Antidepressants For Smoking Cessation (Review)

Download as pdf or txt
Download as pdf or txt
You are on page 1of 125

Antidepressants for smoking cessation (Review)

Hughes JR, Stead LF, Lancaster T

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2011, Issue 8 http://www.thecochranelibrary.com

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

TABLE OF CONTENTS HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.1. Comparison 1 Bupropion. Abstinence at 6m or greater follow-up, Outcome 1 Bupropion versus placebo/control. Subgroups by length of follow-up. . . . . . . . . . . . . . . . . . . . . . Analysis 1.2. Comparison 1 Bupropion. Abstinence at 6m or greater follow-up, Outcome 2 Bupropion versus placebo/control. Subgroups by clinical/recruitment setting. . . . . . . . . . . . . . . . . . . Analysis 1.3. Comparison 1 Bupropion. Abstinence at 6m or greater follow-up, Outcome 3 Bupropion versus placebo. Subgroups by level of behavioural support. . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.4. Comparison 1 Bupropion. Abstinence at 6m or greater follow-up, Outcome 4 Bupropion dose response. 300 mg/day versus 150 mg/day. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.5. Comparison 1 Bupropion. Abstinence at 6m or greater follow-up, Outcome 5 Bupropion and NRT versus NRT alone. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.6. Comparison 1 Bupropion. Abstinence at 6m or greater follow-up, Outcome 6 Bupropion for relapse prevention. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.7. Comparison 1 Bupropion. Abstinence at 6m or greater follow-up, Outcome 7 Bupropion versus nicotine patch. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.8. Comparison 1 Bupropion. Abstinence at 6m or greater follow-up, Outcome 8 Bupropion versus varenicline. Analysis 1.9. Comparison 1 Bupropion. Abstinence at 6m or greater follow-up, Outcome 9 Bupropion for harm reduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 2.1. Comparison 2 Nortriptyline, Outcome 1 Long term abstinence (6-12m). . . . . . . . . . . . Analysis 3.1. Comparison 3 Bupropion versus nortriptyline, Outcome 1 Long term abstinence. . . . . . . . . Analysis 4.1. Comparison 4 Selective Serotonin Reuptake Inhibitors (SSRIs) versus placebo, Outcome 1 Fluoxetine. Long term abstinence. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 4.2. Comparison 4 Selective Serotonin Reuptake Inhibitors (SSRIs) versus placebo, Outcome 2 Paroxetine. Long term abstinence. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 4.3. Comparison 4 Selective Serotonin Reuptake Inhibitors (SSRIs) versus placebo, Outcome 3 Sertraline. Long term abstinence. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 5.1. Comparison 5 Monoamine oxidase inhibitors (MAOIs) versus placebo, Outcome 1 Long term abstinence. Analysis 6.1. Comparison 6 Venlafaxine versus placebo, Outcome 1 Long term abstinence. . . . . . . . . . APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . FEEDBACK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . WHATS NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

1 1 2 2 3 3 4 9 12 15 16 17 18 33 93 95 97 100 102 103 104 104 105 105 112 114 115 116 116 117 117 118 120 120 121 122 122 122 122 122
i

[Intervention Review]

Antidepressants for smoking cessation


John R Hughes1 , Lindsay F Stead2 , Tim Lancaster3
1

Dept of Psychiatry, University of Vermont, Burlington, Vermont, USA. 2 Department of Primary Care Health Sciences, University of Oxford, Oxford, UK. 3 Department of Primary Health Care, University of Oxford, Oxford, UK Contact address: John R Hughes, Dept of Psychiatry, University of Vermont, UHC Campus, OH3 Stop # 482, 1 South Prospect Street, Burlington, Vermont, 05401, USA. john.hughes@uvm.edu.

Editorial group: Cochrane Tobacco Addiction Group. Publication status and date: Edited (no change to conclusions), published in Issue 8, 2011. Review content assessed as up-to-date: 29 July 2009. Citation: Hughes JR, Stead LF, Lancaster T. Antidepressants for smoking cessation. Cochrane Database of Systematic Reviews 2007, Issue 1. Art. No.: CD000031. DOI: 10.1002/14651858.CD000031.pub3. Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT Background There are at least three reasons to believe antidepressants might help in smoking cessation. Nicotine withdrawal may produce depressive symptoms or precipitate a major depressive episode and antidepressants may relieve these. Nicotine may have antidepressant effects that maintain smoking, and antidepressants may substitute for this effect. Finally, some antidepressants may have a specic effect on neural pathways (e.g. inhibiting monoamine oxidase) or receptors, (e.g. blockade of nicotinic-cholinergic receptors) underlying nicotine addiction. Objectives The aim of this review is to assess the effect of antidepressant medications to aid long-term smoking cessation. The medications include bupropion; doxepin; uoxetine; imipramine; moclobemide; nortriptyline; paroxetine; selegiline; sertraline, tryptophan, venlafaxine and St. Johns wort. Search strategy We searched the Cochrane Central Register of Controlled Trials (CENTRAL) which includes trials indexed in MEDLINE, EMBASE, SciSearch and PsycINFO, and other reviews and meeting abstracts, in June 2009. Selection criteria We considered randomized trials comparing antidepressant medications to placebo or an alternative pharmacotherapy for smoking cessation. We also included trials comparing different doses, using pharmacotherapy to prevent relapse or re-initiate smoking cessation or to help smokers reduce cigarette consumption. We excluded trials with less than six months follow up. Data collection and analysis We extracted data in duplicate on the type of study population, the nature of the pharmacotherapy, the outcome measures, method of randomization, and completeness of follow up. The main outcome measure was abstinence from smoking after at least six months follow up in patients smoking at baseline, expressed as a risk ratio (RR). We used the most rigorous denition of abstinence available in each trial, and biochemically validated rates if available. Where appropriate, we performed meta-analysis using a xed-effect model.
Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 1

