Plain language summary
Are there any effective interventions to help individuals with schizophrenia to quit or to reduce smoking?
People with schizophrenia are very often heavy smokers. It is uncertain whether treatments that have been shown to help other groups of people to quit smoking are also effective for people with schizophrenia. In this review, we analysed studies which investigated a wide variety of interventions. Our results suggested that bupropion (an antidepressant medication previously shown to be effective for smoking cessation) helps patients with schizophrenia to quit smoking. The effect was clear at the end of the treatment and it may also be maintained after six months. Patients who used bupropion in the trials did not experience any major adverse effect and their mental state was stable during the treatment. Another medication, varenicline (a nicotine partial agonist which has been shown to be an effective intervention for smoking cessation in smokers without schizophrenia), also helps individuals with schizophrenia to quit smoking at the end of the treatment. However, this evidence is only based on two studies. We did not have sufficient direct evidence to know whether the benefit of varenicline is maintained for six months or more. In addition, there has been ongoing concern of potential psychiatric adverse events including suicidal ideas and behaviour among smokers who use varenicline. We found that two patients, among 144 who used varenicline, had either suicidal ideas or behaviour. Smokers with schizophrenia who receive money as a reward for quitting may have a higher rate of stopping smoking whilst they get payments. However, there is no evidence that they will remain abstinent after the reward stops. There was too little evidence to show whether other treatments like nicotine replacement therapy and psychosocial interventions are helpful.
Postoje li učinkoviti postupci koji bi pomogli oboljelima od shizofrenije u prestanku ili smanjenju pušenja?
Osobe oboljele od shizofrenije su često teški pušači. Nije utvrđeno pomažu li terapije koje su pokazale učinkovitost kod drugih skupina i oboljelima od shizofrenije. U ovom Cochrane sustavnom pregledu analizirane su studije koje su istraživale različite intervencije. Rezultati upućuju da bupropion (lijek antidepresiv koji se pokazao učinkovit za prestanak pušenja) pomaže pacijentima sa shizofrenijom u prestanku pušenja. Učinak je bio jasan na kraju terapije i mogao se održavati i nakon šest mjeseci. Pacijenti koji su koristili bupropion nisu iskusili nikakve značajnije nuspojave i njihovo mentalno stanje je bilo stabilno tijekom terapije. Drugi lijek, vareniklin (parcijalni agonist nikotinskih receptora koji se pokazao učinkovit u prestanku pušenja za pojedince koji nisu oboljeli od shizofrenije), isto pomaže pojedincima oboljelim od shizofrenije u prestanku pušenja na završetku terapije. Dokazi su temeljeni na samo dvije studije. Nije pronađeno dovoljno izravnih dokaza kako bi se znalo je li učinak vareniklina održan šest mjeseci ili više. Dodatno, postoji bojazan da bi se mogle razviti psihijatrijske nuspojave, uključujući samoubilačke (suicidalne) misli i ponašanje među pušačima koji koriste vareniklin. Pronađeno je da su dva pacijenta, od 144 koji su koristili vareniklin, pokazivali suicidalne misli ili ponašanje. Pušači sa shizofrenijom koji su dobivali novac kao nagradu za prestanak pušenja mogu imati veće stope prestanka pušenja dok primaju novac. Međutim, ne postoje dokazi da će nastaviti apstinirati nakon prestanka nagrađivanja. Bilo je premalo dokaza koji pokazuju pomaže li toj skupini pacijenata u prestanku ili smanjenju pušenja neka druga terapija poput terapije nadoknade nikotina ili psihosocijalnih intervencija.
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Streszczenie prostym językiem
Czy istnieją skuteczne interwencje, które mogą pomóc osobom chorującym na schizofrenię rzucić lub ograniczyć palenie?
