eg, risperidone) may also be substrates of CYP2D6, which means that their use with bupropion should be closely monitored as well. It has been shown that nicotine can reverse the cognitive side effects of haloperidol use, and therefore, patients on haloperidol should be monitored closely for these side effects once smoking cessation is initiated.40

Certain patient-specific factors should be taken into account when choosing an agent, such as cost of pharmacotherapies, stability of disease, comorbid conditions, and patient compliance. Nicotine replacement therapy, bupropion, and varenicline are all effective smoking cessation therapies for patients with schizophrenia.