Main results Thirteen new trials were identied since the 2006 update bringing the total number of included trials to 66. There were 49 trials of bupropion and nine trials of nortriptyline. When used as the sole pharmacotherapy, bupropion (36 trials, N = 11,140, risk ratio [RR] 1.69; 95% condence interval [CI] 1.53 to 1.85) and nortriptyline (six trials, N = 975, RR 2.03; 95% CI 1.48 to 2.78) both signicantly increased long term cessation. There is insufcient evidence that adding bupropion (6 trials, N = 1,106, RR 1.23; 95% CI 0.67 to 2.26) or nortriptyline (3 trials, N = 1,219, RR 1.29; 95% CI 0.97 to 1.72) to nicotine replacement therapy provides an additional long-term benet. From the available data bupropion and nortriptyline appear to be equally effective and of similar efcacy to nicotine replacement therapy. Pooling three trials comparing bupropion to varenicline showed lower quitting with bupropion (N = 1,622, RR 0.66, 95% CI 0.53 to 0.82). There is a risk of about 1 in 1000 of seizures associated with bupropion use. Bupropion has been associated with suicide risk, but whether this is causal is unclear. Nortriptyline has the potential for serious side-effects, but none have been seen in the few small trials for smoking cessation. There was no evidence of a signicant effect for selective serotonin reuptake inhibitors; uoxetine 4 trials, N = 1,486, RR 0.92 (95% CI 0.68 to 1.24); paroxetine 1 trial, N = 224, RR 1.08 (95% CI 0.64 to 1.82); sertraline 1 trial, N = 134, RR 0.71 (95% CI 0.30 to 1.64). Signicant effects were not detected for the monoamine oxidase inhibitors moclobemide (1 trial, N = 88, RR 1.57, 95% CI 0.67 to 3.68) or selegiline (3 trials, N = 250, RR 1.49, 95% CI 0.92 to 2.41) or the atypical antidepressant venlafaxine (N = 147, RR 1.22, 95% CI 0.64 to 2.32). No long term trials have been published for St Johns Wort. Authors conclusions The antidepressants bupropion and nortriptyline aid long-term smoking cessation but selective serotonin reuptake inhibitors (e.g. uoxetine) do not. Evidence suggests that the mode of action of bupropion and nortriptyline is independent of their antidepressant effect and that they are of similar efcacy to nicotine replacement. Adverse events with both medications appear to be rarely serious or lead to stopping medication.

PLAIN LANGUAGE SUMMARY Do medications used to treat depression help smokers who are trying to quit Multiple trials of bupropion (Zyban) for smoking cessation show that it increases the number of successful quit attempts. The side effects of bupropion include insomnia, dry mouth and nausea and rarely (1:1000) seizures and perhaps psychiatric problems, but the last is unclear. The tricyclic antidepressant nortriptyline increases quit rates. The side effects of this medication include dry mouth, constipation, nausea, and sedation, and it can be dangerous in overdose. The efcacy of bupropion and nortriptyline appears to be similar to that for nicotine replacement and not restricted to people with a history of depression or depressive symptoms during smoking abstinence. Selective serotonin reuptake inhibitor antidepressants (for example, uoxetine) have not been shown to help smoking cessation.

BACKGROUND
Whilst nicotine replacement is the most widely used pharmacotherapy for smoking cessation, some people prefer a treatment that does not use nicotine. Others require alternative treatments having failed to quit with nicotine replacement. Observations that a history of depression is found more frequently amongst smokers than nonsmokers; that cessation may precipitate depression; that nicotine may have antidepressant effects; and that antidepressants inuence the neurotransmitters and receptors involved in nicotine addiction provided a rationale for the study of antidepressant med-

ications for smoking cessation (Benowitz 2000; Kotlyar 2001). The following antidepressants have been investigated for their effect on smoking behaviour in at least one study: the tricyclic antidepressants (TCAs) doxepin, imipramine and nortriptyline the monoamine oxidase inhibitors (MAOI) moclobemide and selegiline
2

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

the selective serotonin reuptake inhibitors (SSRIs) uoxetine, paroxetine and sertraline the atypical antidepressants bupropion, tryptophan and venlafaxine extracts of Hypericum perforatum L. (St. Johns wort) The focus of this review and meta-analysis is on trials that provide evidence for an effect on long-term smoking cessation. We describe these in the Results section. For pharmacotherapies for which there is still a lack of long-term data, we briey describe results from excluded short-term trials in the Description of Studies section.

Trials in which all participants received the same pharmacotherapy regimen but different behavioural support were not included. Types of outcome measures Efcacy was measured via a) abstinence from smoking or b) incidence of reducing cigarette consumption to 50% or less of baseline, both assessed at follow up at least six months from start of treatment. Safety was assessed by incidence of serious and other adverse events, and drop-outs due to adverse events.

Search methods for identication of studies


We identied studies from the Tobacco Addiction Groups specialised register. All trials using pharmacotherapy other than nicotine, clonidine or lobeline for smoking cessation were found, and those using medications generally classied as having an antidepressant effect were selected for inclusion in this review. The date of the last search was June 2009. We checked the citation lists of these studies, recent reviews of non-nicotine pharmacotherapy and abstracts from the meetings of the Society for Research on Nicotine and Tobacco. For each medication found from these sources we searched MEDLINE and EMBASE (via Ovid, 9th June 2009) using the medication name and smoking as a free text term. Several studies were located by contacting investigators in the area. We also checked all records of trials of bupropion held on the GlaxoSmithKline Clinical Trials Register (http:ctr.glaxowellcome.co.uk) for unpublished studies.

OBJECTIVES
To assess the evidence for the efcacy and safety in assisting longterm smoking cessation of medications with antidepressant properties, including: bupropion, doxepin, uoxetine, imipramine, moclobemide, nortriptyline, paroxetine, tryptophan, selegiline, sertraline, venlafaxine and hypericum (St Johns Wort). For each medication identied as having been used in a smoking cessation trial we tested the hypothesis that it was more effective than placebo, or an alternative treatment, in achieving long-term smoking cessation.

METHODS

Data collection and analysis Criteria for considering studies for this review
LS and TL independently extracted data on the number of study participants who had ceased to smoke at nal follow up. In each study we used the strictest available criteria to dene cessation, so we extracted gures for sustained abstinence in preference to point prevalence where both were presented. In studies that used biochemical validation of cessation, only those subjects meeting the criteria for biochemically conrmed abstinence were regarded as having stopped smoking. We treated subjects in either group lost to follow up as continuing smokers. As far as possible we used an Intention-to-Treat analysis. Where subjects appeared to have been randomized but were not included in the data presented by the author we noted this in the study description (see Characteristics of Included Studies). Assuming that people lost to follow up are smokers will ensure that actual quit rates are conservative, but may not necessarily lead to conservative relative treatment effects (e.g. risk ratios), if loss to follow up is higher in the control group (Hall 2001). Some studies now use alternative methods to model effects of missing data (Hall 2001; Niaura 2002). Where differential results using alternative models were reported we considered whether the results of the meta-analysis were sensitive to the use of different denominators.
3

Types of studies For efcacy, we examined randomized trials comparing antidepressant with placebo or with an alternative therapeutic control, or comparing different dosages of an antidepressant that reported six-month or longer follow ups. For safety, we examined data from randomized controlled trials and non-randomized post-marketing surveillance data.

Types of participants Current smokers, or recent quitters (for trials of relapse prevention).