Osoby chorujące na schizofrenię bardzo często palą nałogowo papierosy. Nie jest pewne, czy terapie antynikotynowe o udowodnionej skuteczności w innych grupach osób, są także skuteczne wśród osób chorych na schizofrenię. W niniejszym przeglądzie dokonano analizy badań oceniających szeroki zakres interwencji. Nasze wyniki sugerowały, że bupropion (lek przeciwdepresyjny, którego skuteczność w terapii antynikotynowej już wykazano) pomaga pacjentom ze schizofrenią rzucić palenie. Efekt zaznaczył się wyraźnie pod koniec leczenia i może się także utrzymywać po sześciu miesiącach. Pacjenci, którzy stosowali bupropion podczas badań, nie doświadczali żadnych poważnych działań niepożądanych, a ich stan psychiczny był stabilny podczas leczenia. Inny lek, wareniklina, (częściowy agonista nikotyny, o udowodnionej skuteczności w terapii antynikotynowej u osób bez schizofrenii), pomaga również osobom ze schizofrenią rzucić palenie pod koniec leczenia. Dane te są jednak oparte tylko na dwóch badaniach. Nie dysponowano wystarczającymi danymi bezpośrednimi, aby stwierdzić czy korzyść ze stosowania warenikliny utrzymuje się przez sześć lub więcej miesięcy. Dodatkowo, cały czas obecne były obawy związane ze zdarzeniami niepożądanymi, w tym myślami i zachowaniami samobójczymi, u palaczy wykorzystujących wareniklinę. Stwierdzono, że u dwóch pacjentów, spośród 144 zażywających wareniklinę, występowały myśli lub zachowania samobójcze. Palacze ze schizofrenią, którzy otrzymywali pieniądze jako nagrodę za zerwanie z nałogiem, częściej rzucali palenie, gdy dostawali zapłatę. Nie ma jednak danych wskazujących, to, że pozostaliby w abstynencji po tym, jak przestaną otrzymywać nagrodę. Dysponowano zbyt niewielką ilością danych, aby stwierdzić, czy inne leczenie jak nikotynowa terapia zastępcza i interwencje psychospołeczne są pomocne.
Uwagi do tłumaczenia
Tłumaczenie Bartłomiej Matulewicz Redakcja Katarzyna Mistarz
Schizophrenia is a chronic and severe mental illness affecting approximately one per cent of the general population (American Psychiatric Association 1994). A meta-analysis of 42 epidemiological studies across 20 different countries shows that people with schizophrenia have more than five times the odds of current smoking than the general population, and smoking cessation rates are much lower in smokers with schizophrenia compared with the general population (de Leon 2005a). In addition, smokers with schizophrenia smoke more heavily and extract more nicotine from each cigarette (Olincy 1997; Kelly 1999; de Leon 2005a; Williams 2005). People with schizophrenia have a shorter life expectancy than the general population, and chronic cigarette smoking has been suggested as a major contributing factor to higher morbidity and mortality from malignancy and cardiovascular and respiratory diseases in this group of patients, especially in people aged 35 to 54 years. (Brown 2000; Lichtermann 2001; Kelly 2011). Tobacco use among individuals with schizophrenia is financially costly; a study has shown that it consumed 27% of the monthly income of those residing in a high tobacco tax state (Steinberg 2004).
Heavy smoking in patients with schizophrenia has been reported to be associated with more of the positive symptoms of the condition, increased substance misuse, more frequent psychiatric hospitalisation and a higher suicide risk (Goff 1992; Ziedonis 1994; Workgroup on Substance Use Disorders 2006). Tobacco smoking also increases the metabolism of some antipsychotic medications (Desai 2001), and some patients may use tobacco to alleviate the side effects of neuroleptic medications. Individuals with schizophrenia often have impairment in their cognitive function, including difficulty in filtering out unnecessary information (Kumari 2002), secondary to abnormalities in the sensorimotor gating. Cigarette smoking appears to improve sensory gating in patients with schizophrenia (Adler 1998). Hence, patients with schizophrenia may use cigarette smoking to improve their cognitive function. In addition to the cognitive deficits of frontal executive function and in attention among individuals with schizophrenia, depressive symptoms, drug misuse, disorganised thinking and poor task persistence may also explain their lower motivation and greater difficulty for smoking cessation (Culhane 2008; Moss 2009). Patients with schizophrenia may be ambivalent about giving up smoking, as there are few role models of ex-smokers and less specific support available for quitting smoking. Recent research also showed that they perceived a lower risk to their health associated with smoking when compared to people without schizophrenia (Kelly 2012). Furthermore, smoking is sometimes condoned in mental health settings, and in the past cigarettes were used in token economies to reinforce positive patient behaviour (Gustafson 1992). Smoking has also been recently shown as a possible way for social facilitation and stimulation enhancement among individuals with schizophrenia (Kelly 2012)
Tobacco control specialists and healthcare providers previously have not offered tobacco dependence treatment to patients with schizophrenia, probably secondarily to stigma, lack of information, or perceived hopelessness regarding abstinence (Williams 2006). More recent initiatives have aimed to improve the physical health of those with schizophrenia, and guidelines for cessation interventions for smokers with schizophrenia have now been published (Zwar 2007; Fiore 2008; Dixon 2009; Buchanan 2009).