Types of interventions Treatment with any medication with antidepressant properties to aid a smoking cessation attempt or to prevent relapse, or to reduce the number of cigarettes smoked and aid subsequent cessation.

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

We summarized individual study results as a risk ratio (RR), calculated as: (number of quitters in intervention group/ number randomized to intervention group) / (number of quitters in control group/ number randomized to control group). A risk ratio greater than 1.0 indicates a higher rate of quitting in the treatment group than in the control group. For each type of medication where more than one eligible trial was identied, we performed meta-analysis using a Mantel-Haenszel xed-effect method to estimate a pooled risk ratio with 95% condence intervals (Mantel 1959). This is a change from previous review versions that used odds ratios (OR), because ORs can be misleading (Higgins 2008). To investigate statistical heterogeneity we use the I statistic, given by the formula [(Q - df )/Q] x 100%, where Q is the chi squared statistic and df is its degrees of freedom (Higgins 2003). This describes the percentage of the variability in effect estimates that is due to heterogeneity rather than sampling error (chance). We used threshold values of 50% and 70% as suggesting moderate and substantial heterogeneity respectively. Although we give a summary statistic, the conclusions that can be drawn from it must be cautious. Where trials are small and few in number the condence intervals will be wide. The derivation of the summary statistic implicitly assumes that data from all randomized trials are available without any bias due to non-publication of unpromising results or to exclusion of randomized individuals. There is evidence that publication bias occurs in the eld of smoking cessation research (Egger 1997), and this issue is discussed further in the Cochrane review of nicotine replacement therapy (NRT) (Stead 2008). Thus, we included unpublished studies or studies found only as abstracts where sufcient detail was available. We contacted authors for further data if necessary. We have added a subgroup meta-analysis by level of additional support using the same criteria applied in the Cochrane NRT review (Stead 2008); low intensity support was regarded as part of the provision of routine care, so the duration of time spent with the smoker (including assessment for the trial) had to be less than 30 minutes at the initial consultation, with no more than two further assessment and reinforcement visits. We distinguished in the meta-analyses between trials testing an antidepressant as a single pharmacotherapy or as an adjunct to NRT for initial cessation. We also distinguished between cessation trials and those where the intervention addressed relapse prevention or reduction in number of cigarettes smoked. None of the trials located were specically designed to directly compare antidepressant pharmacotherapy with non-pharmacological therapies. Adverse events: Tables in the results section summarize the adverse events reported in clinical trials for smoking cessation for medications which have shown evidence of efcacy (bupropion and nortriptyline). For other medications adverse effects are noted in the included studies . The number of people who have received bupropion and nortriptyline in smoking cessation trials is still relatively small, so there is limited power to estimate accurately the risk of uncommon ad-

verse events. Because the safety of bupropion has been questioned in some countries, we have supplemented trial data with data from observational studies including national post-marketing surveillance schemes where it was possible to estimate a denominator. Nortriptyline is not currently licensed for smoking cessation, so this was not possible for this medication. We did not directly examined safety data for bupropion or nortriptyline when used to treat depression because these studies used higher doses and different populations than those used for smoking cessation.

RESULTS

Description of studies
See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of ongoing studies. We identied thirteen additional trials for this update, giving a total of 66 included trials. The new trials were of bupropion (Covey 2007; Croghan 2007; Fossati 2007; Grant 2007; Muramoto 2007; Schmitz 2007; George 2008; McCarthy 2008; Simon 2009), nortriptyline Aveyard 2008) and selegiline, (Biberman 2003; George 2003; Weinberger 2009, not previously covered by this review). Five trials that were previously included based on unpublished results have now been published and the study identiers are now based on year of publication (Brown 2007; Evins 2007; Piper 2007; Spring 2007; Uyar 2007). The forty-nine trials of bupropion included ve (Hays 2001; Hurt 2003; Killen 2006; Covey 2007; Croghan 2007) testing the medication for relapse prevention and one of reduction (Hatsukami 2004). Three of the bupropion trials allowed a direct comparison with nicotine patch therapy (Jorenby 1999; Grecka 2003; Uyar 2007), and three a direct comparison with the nicotine receptor partial agonist varenicline (Gonzales 2006; Jorenby 2006; Nides 2006). Nine trials used nortriptyline including three which also used bupropion (Hall 2002; Wagena 2005; Haggstrm 2006), There were four trials of uoxetine (Blondal 1999; Niaura 2002; Saules 2004; Spring 2007), three of selegiline (Biberman 2003; George 2003; Weinberger 2009), one of paroxetine (Killen 2000), one of sertraline (Covey 2002), and one of venlafaxine (Cinciripini 2005). These studies excluded smokers with current depression but almost all included smokers with a past history of depression. Further details of the study designs are given in the table Characteristics of included studies. We list 58 excluded studies. Most of these were short-term or laboratory-based studies. For medications where there is little or no evidence from long-term studies we briey describe the results of the excluded short-term trials. The reasons for exclusion are given in the table Characteristics of excluded studies. Papers reporting additional outcomes or subgroup analyses from included studies are listed as references under the study identier. Six further studies
4

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

are potentially relevant but are either ongoing or do not have sufcient data to assess for inclusion yet.

Bupropion This antidepressant has both dopaminergic and adrenergic actions, and appears to be an antagonist at the nicotinic acetylcholinergic receptor (Fryer 1999). It may work by blocking nicotine effects, relieving withdrawal (Cryan 2003; West 2008) or reducing depressed mood (Lerman 2002a). It has been licensed as a prescription aid to smoking cessation in many countries. The usual dose for smoking cessation is 150mg once a day for three days increasing to 150 mg twice a day continued for 7 to 12 weeks. The quit attempt is generally initiated a week after starting pharmacotherapy. Forty-nine studies with long-term follow up are included. Outcomes for four studies are based on conference abstracts or pharmaceutical company data (Ferry 1992; Ferry 1994; Selby 2003; SMK20001). The majority of trials were conducted in North America but studies are also included from Europe (Aubin 2004; Dalsgar 2004; Grecka 2003; Wagena 2005; Zellweger 2005; Fossati 2008); Turkey (Uyar 2007); Brazil (Haggstrm 2006); New Zealand (Holt 2005); Australia (Myles 2004) and two multicontinent studies (Tonnesen 2003; Tonstad 2003). Special populations recruited include smokers with the following conditions; chronic obstructive pulmonary disease (Grecka 2003; Tashkin 2001; Wagena 2005); schizophrenia (Evins 2001; Evins 2005; Evins 2007; George 2002; George 2008); post traumatic stress disorder (Hertzberg 2001); alcoholism (Grant 2007); and cardiovascular disease (Rigotti 2006 - inpatients; Tonstad 2003) as well as hospital inpatients (Simon 2009). Other populations included adolescents (Killen 2004; Muramoto 2007); smokers awaiting surgery (Myles 2004) hospital staff (Dalsgar 2004); healthcare workers (Zellweger 2005); African-Americans (Ahluwalia 2002), and Maori (Holt 2005). Two studies recruited smokers who had previously failed to quit smoking using bupropion (Gonzales 2001; Selby 2003), and one included smokers who had just failed to quit using NRT (Hurt 2003). More than half the bupropion studies followed participants for at least 12 months from the start of treatment or the target quit day. Eighteen studies (37%) had only six months follow up (Evins 2001; Hertzberg 2001; Ahluwalia 2002; George 2002; Aubin 2004; Collins 2004; Dalsgar 2004; Hatsukami 2004; Killen 2004; Myles 2004; Evins 2005; Wagena 2005; Haggstrm 2006; Grant 2007; Muramoto 2007; Uyar 2007;George 2008; Simon 2009). The majority of studies reported an outcome of sustained abstinence. In 12 (24%) only point prevalence rates were given, or the denition of abstinence was unclear (George 2002; Selby 2003; Swan 2003; Killen 2004; Myles 2004; Evins 2005; Grant 2007; Muramoto 2007; Piper 2007; Schmitz 2007; Uyar 2007; George 2008).