Smokers with schizophrenia have a more severe nicotine dependence compared to smokers without schizophrenia (de Leon 2005a). Hence, interventions may not be as effective as they have been shown to be in the general population. We also need to consider the safety of these interventions, particularly those involving drug therapy. Some of the pharmacological treatments for nicotine dependence act on neurotransmission. For example, previous smoking cessation guidelines do not recommend the use of bupropion in smokers with schizophrenia, because there may be a theoretical risk of psychotic relapse if bupropion, a dopamine agonist, is used among patients with schizophrenia (Strasser 2001). Some case reports have suggested that varenicline (another medication which has been proven to be effective for smoking cessation in the general population) may exacerbate psychiatric symptoms including psychosis and mood symptoms (Freedman 2007; Liu 2009). Moreover, drug treatment for smoking cessation and reduction may interact with and alter the effectiveness of the antipsychotic medications commonly used among patients with schizophrenia. In addition, nicotine withdrawal can cause symptoms like depression, anxiety and irritability. All these factors may contribute to changes in the mental state of these patients, and the extent of these changes remains unclear. The aim of this review is to summarize existing evidence for different interventions in smoking cessation and reduction for individuals with schizophrenia.
Summary of main results
Interventions used in trials to help smokers with schizophrenia to stop or to reduce smoking are heterogeneous. Summary of findings for the main comparison and Summary of findings 2 summarize the main results of this review for the most important outcomes. Smokers with schizophrenia who used bupropion to aid smoking cessation were nearly three times as likely as those on placebo to be abstinent at the end of the drug therapy. Although there were fewer trials with follow-up of six months or longer, the relative effect on abstinence seemed to be sustained at six months, and the results appeared consistent among trials. However, the evidence for sustained abstinence was based on five small trials from just two research groups.
At the end of treatment, smokers with schizophrenia who received bupropion smoked about 11 fewer cigarettes per day (CPD), than those who took placebo. A reduction of expired carbon monoxide (CO) level also occurred in the bupropion group, compared with the placebo group, but was not sustained to six months. The findings for smoking reduction should be interpreted with caution, as these data included the entire sample, combining abstainers and continuing smokers. Hence, the mean reduction included smoking abstinence, as well as reduction in those who did not manage to stop smoking. This explanation may be further supported by the lack of evidence of significant reduction in smoking in those trials aimed primarily at smoking reduction. We found no evidence in support of bupropion as an adjunct to contingency management.
We found no evidence to suggest that smokers with schizophrenia had significant deterioration in positive, negative or depressive symptoms of schizophrenia linked with bupropion. Although some adverse effects of treatment which may be important to patients were noted, there were no serious adverse clinical events such as seizure or suicide. However, the total number of people on bupropion was small (170 in trials for abstinence and 94 in trials for reduction), so there may not be adequate power to test for differences in risks of low event rates, such as seizure; the risk of seizure with bupropion in the general population is between 0.1% and 0.4%.
It was unclear whether transdermal nicotine patch (TNP) helped smoking cessation in this group of patients, as it was tested in only a few trials with small sample sizes. There was some indirect evidence that the abstinence rate was higher in the group with contingency reinforcement with TNP, compared to the group with contingency reinforcement alone (*Gallagher 2007). Some studies showed that TNP may reduce the number of CPD (+Hartman 1991) or the Fagerström Test for Nicotine dependence (FTND) score (*Gallagher 2007), but the available evidence did not show that TNP reduced the expired CO level (+Dalack 1999; *Gallagher 2007). One study showed that TNP may reduce the relapse rate of smoking after smoking abstinence in schizophrenia. Higher doses of TNP did not show any additional benefit in smoking abstinence or preventing relapse after smoking cessation in schizophrenia.