Thirty-six trials evaluated bupropion as a single pharmacotherapy to assist initial cessation. Included in separate analyses are trials that tested bupropion as an adjunct to nicotine replacement therapy (Evins 2007; Killen 2004; Jorenby 1999 (part); Simon 2004; Grant 2007; George 2008) and trials making direct comparisons between bupropion and nicotine replacement therapy (Grecka 2003; Jorenby 1999; Uyar 2007), bupropion and nortriptyline (Haggstrm 2006; Hall 2002; Wagena 2005) and between bupropion and varenicline (Gonzales 2006, Jorenby 2006; Nides 2006). Trials testing the extended use of bupropion for relapse prevention (Hays 2001; Hurt 2003; Killen 2006; Covey 2007; Croghan 2007), and its use for assisting in reducing the amount smoked (Hatsukami 2004) are pooled separately. The ve studies that evaluated bupropion SR for relapse prevention each had slightly different designs (Hays 2001; Hurt 2003; Killen 2006; Covey 2007; Croghan 2007). These studies also contribute to a separate Cochrane review on interventions for relapse preventions (Hajek 2009) One study evaluated bupropion for reducing smoking in people not wanting to make a quit attempt but interested in reducing (Hatsukami 2004). During treatment, if participants decided they wanted to try to quit, they were enrolled in a cessation programme during which they continued to use bupropion and were then followed up for 19 weeks. Two placebo-controlled trials studied the use of bupropion for smokeless tobacco cessation (Dale 2002; Glover 2002). These trials are excluded from the present review but are covered in the Cochrane review of interventions for smokeless tobacco cessation (Ebbert 2007). Most of the bupropion trials excluded participants with current depression but not those with a history of depression. One study (Ahluwalia 2002) did include participants who may have been depressed (i.e. several had a Center for Epidemiologic Studies Depression (CES-D) score of over 16). Two studies explicitly excluded participants with a history of major depression (Dalsgar 2004) or any psychiatric disorder (Collins 2004). Amongst the studies recording the prevalence of a history of depression at baseline the proportion ranged from 6% (Hatsukami 2004) to 44% (Swan 2003), but was typically 20-30%.

Nortriptyline Nine published studies of the tricyclic antidepressant nortriptyline are included. Aveyard 2008 is new since the last review. Hall and colleagues conducted three trials, and Prochazka and colleagues two, both in the USA. Two studies were conducted in Brazil (Da Costa 2002; Haggstrm 2006), one in the Netherlands (Wagena 2005) and one in the UK (Aveyard 2008). Seven studies excluded participants with current depression but most of these included people with a history of depression. All studies were placebo controlled and used doses of 75 to 100 mg/day or titrated doses to serum levels recommended for depression during the week prior
5

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

to the quit date. All studies used a denition of cessation based on a sustained period of abstinence. The three studies by Hall and colleagues, and Aveyard 2008 reported outcomes after 12 months of follow up and the other ve had six months of follow up. The design, length of treatment, level of common behavioural support and use of nicotine replacement as common therapy varied as summarised below. Hall 1998 used a 2x2 factorial design with nortriptyline versus placebo for 12 weeks crossed with a 10-session cognitive behavioural mood management intervention versus a ve session standard health education control. The behavioural arms are collapsed in this meta-analysis. Hall 2002 used a 3x2 factorial design with nortriptyline versus bupropion versus placebo for 12 weeks crossed with a ve session psychosocial behaviour therapy intervention versus medical management involving only brief advice and counselling. The behavioural arms are collapsed. Hall 2004 used a 2x2 factorial design with nortriptyline versus placebo crossed with extended treatment versus brief treatment. All participants received nicotine patch therapy for eight weeks and ve sessions of group-based counselling. The brief treatment was 12 weeks of nortriptyline or placebo and weekly individual counselling. The extended treatment was 52 weeks of nortriptyline or placebo and weekly and the monthly individual counselling sessions. Since the brief nortriptyline regimen is similar to that of the other nortriptyline trials, we include the results of brief nortriptyline versus placebo and extended nortriptyline versus placebo separately in the metaanalysis (Hall 2004 Brief; Hall 2004 Extended). Prochazka 1998 tested nortriptyline versus placebo for 10 weeks with a behavioural intervention of two group sessions and 12 individual follow-up visits. Prochazka 2004 tested nortriptyline versus placebo for 14 weeks as an adjunct to nicotine patch and brief behavioural counselling. Da Costa 2002 tested nortriptyline versus placebo for six weeks with a behavioural intervention of six weekly group cognitive therapy sessions. Wagena 2005 compared nortriptyline, bupropion or double placebo for 12 weeks with individual counselling and telephone support. Haggstrm 2006 tested nortriptyline versus placebo for 60 days with six individual counselling sessions. Aveyard 2008 compared nortriptyline to placebo as an adjunct to participants choice of NRT which could include a combination of products, and four weeks of behavioural support, mainly in a group setting.

Fluoxetine

Four trials with long-term follow up are included. Two studies used uoxetine as the only pharmacotherapy and had six months follow up; a multicentre trial compared 30 mg daily, 60 mg daily or placebo for 10 weeks (Niaura 2002), and a single-site study used 60 mg or placebo for 12 weeks (Spring 2007). Two trials provided NRT to all participants and compared the addition of uoxetine and placebo over 12 months follow up; Blondal 1999 used 20 mg/ day or placebo for three months as an adjunct to nicotine inhaler; Saules 2004 used 20 or 40 mg/day of placebo for 10 weeks as an adjunct to nicotine patch. Participants in all trials were not currently depressed but may have had a past history of depression. Spring 2007 stratied by history of depression. We excluded other short-term studies. One study tested 14 weeks of uoxetine (40 mg/day) or dexfenuramine (30 mg/day) versus placebo in normal weight women in a study investigating the effects of these medications in controlling post-cessation weight gain (Spring 1995). This study found an apparently lower abstinence rate with uoxetine (20%) than with placebo (31%) at three months, but the difference was not statistically signicant. Pomerleau 1991 and Dalack 1995 were also studies on uoxetine in smokers attempting to quit, but considered outcomes other than abstinence. Another pharmaceutical company-sponsored multicentre trial was completed but its results were never presented or published. One further trial is known to be underway (Brown 2007b).

Paroxetine

One trial with six-month follow up assessed paroxetine (40 mg, 20 mg or placebo) for nine weeks as an adjunct to nicotine patch (Killen 2000).

Sertraline

One trial with six-month follow up assessed sertraline (200 mg/ day) for 11 weeks versus placebo in conjunction with six individual counselling sessions. There were 134 participants, all current smokers with a past history of major depression (Covey 2002). One trial that combined sertraline with buspirone was excluded because the specic effect of sertraline could not be evaluated (Carro 2007).

Citalopram/zimelidine

Selective Serotonin Reuptake Inhibitors (SSRIs) No new studies with SSRIs have been completed since the last update of the review.

One short-term study used a crossover design to investigate the effect of the SSRIs citalopram or zimelidine on the smoking behaviour of heavy drinkers who were not attempting to stop smoking. Their cigarette use did not change signicantly between active medication and placebo periods (Sellers 1987).
6

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Monoamine oxidase inhibitors

The current review now includes selegiline in this category.

Moclobemide Moclobemide is a reversible monoamine oxidase-A inhibitor. Since smoking acts as a monoamine oxidase-A inhibitor, substituting moclobemide for smoking might help with cessation. This has been tested in one long-term placebo-controlled trial in France (Berlin 1995). Treatment with 400 mg/day began one week before quit day and continued for two months, reducing to 200 mg/day for a further month. No behavioural counselling was provided. Final follow up was at 12 months.

term follow up (Edwards 1989). Treatment was with 150 mg doxepin daily for three weeks prior to quit day and four weeks afterwards. Subjects forfeited a US$135 deposit if they failed to stop smoking for seven days. Two months after cessation, 78% (7/9) of the doxepin group and 10% (1/10) of the placebo group reported abstinence, a statistically signicant difference (P < 0.02). However one week post-cessation abstinence rates using stringent validated abstinence criteria failed to show a statistically signicant difference. Among withdrawal symptoms, there was a signicant group difference only for craving.

Imipramine There are no long-term studies of this noradrenergic tricyclic antidepressant. One trial (Jacobs 1971) compared imipramine (25 mg 3 times/day) with lobeline, dextroamphetamine, placebo and a no-medication control. Some participants attended group support sessions. After three months, success rates, which included a reduction in smoking to less than 10% of baseline, were 56% (10/18) for imipramine, 40% (6/15) for placebo and 69% (27/ 39) for the no-medications control. These differences were not statistically signicant.

Selegiline Selegiline is an irreversible, selective monoamine oxidase-B inhibitor at low doses (10 mg/day) and has shown antidepressant activity at higher doses, when it is non-selective (Gaszner 2006). In a short-term study it reduced smoking behaviour under laboratory conditions and reduced craving during two days of attempted abstinence (Houtsmuller 2002). Two long-term trials have been published and one is included based on a conference abstract (Weinberger 2009). All used 10mg/day oral treatment. Two had treatment durations of 9 weeks (George 2003; Weinberger 2009) and one continued therapy for 26 weeks (Biberman 2003). An unpublished study with preliminary short-term data is excluded (Brauer 2000). Three other phase II trials are known to be in progress (Glover (NCT00439413); Killen (NCT00218647); Le Foll (NCT00390923)), two of which are evaluating transdermal delivery.

Tryptophan Tryptophan may have antidepressant properties because it increases the level of serotonin. There have been no long-term studies reported. Bowen and colleagues postulated that this serotoninenhancing action in conjunction with a high carbohydrate (CHO) diet might relieve the negative affect of cigarette withdrawal. Oral l-tryptophan (50mg/kg/day) and instructions to follow a high CHO, low-protein diet were compared with placebo pills and instructions for a low-carbohydrate diet (Bowen 1991). Participants in both groups also received four two-hour weekly multi-component group therapy sessions. Two weeks following the target cessation date 75% (12/16) of the tryptophan and high CHO diet group were abstinent versus 47% (7/15) of the placebo and low CHO diet group. This difference was not statistically signicant.

Lazabemide This selective monoamine oxidase-B inhibitor was evaluated in an eight-week, dose nding, exploratory study (Berlin 2002). The trial was halted early due to liver toxicity observed in trials of the medications for other indications, and lazabemide is not being developed further. Continuous four-week quit rates at the end of treatment, including all drop-outs as treatment failures, were 17% (18/108) for 200 mg/day, 11% (12/108) for 100 mg/day and 9% (10/114) for placebo.

Venlafaxine
Other antidepressants

No new studies of other antidepressants have been completed since the last review.

Doxepin There are no long-term studies of this serotonergic tricyclic antidepressant. It has been evaluated in a single small trial with short-

This antidepressant inhibits re-uptake of serotonin and norepinephrine. One trial with 147 participants compared venlafaxine at a dose of up to 225 mg/day with placebo. All participants also received nicotine patches and nine brief individual counselling sessions; follow up was for 12 months (Cinciripini 2005). An unpublished short-term study (Frederick 1997) reported no difference in abstinence rates at eight weeks, and frequent side effects in the treatment group.
7

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Hypericum (St Johns Wort) Extracts of hypericum have antidepressant properties. No studies are eligible to be included in the review. Barnes 2006 compared two doses for smoking cessation in an open randomized study with no placebo control. Quit rates were low and did not differ between dose levels. No participants maintained abstinence for 12 months. One uncontrolled study is excluded (Lawvere 2006). A controlled study has been completed but not yet published (Sood (NCT00405912)).

of the third week after the target quit date (TQD) onward and validated at intermediate and nal follow ups. Additional details about the methodology of individual trials are given in the table Characteristics of Included Studies. Consistent with Cochrane methods, we included some trials that have only been published as abstracts, which have limited information on methodological issues (Clarke 2002). For some studies we have obtained additional information from authors, or from the pharmaceutical company funding the study. Use of unpublished data in the meta-analysis is noted in the Included Studies table.