We found some evidence that smokers with schizophrenia who used varenicline for smoking cessation were nearly five times more likely to abstain from smoking at the end of treatment, compared with those who took placebo. However, this evidence was based on only two trials, one of which reported preliminary results with a small number of participants. In addition, there was insufficient evidence from one trial as to whether an effect was sustained at six-month follow-up. There was no study investigating the efficacy of varenicline used primarily for smoking reduction. After considering studies for abstinence and studies that examined the effect of varenicline for other non-smoking purposes, we did not find consistent evidence suggesting that varenicline reduced smoking among people with schizophrenia. Regarding the mental state of the participants, there was no evidence that varenicline caused worsening of positive, negative or depressive symptoms. However, two people out of a total of 144 smokers receiving varenicline reported suicidal ideation or behaviour.
We found no evidence to support the use of naltrexone for smoking reduction in smokers with schizophrenia and alcohol dependence. There were inconclusive findings that the antipsychotic clozapine helped in smoking reduction in people with schizophrenia. There was also no evidence to support the use of galantamine, atomoxetine or topiramate as aids to smoking cessation or to smoking reduction for individuals with schizophrenia.
Regarding non-pharmacological interventions, there was some evidence to support the use of financial contingency reinforcement (CR) for smoking cessation and reduction in people with schizophrenia. In one study, CR, with and without TNP, increased the abstinence rate for smoking in schizophrenia sufferers at week 20 and week 36. There was also some evidence from two trials that CR, with and without TNP or bupropion, significantly reduced the level of smoking in those with schizophrenia. Nevertheless, there was no evidence that CR produced sustained results for these outcomes once it was withdrawn. In addition, these findings should be treated with caution, as the evidence was based on only two trials.
We found evidence from one small trial that a smoking reduction intervention group, compared to waiting list controls, may reduce the number of CPD in inpatient smokers with schizophrenia who had been in hospital for at least one year. However, there were some concerns with the methodology of this study, and they did not use biological verification. Otherwise, we found no evidence that a single session of motivational interviewing reduced smoking in people with schizophrenia. There was also no evidence that specialised smoking cessation group therapy specifically designed for patients with schizophrenia was more effective for either smoking cessation or reduction, compared with a standard smoking cessation programme. We did not find any evidence to suggest that intensive individual behavioural counselling sessions designed for people with schizophrenia improved smoking cessation or reduction. In addition, repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex (DLPFC) did not increase the smoking abstinence rate among smokers with schizophrenia.
There were design limitations in most of the included trials. For example, most studies had small numbers of participants and only a few studies reported outcomes beyond the six-month follow-up. These factors have limited the validity and precision of the evidence.
Overall completeness and applicability of evidence
In this review, the participants of the included studies were recruited from inpatient units, the community, or from outpatient psychiatric treatment sites, and represent a range of patients with schizophrenia. Interest in quitting smoking varied across sites and studies. As a result, there was significant clinical heterogeneity between the included trials. We therefore considered it was appropriate to perform a meta-analysis and report the pooled estimates only for studies testing bupropion and varenicline, because they were relatively more homogenous.
Our review includes both pharmacological and non-pharmacological interventions. For medication treatments, the U.S. Food and Drug Administration (FDA) has approved nicotine replacement therapies (gum, patch, nasal spray, inhaler and lozenge), bupropion, and varenicline as first-line medications for the treatment of nicotine dependence in the general public. For this review, we found several studies that examined the use of these drug treatments for smoking cessation and reduction in schizophrenia, including those who investigated varenicline for other purposes rather than primarily for smoking cessation or reduction. There are also a number of ongoing studies which investigate the use of varenicline (Evins (NCT00621777); Fatemi (NCT01111149); Smith (NCT00802919)) and hopefully these trials will be able to provide more evidence of the effectiveness of varenicline in the near future. We did not find any studies that examined the effect of other forms of nicotine replacement, such as gum, nasal spray, inhaler and lozenge in people with schizophrenia, but there is an ongoing study which investigates the use of nicotine nasal spray for smoking cessation in people with schizophrenia (Williams (NCT01010477)).
Apart from one trial which investigated the use of naltrexone in smokers with schizophrenia and alcohol dependence, we did not find any trials of other medications that have been investigated for possible efficacy for smoking cessation in the general public, such as clonidine, nortriptyline and selegiline. We also examined the effects of antipsychotics (in particular clozapine) in smoking reduction in those with schizophrenia, as there have been a number of reports about the possible link between antipsychotic use and nicotine dependence in schizophrenia patients (Ereshefsky 1985; McEvoy 1995a). In addition, smokers with schizophrenia may use nicotine to improve their cognitive function (Adler 1998; Sacco 2004). We found studies which examined the effects of medications such as galantamine and atomoxetine for smoking reduction in individuals with schizophrenia. Finally, topiramate modulates dopaminergic activity in the brain through its action on GABAergic and glutamatergic systems, and it has been suggested that topiramate may have an effect on addiction (Johnson 2005). We identified one study which examined its effects on smoking in patients with schizoaffective disorder.
Previous reviews have shown that individual behavioural counselling, group behavioural therapy and telephone counselling are effective interventions to help smokers in the general public to quit smoking (Lancaster 2005a; Stead 2005; Stead 2006). Simple advice from a physician and self help material may also increase smoking cessation rates in the general public (Lancaster 2005b; Stead 2008). Motivational interviewing, especially by primary care physicians and trained practitioners, may also increase the rate of smoking cessation in the general public (Lai 2010). There was no evidence that single session motivational interviewing reduced smoking in people with schizophrenia, or that specialised smoking cessation therapies (group or individual) designed for patients with schizophrenia were superior to non-specialised therapy. We found no studies comparing group therapy with individual therapy in participants with schizophrenia, nor any studies of telephone counselling, simple advice from a physician, or self help interventions in smoking cessation or reduction in those with schizophrenia. There was no evidence to support the use of active repetitive transcranial magnetic stimulation (rTMS) for smoking cessation in people with schizophrenia.
Interestingly, we found some evidence from two studies with different designs to support the use of money as an incentive to increase abstinence rates and reduce smoking in people with schizophrenia, at the end of the trial. The durations of these two trials was 22 days and 36 weeks respectively, with no follow-up data after withdrawal of the incentive. A previous review has suggested that incentives do not enhance long-term cessation rates, and that early success may not be maintained when the rewards are no longer offered (Cahill 2011).
A recent review suggests that combined pharmacotherapy and behavioural support increase smoking cessation success in the general public when compared with a minimal intervention, or with usual care (Stead 2012). We found three trials of combined pharmacological and non-pharmacological interventions (two with contingent reinforcement and one with an individual counselling intervention). Although both the CR trials showed a higher rate of smoking reduction, with or without smoking cessation, there was no direct conclusive evidence that adding drug treatment (TNP or bupropion) increased the effectiveness of the non-pharmacological intervention. The other study, examining the effect of an intervention based on cognitive behavioural therapy and motivational interviewing among smokers with schizophrenia, did not demonstrate increased abstinence rates.
In this review, we report smoking reduction as one of the secondary outcomes. Smoking cessation is the recommended method to reduce the harms to smokers (US Department of Health and Human Services 2000). Smoking reduction has been proposed as a non-cessation method to reduce harm from tobacco. There is evidence to suggest that smokers who are not interested in quitting can make significant reductions in their smoking when they receive appropriate treatment, and that these reductions can be maintained over time (Hughes 2005). One of the concerns over smoking reduction is that it may undermine smokers' motivation to quit smoking, as they may see reduction as an easier alternative to abstinence, and that reduction may be all that they want or are able to achieve. Nevertheless, recent literature has shown that smoking reduction increases the probability of future cessation (Hughes 2006). Individuals with schizophrenia have much lower smoking cessation rates compared with the general population (de Leon 2005a), and smoking reduction may be a step towards cessation. We hypothesize that this step towards accomplishing the task of smoking cessation might increase their self efficacy and make subsequent success more likely. Smoking reduction may also make it easier to quit smoking by reducing the level of nicotine dependence, which is a major barrier to smoking cessation (Shadel 2000).
Most of the trials also provided some information about any potential harmful effects of interventions, in particular on the mental state of the participants. Some medications for smoking cessation are psychotropic themselves (e.g. bupropion), or have been reported to have possible serious neuropsychiatric side effects (e.g. varenicline). It is important to monitor whether these medications have a major impact on mental stability in these patients. Additionally, nicotine withdrawal can cause changes in the mental state, including depression and anxiety (Zwar 2007).