Risk of bias in included studies


All of the trials used placebo controls except Uyar 2007, and Swan 2003 which compared two different doses of a pharmacotherapy. All the trials were described as randomized, but most failed to report randomization and concealment methods in detail. Thirtytwo studies (48%) reported a method of allocation judged adequate to ensure that treatment assignment was concealed at the time of enrollment. All but one of the other trials were categorised unclear because the method of allocation was not described. One bupropion trial (Myles 2004) described the use of a random number table but no mention of a blinded allocation list so was categorised as potentially inadequate. This was a small trial so its inclusion or exclusion did not change the results. Restricting inclusion in the largest meta-analysis (bupropion versus placebo) to studies assessed as using adequate allocation concealment no effect on the results. The denition of abstinence was not always explicit and biochemical validation of self-reported smoking status was not always used; however all but one of the bupropion studies (Swan 2003) and all but one of the nortriptyline studies (Da Costa 2002) for which details were available did use biochemical verication for most selfreported quitters at some assessment points. In a small number of studies we were able to obtain a sustained outcome that was not given in the published report. Most of the sustained abstinence rates are based on self-reported slip-free abstinence from the start

Effects of interventions
(Selected analyses are displayed as Figures in the text. Other analyses are shown in the Data & Analyses section online and full pdf versions of the review) Bupropion We distinguish between the subgroup of trials where bupropion was tested as the only pharmacotherapy, and those trials where the effect of bupropion when added to NRT was assessed. One trial (Jorenby 1999) contributed arms to both subgroups.

Compared to placebo control, no other pharmacotherapy

There were 36 trials in which bupropion was the sole pharmacotherapy, with over 11,000 participants. The pooled risk ratio [RR] was 1.69 (95% condence interval [CI] 1.53 to 1.85) with little evidence of heterogeneity (I = 11%), see gure 1, analysis 1.1. The estimated effect is smaller when expressed as a risk ratio, but has not really changed since the last version of the review, comparing odds ratios (i.e. OR in 2006; 1.94, OR now; 1.86). The control group quit rates ranged from 0% to 22%, with a weighted average of 9%. Intervention group quit rates ranged from 4% to 43% with a weighted average of 17%. Figure 1

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Figure 1. Forest plot of comparison: 1 Bupropion. Abstinence at 6m or greater follow-up, outcome: 1.1 Bupropion versus placebo/control. Subgroups by length of follow-up.

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Sensitivity to length of follow-up Although in this update there was no overall evidence of heterogeneity amongst the 36 trials of bupropion as the only pharmacotherapy we continued to use subgroup analyses to explore potential moderators of treatment effect. Twenty two of these trials had 12-month follow up and fourteen had six months. The estimated RR for the 12-month follow-up group was 1.64 (95% CI 1.46 to 1.84, I = 34%, analysis 1.1.1) which was not signicantly lower than that for trials with only six months (RR 1.81; 95% CI 1.51 to 2.16), I = 0%, analysis 1.1.2). Much of the difference, and the heterogeneity in the 12-month subgroup, could be attributed to Zellweger 2005.

analysis was based on the 36 trials contributing to analysis 1.1 but excludes two trials where the level of support could not be classied.)

Effect of dose In the rst multi-dose study (Hurt 1997), cessation rate was linearly related to dose (100 mg versus 150 mg versus 300 mg) through the end of treatment, consistent with pharmacological efcacy, although the difference between 300 mg and 150 mg doses was not signicant at long-term follow up. A larger study compared 150 mg and 300 mg daily doses, without a placebo group, and reported similar 12-month point prevalence quit rates for both doses (Swan 2003). A study in adolescents also included 150 mg and 300 mg doses (Muramoto 2007), with higher quit rates in the larger does group. Doses above 300 mg have not been tested. Pooling the three studies and comparing 300 mg versus 150 mg shows no evidence of a signicant difference in abstinence (N = 2,042, RR 1.08; 95% CI 0.93 to 1.26, analysis 1.4).

Sensitivity to clinical setting In a post hoc subgroup analysis we distinguished between trials that recruited community volunteers and trials that recruited patients in healthcare settings or with specic diagnoses. Whilst the estimated effect was smaller amongst trials that recruited community volunteers than those recruiting in health care settings the condence intervals overlapped and effects were signicant in both groups (analysis 1.2).

Bupropion & nicotine replacement combined therapy compared to NRT alone

Effect of level of behavioural support Three trials compared bupropion and placebo in factorial designs varying the behavioural support. There was no evidence from any that the efcacy of bupropion differed between lower and higher levels of behavioural support (Hall 2002; McCarthy 2008) or by type of counselling approach used (Schmitz 2007). Two other studies have compared different levels of behavioural support for people prescribed bupropion (Strayer 2004; Swan 2003). These did not include placebo arms so do not provide evidence about within-study interactions between behavioural interventions and pharmacotherapy. We also explored a between-study subgroup analysis of the possible interaction with behavioural support using the classication into low and high intensity used in the Cochrane NRT review (Stead 2008). Low intensity was less than 30 minutes at the initial consultation, with no more than two further assessment and reinforcement visits. Only one of the included trials had such low intensity support (Myles 2004) and it was too small to draw conclusions from. Fossati 2007 (in a primary care setting) and part of McCarthy 2008 had limited behavioural support but in both cases there were more than three visits. We also examined, within the more intensive therapy trials, evidence of a different effect of bupropion versus placebo in eight trials that provided group-based behavioural interventions compared to the majority where individual therapy was provided. We found no evidence of a difference between subgroups (analysis 1.3). (This subgroup

There was substantial heterogeneity in the results of six studies adding bupropion to nicotine patch therapy (Jorenby 1999; Killen 2004; Simon 2004; Evins 2007; Grant 2007; George 2008, I = 64%). Using a random-effects model to pool the studies did not show evidence of a signicant effect of adding bupropion (N = 1,106, RR 1.23; 95% CI 0.67 to 2.26, analysis 1.5). Of the six trials, four recruited people who were potentially hard to treat; adolescents (Killen 2004), smokers with schizophrenia (Evins 2007; George 2008) and smokers in treatment for alcohol dependence (Grant 2007). George 2008 was a small study with no quitters at all in the control group. The signicant benet seen in one trial (Jorenby 1999) may be due in part to the unusually poor results from nicotine patch alone in this study. The condence intervals around the estimate do not exclude a benet that would be clinically useful. One relapse prevention study (Croghan 2007) has compared open label nicotine inhaler, bupropion or both combined as initial therapy for cessation. After 12 weeks there was a second phase of randomization, so long term effects cannot be compared.