There is some literature reporting interventions which address tobacco addiction at an organization or system level (Lawn 2005; Shmueli 2008; Wye 2009). These interventions may include training of staff to manage tobacco addiction among patients with schizophrenia, and changing psychiatric facilities into smoke-free settings (Ziedonis 2007). This is particularly important as a number of countries including the UK and the USA have enforced smoking bans in mental health units. However, we did not find any RCTs for these interventions in our search.
Quality of the evidence
For this review, the largest body of evidence was for bupropion, including seven studies and a total of 340 participants in the meta-analysis. The number of studies was relatively small, and there was no significant heterogeneity between them. In addition, we found some evidence for varenicline from two studies with a total of 137 participants, and no significant heterogeneity between them. There was also some evidence for contingency reinforcement with money from two trials, but their clinical heterogeneity meant that we did not combine the data.
The evidence for the other interventions, including NRT, individual counselling and group therapy, was limited, even though there is good evidence of their benefit for other populations of smokers. Hence, gaps in the evidence for treatments other than bupropion in patients with schizophrenia is probably due to a low number of trials rather than to unpublished studies with negative findings.
The main aim of some included studies was to examine the efficacy of an intervention for other purposes, rather than primarily for smoking cessation or reduction (McEvoy 1995 and de Leon 2005b for clozapine; Kelly 2008 for galantamine; Weinberger 2008 for topiramate; Sacco 2009 for atomoxetine; Hong 2011, Meszaros 2012 and Shim 2012 for varenicline). Apart from Meszaros 2012, all these trials included smokers who were not trying to quit. These studies all reported smoking status as a secondary outcome, with subgroup analyses used in some of them to investigate the effects of the interventions for smokers. In three of the trials, some of the smokers were excluded from the subgroup analyses without justification. The results of these studies should therefore be viewed with caution.
Potential biases in the review process
We have used comprehensive search strategies and wide inclusion criteria, thereby improving the chances of identifying all relevant trials. We obtained reports in any language and unpublished data such as conference abstracts, to reduce potential selection and publication biases. Outcomes had to be at least six months after the intervention and at the end of the intervention, so that the immediate effect and long-term sustained abstinence could be compared. We conducted sensitivity analyses in the meta-analysis, and evaluated the robustness of the findings.
There are two issues to consider in this review. Firstly, the number of studies which were included in the meta-analysis for bupropion and varenicline is relatively small, so we did not produce a funnel plot to explore potential publication bias. We can not exclude the possibility that we may have missed studies with negative results and small sample size. Publication bias can significantly distort the results of a meta-analysis, especially when the number of studies is relatively small. Secondly, the findings may not apply to all smokers with schizophrenia, as some of the included trials explicitly excluded patients with a diagnosis of both schizophrenia and a co-morbid substance misuse other than nicotine.
There has been more emphasis recently on the importance of evaluating the potential harms associated with interventions in both clinical trials and systematic reviews (Cuervo 2003; Tunis 2003). This review also examines as one of its outcomes, the effect of different interventions on the mental state of smokers with schizophrenia. This allows us to address the question of whether different interventions can safely be used in this population.
Agreements and disagreements with other studies or reviews
In the Cochrane review of antidepressants for smoking cessation, Hughes 2007 estimated that bupropion increased the odds of quitting smoking after at least six months by approximately 70%, when used as the sole pharmacotherapy (odds ratio (OR) 1.69, 95% confidence interval (CI) 1.53 to 1.85, 36 trials, 11440 participants). It did not detect a significant effect from combining bupropion and nicotine replacement therapy (NRT), compared with NRT alone after six months (OR 1.23, 95% CI 0.67 to 2.26, 6 trials, 1106 participants). Although our pooled estimates suggest that bupropion may have a significant beneficial effect on smoking abstinence in people schizophrenia, neither the subgroup analysis for bupropion alone, or for bupropion and TNP, reached statistical significance.
Cahill 2012 reported that varenicline at standard dose at least doubles the chances of successful smoking cessation after six months or more, compared with placebo (risk ratio (RR) 2.27, 95% CI 2.02 to 2.55, 14 trials, 6166 participants). Lower dose regimens also increased the rate of smoking cessation, while reducing the incidence of adverse events (RR 2.09, 95% CI 1.56 to 2.78, 4 trials, 1272 participants). More participants quit successfully with varenicline than with bupropion (RR 1.52, 95% CI 1.22 to 1.88, 3 trials, 1622 participants). In this review, current evidence from the limited number of studies suggests that varenicline may increase the smoking cessation rate among individuals with schizophrenia in the short term, but the effect did not last in the longer term. Regarding safety, Cahill 2012 reported that possible serious adverse events including significant psychiatric side effects cannot be ruled out on the current evidence. There were a number of studies investigating a possible association between varenicline and suicidality using different data sources and methodology, focusing on studies in the general public (Gunnell 2009; Kasliwal 2009; Harrison-Woolrych 2011; Moore 2011). These results need to be viewed with caution in view of the difficulties in disentangling treatment-related events with other potential confounding factors (e.g. psychiatric effects of nicotine withdrawal, increased suicide rates among smokers). In addition, it is essential to remember that these trials routinely excluded participants with psychiatric disorders and/or other alcohol or substance misuse. A recent review of published case reports, case series and prospective studies of the use of varenicline in patients with schizophrenia and schizoaffective disorder suggested that 5% of participants (13 out of 260) experienced the onset or worsening of psychiatric symptoms (Cerimele 2012). Three of the 13 participants experienced a very brief negative effect after one dose of varenicline. They did not find any report of patients with suicidal ideation or suicidal behaviour. However, the authors only included studies published until July 2011, and as a result they missed the two trials which reported two participants with suicidal ideation or behaviours (*Williams 2012; Meszaros 2012) as summarised in this review.
Regarding using contingent reinforcement for smoking cessation, Cahill 2011 concluded that incentives did not enhance long-term smoking cessation rates among general populations. In addition, early success usually disappeared when rewards were no longer offered, although in one trial of 878 smokers, it achieved high and long-lasting success rates by giving large cash rewards (up to USD750). Our review found some evidence that contingent reinforcement using money increased the smoking cessation rate, as well as reducing the amount of smoking among people with schizophrenia when the rewards were offered. We did not find any follow-up data to examine the effect of longer-term efficacy.
We did not find evidence to support the use of nicotine replacement therapy for smoking cessation or reduction in people with schizophrenia, which does not square with the strong evidence supporting the efficacy of all forms of NRT (Stead 2012b). Neither did higher doses of NRTshow any additional benefit for individuals with schizophrenia who smoke more heavily, compared to the general population. However, there are only a handful of small studies of the use of NRT for smoking cessation in people with schizophrenia, suggesting a lack of research in this area.
The results of this review largely concur with national guidelines, which make some recommendations about the treatment of nicotine dependence in people with schizophrenia. The Clinical Practice Guideline published by the United States Department of Health and Human Services (Fiore 2008) suggests that bupropion and nicotine replacement therapies may be effective for treating smoking in individuals with schizophrenia. Zwar 2007 also makes a similar suggestion for individuals with schizophrenia in the non-systematically reviewed Australian guidelines on pharmacotherapy for tobacco addiction.
The Schizophrenia Patient Outcomes Research Team (PORT) has also published treatment guidance (Kreyenbuhl 2009). They recommend that those with schizophrenia who want to quit or to reduce cigarette smoking should be offered bupropion SR, 150 mg twice daily, for 10 to 12 weeks, with or without NRT to achieve short-term abstinence. They also suggest that this pharmacological treatment should be accompanied by a smoking cessation education or support group, although they do not think there is sufficient evidence to recommend a particular psychosocial approach.
Appendix 1. MEDLINE search strategy
1. exp schizophrenia/
2. exp paranoid-disorders/
14. ((chronic* or sever*) adj mental* adj (ill* or disorder*)).mp.
15. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 14
18. (tardiv* adj dyskine*).mp.
24. 21 and (malignant adj syndrome).mp.
27. 21 and 25 and 26
32. (parkinson's adj disease).m_titl.
33. 18 or 19 or 20 or 24 or 27 or 28 or 29
34. 33 not 32
35. exp dyskinesia-drug-induced/
36. exp akathisia-drug-induced/
37. exp neuroleptic-malignant-syndrome/
38. 34 or 35 or 36 or 37
39. 38 or 15
40. smoking cessation.mp.
41. smoking-cessation/ or tobacco-use-disorder/
44. tobacco, -smokeless/
45. exp Smoking/th, pc [Therapy, Prevention & Control]
46. ((quit$ or stop$ or ceas$ or giv$) adj smok$).mp. [mp=title, original title, abstract, name of substance word, subject heading word]
48. 40 or 41 or 42 or 43 or 44 or 45 or 46 or 47
50. 49 or 48
51. randomised controlled trial.pt.