Bupropion for relapse prevention

Five trials have evaluated extended use of bupropion for preventing relapse in people who have already stooped smoking. Pooling studies suggests the possibility of a small benet but condence intervals just include 1 (N = 1,587, RR 1.17; 95% CI 0.99 to

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

10

1.39, analysis 1.6). The studies were heterogeneous with respect to the length of initial abstinence, the period of pharmacotherapy and the length of post treatment follow-up. The results are discussed in more detail in a Cochrane review of relapse prevention interventions (Hajek 2009).

of this interaction was not tested (Tashkin 2001). One study has reported a larger treatment effect for four- to seven-week abstinence in males (Gonzales 2001). This was a study re-treating smokers who had already failed to quit with bupropion. In the Hays 2001 relapse prevention study, there were no signicant gender effects (Gonzales 2002a). In summary, gender does not appear to consistently inuence the efcacy of bupropion. Whilst most reports have not indicated any difference in treatment effects between older and younger smokers, subgroup analyses of two trials, Hays 2001 (reported in Hurt 2002), and Hurt 1997 (reported in Dale 2001), found evidence of an interaction, with a larger treatment effect for older smokers. One study in adolescents did not show evidence of an effect for bupropion over nicotine patch alone (Killen 2004).
Bupropion as second treatment

Bupropion and depression

There was not sufcient detail in most studies about results in smokers with and without depression to conduct a meta-analysis. In three within-trial analyses, smokers with a past history of depression did not benet more than those without such a history (Hayford 1999 subgroup analysis of Hurt 1997; Hurt 2002 & Cox 2004 subgroup analyses of Hays 2001; Brown 2007). In the only analysis specically within the subgroup of smokers with no history of depression, bupropion was effective (Hayford 1999). Bupropion may alleviate some subclinical symptoms of depression during treatment (Ahluwalia 2002; Catley 2005; Lerman 2002a), but although this may facilitate smoking cessation, other mechanisms are probably more important (Catley 2005). In one trial (Collins 2004 reported in Lerman 2004), there was an interaction between nicotine dependence and treatment on post-cessation depression symptoms. Most smokers showed a reduction in depression symptoms during the treatment phase, whether they received bupropion or placebo. The reduction was maintained during follow up. However highly dependent smokers showed a greater reduction in depression scores whilst receiving bupropion, and an increase when treatment ended.

Gender/age differences with bupropion

One relapse prevention trial described above (Hurt 2003) also randomized 194 smokers who had not quit successfully using nicotine patch therapy to bupropion or placebo as a second line treatment. Only one person, in the bupropion group, quit and sustained abstinence at six months. This is consistent with the results of other studies, which nd low overall success rates in smokers offered further pharmacotherapy soon after treatment failure (eg Gourlay 1995; Tonnesen 1993). In contrast, a subgroup analysis of Jorenby 1999 (reported in Durcan 2002) suggested that bupropion was equally effective in smokers with and without a past history of failure with NRT. In this trial the gap between the previous failed attempt and the second attempt at cessation would have been longer.
Bupropion versus NRT

Too few of the studies have published data on long-term quit rates by gender for it to be possible to conduct a denitive subgroup meta-analysis. A meta-analysis of mainly short-term outcomes and including 12 trials with 4421 participants showed no evidence of a treatment-gender interaction (Scharf 2004). In these trials women were less successful at quitting than men overall, but bupropion was equally benecial in men and women. A subgroup analysis of long-term data from one study (Jorenby 1999, reported in Smith 2003) did report an interaction such that women appeared to benet relatively more from medication. A more recent study reported a signicant gender by smoking rate by treatment group interaction, such that bupropion seemed to benet male heavy smokers and female light smokers but not others (Collins 2004). This study also showed an interaction among treatment effect, gender and genotype (Lerman 2002b). At the end of treatment, women with a variant CYP2B6 gene had signicantly higher quit rates when treated with bupropion than on placebo. The bupropion treatment effect was not signicant for the other three gender/ genotype subgroups. A study in smokers with chronic obstructive pulmonary disease (COPD) noted a larger treatment effect for women (ORs 2.7 versus 1.7), although the statistical signicance

Three studies allowed a direct comparison between bupropion and nicotine patch (Grecka 2003; Jorenby 1999; Uyar 2007). In the only one that was placebo-controlled, bupropion was signicantly more effective than nicotine patch (Jorenby 1999); however, nicotine patch itself was not efcacious in this particular study. The other two smaller studies were open label and had non-signicant effects. Because there was slight indication of heterogeneity (I = 44%) and there was borderline signicance using a xed-effect model we used a random-effects model to estimate the pooled effect, which did not show a signicant difference (N = 657, RR 1.26; 95% CI 0.73 to 2.18, analysis 1.7).
Bupropion versus varenicline

In three studies there was a direct comparison between bupropion and varenicline (Gonzales 2006; Jorenby 2006; Nides 2006). The pooled estimate showed a signicantly lower rate of quitting with bupropion than varenicline (N = 1622, RR 0.66; 95% CI 0.53 to 0.82, analysis 1.8), with no evidence of heterogeneity. The average
11

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

quit rate across the bupropion arms was 14% compared to 21% for varenicline.

Pooling six trials using nortriptyline as the only pharmacotherapy shows evidence of a signicant benet of nortriptyline over placebo (N = 975, RR 2.03; 95% CI 1.48 to 2.78, gure 2, analysis 2.1.1) without evidence of statistical heterogeneity (I = 7%).

Bupropion for smoking reduction

One study offered bupropion to smokers not wishing to quit ( Hatsukami 2004). There were no signicant differences in reduced cigarettes/day, cotinine or cessation (analysis 1.9). Nortriptyline

Nortriptyline & nicotine replacement combined therapy compared to NRT alone

Compared to placebo control, no other pharmacotherapy

Pooling three trials (one with a factorial design entered as two studies) using nortriptyline as an adjunct to nicotine patch therapy does not show evidence of an additional benet from nortriptyline (N = 1,219, RR 1.29; 95% CI 0.97 to 1.72, gure 2, analysis 2.1.2) with much heterogeneity (I = 34%). Figure 2

Figure 2. Nortriptyline versus placebo, long term abstinence

Subgroup and sensitivity analyses

There were too few trials of nortriptyline to examine effect of duration of follow up, past depression, or amount of behavioural therapy between subgroups of trials. In one within-study comparison, a past history of depression did not appear to modulate the efcacy of nortriptyline, but subgroup numbers were small

(Hall 1998). In two within-study comparisons, the intensity of adjunctive behaviour therapy did not inuence the active versus placebo effect (Hall 1998; Hall 2002). In the study by Hall and colleagues of extended treatment (longer duration of both nortriptyline and behaviour therapy) versus brief treatment (similar to other nortriptyline trials), the condence intervals for nortripty12

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

line versus placebo included 1.0 (i.e. no evidence of an effect) for each treatment. The extended treatment increased absolute rates of abstinence and the relative effect for nortriptyline (RR 1.34 versus 0.62) but this was not statistically signicant. Dose-response studies with nortriptyline have not been reported.
Bupropion versus nortriptyline

clinically useful effect (RR 1.22; 95% CI 0.64 to 2.32, analysis 6.1). Post hoc subgroup analyses suggested that there might be greater evidence for an effect amongst lighter smokers.