52. controlled clinical trial.pt.
55. clinical trials as topic.sh.
58. 52 or 53 or 57 or 56 or 51 or 55 or 54
59. (animals not (human and animals)).sh.
60. 58 not 59
61. 60 and 50 and 39
Appendix 2. EMBASE search strategy
4. cross over$.af.
7. (doubl$ adj blind$).af.
8. (singl$ adj blind$).af.
12. crossover procedure/
13. double blind procedure/
14. Randomized Controlled Trial/
15. Single Blind Procedure/
16. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15
17. smoking cessation.mp.
18. exp smoking cessation/
19. exp smoking-/
20. ((quit$ or stop$ or ceas$ or giv$ or prevent$) adj smok$).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name]
21. exp passive-smoking/ or exp smoking-habit/ or exp cigarette-smoking/ or exp "smoking-cessation"/
22. 17 or 18 or 19 or 20 or 21
25. psychosis.mp. or Psychosis/
27. 26 or 23 or 25 or 24
28. exp Schizophrenia/
29. exp Psychosis/
37. ((chronic* or severe* or persistent*) adj (mental* or psychological*) adj (disorder* or ill*)).mp.
38. "mental-patient".mp. or exp Mental Patient/
41. (tardiv* adj dyskine*).mp.
46. 43 and (malignant adj syndrome).mp.
47. exp Tardive Dyskinesia/
48. exp Akathisia/
50. exp Neuroleptic Malignant Syndrome/
53. 43 and 51 and 52
54. 27 or 28 or 29 or 37 or 38
57. 41 or 42 or 46 or 47 or 48 or 49 or 50 or 53 or 55 or 56
59. 57 not 58
60. 59 or 54
61. 22 and 60 and 16
Appendix 3. PsycINFO search strategy
12. ((chronic* or sever*) adj mental* adj (ill* or disorder*)).mp.
13. exp schizophrenia/
14. exp psychosis/
15. exp schizoaffective disorder/
16. 1 or 2 or 3 or 4 or 5 or 6 or 12 or 13 or 14 or 15
19. (tardiv* adj dyskine*).mp.
25. 22 and (malignant adj syndrome).mp.
28. 22 and 26 and 27
33. (parkinson's adj disease).m_titl.
34. 19 or 20 or 21 or 25 or 28 or 29 or 30
35. 34 not 33
36. exp Neuroleptic Malignant Syndrome/
37. exp dyskinesia/
38. exp akathisia/
39. exp parkinsonism-/
40. 35 or 36 or 37 or 38 or 39
41. 40 or 16
42. smoking cessation.mp. or exp smoking cessation/
43. (antismoking or anti-smoking).mp.
44. (quit$ or cessat$).mp.
45. (abstin$ or abstain$).mp.
46. (control$ adj smok$).mp. [mp=title, abstract, heading word, table of contents, key concepts]
47. exp behavior modification/
48. 43 or 44 or 45 or 46 or 47
50. (smok$ or cigar$ or tobacco$).mp.
52. 49 or 50
53. 48 and 52
54. 51 and 52
55. 42 or 53 or 54
63. ((singl* or doubl* or trebl* or tripl*) adj (blind* or mask*)).mp.
66. (CLIN* adj trial*).mp.
68. exp Placebo/
70. exp Treatment Effectiveness Evaluation/
71. exp mental health program evaluation/
75. (random* adj (assign* or allocat*)).mp.
76. 75 or 71 or 70 or 69 or 68 or 67 or 66 or 63 or 56
77. 76 and 55 and 41
Differences between protocol and review
1. We widened the inclusion criteria in two ways:
a) To include patients with schizoaffective disorder, since individuals with this diagnosis share certain core symptoms with patients with schizophrenia.
b) To include trials of interventions for other purposes that reported smoking-related outcomes, if the trials met the study and participant inclusion criteria. Trials which tested an intervention for another primary purpose were reported separately and did not contribute to any meta-analysis.
2. We changed the primary outcome measure to abstinence from smoking, assessed at least six months from the start of the intervention, to be consistent with other reviews by the Cochrane Tobacco Addiction Group, and the 'Russell Standard'. We reported smoking abstinence at the end of the trial and smoking reduction as secondary outcomes.