Adverse Events We summarize adverse events (AEs) reported in trials of bupropion (analysis 1.10) and nortriptyline (analysis 2.2). In addition, for bupropion we summarize data from national surveillance schemes in the United Kingdom (UK), Australia and Canada (see Appendix 1). Although there are no new data, there have been some new warnings since the last review. Assessing AEs in smoking cessation medications is difcult because any AEs may be due, not to the medication, but to nicotine withdrawal (i.e., physical dependence). In addition, given smokers are more likely to have several medical and psychiatric illnesses, some new AEs may be exacerbations of pre-existing illnesses (Hughes 2008).

Three trials included a direct comparison between bupropion and nortriptyline (Haggstrm 2006; Hall 2002; Wagena 2005). In each study the comparison favoured bupropion but none showed signicant differences. There was no evidence of heterogeneity. When pooled the difference remains non-signicant, but does not exclude a clinically useful difference in favour of bupropion (N = 417, RR 1.30; 95% CI 0.93 to 1.82 analysis 3.1). Selective Serotonin Reuptake Inhibitors (SSRIs) Four trials of uoxetine (Blondal 1999; Niaura 2002; Saules 2004; Spring 2007) and one each of paroxetine (Killen 2000) and sertraline (Covey 2002) were included. The pooled RR for the uoxetine trials was 0.92 (N = 1,486, 95% CI 0.68 to 1.24, analysis 4.1). Pooling only Niaura 2002 and Spring 2007 that used uoxetine alone and not an adjunct to NRT did not alter the conclusion that there was no evidence of a clinically important benet (N = 1,236, RR 0.92; 95% CI 0.65 to 1.30). There was no evidence of benet from paroxetine (Killen 2000, N = 224, RR 1.08; 95% CI 0.64 to 1.82) or sertraline (Covey 2002, N = 134, RR 0.71; 95% CI 0.30 to 1.64) Monoamine oxidase inhibitors (MAOIs) One trial of moclobemide (Berlin 1995) and three of selegiline (Biberman 2003; George 2003; Weinberger 2009) were included. The effect of moclobemide was signicant at six-month follow up but was not at the nal 12-month follow up (N = 88, RR 1.57 95% CI 0.67 to 3.68, analysis 5.1.1). The selegiline trials were all relatively small and had heterogeneous effects, with the unpublished trial (Weinberger 2009) reporting higher quit rates in the placebo group. When pooled there was no evidence of a signicant effect (N = 250, RR 1.45; 95% CI 0.81 to 2.61, I = 55%, analysis 5.1.2). Pooling all four trials of MAOIs also gave a non signicant estimate (RR 1.49; 95% CI 0.92 to 2.41, analysis 5.1). Biberman 2003 also reported signicantly reduced ratings of craving for cigarettes. One trial of beoxatone showed no effect on cessation but data are unpublished (Berlin 2005). Venlafaxine One trial of venlafaxine (Cinciripini 2005) failed to show a significant increase in 12-month quit rates compared to nicotine patch and counselling alone, but condence intervals do not exclude a

Adverse events reported for bupropion

The most common side effects are insomnia, occurring in 30% to 40% of patients, dry mouth (10%) and nausea (GlaxoSmithKline; Goldstein 1998). Typical drop-out rates due to adverse events range from 7% to 12%, but in one study 31% of those on 300 mg and 26% on 150 mg discontinued medication (Swan 2003). Early trials of bupropion as a treatment for depression using the immediate release formulation and often doses greater than 300 mg/day suggested it increased the risk of seizures in those with a prior history of alcohol withdrawal, anorexia or head trauma. This led to the development of the slow release (SR) preparation now licensed for smoking cessation. Using this preparation in doses of 300 mg/day or less, and excluding those at risk of seizures, no seizures had been reported in any of the smoking cessation trials until the study in physicians and nurses in Europe (Zellweger 2005). In this study there were two seizures amongst 502 people randomized to bupropion, one of whom had a familial history (data from GlaxoSmithKline). Since then two seizures have been reported in a study in which 126 participants received bupropion (Nides 2006) and one in a study with 329 treated (Gonzales 2006). Two seizures were also reported in an unpublished study with 100 participants prescribed bupropion (Strayer 2004, personal communication). This gives a total of 7 seizures amongst around 8,000 people exposed in clinical trials, so despite the recent reports the overall seizure rate remains less than the rate of 1:1000 given in product safety data. The gure of 1:1000 derives from a large, open, uncontrolled observational safety surveillance study conducted by the manufacturers (Dunner 1998) which examined 3100 adult patients using slow release bupropion for eight weeks for treatment of depression (not smoking cessation). Treatment was extended if necessary to a year, at a maximum dose of 150 mg twice daily. Patients with a history of eating disorder, or a personal or family history of epilepsy were excluded. Three participants (i.e.
13

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

1:1000) had a seizure considered to be related to the therapeutic use of bupropion. Post-marketing surveillance data are available from some countries in which bupropion is licensed only for smoking cessation. Their limitation is that the denominator is not denitely known, and serious adverse events in medical practice are underreported by as much as a factor of 10 (Furberg 2006). However, using number of prescriptions as the denominator, the rate of reported seizures in the United Kingdom and Canada appears to be no higher (and possibly lower) than the rate of 1 in 1000 reported by Dunner et al. In England an observational study provided data on a cohort of 11,753 patients who had been dispensed bupropion (Boshier 2003). Eleven seizures were reported for a rate of 1 in 1000; four of these were associated with a past history of seizure. A second UK study (Hubbard 2005) used a general practice database (The Health Improvement Network) and a self-controlled case series method to estimate the relative incidence of death or seizure in 9329 individuals over a mean (SD) follow up of 1.9 (0.9) years. The self-controlled cases series method involves comparing each individual during a high risk period with him/herself outside this period. The denition of high risk period in this study was 28 days after a prescription for bupropion (a 63 day high risk period was also used to test for robustness of the analysis). The reported death rates (case-series age adjusted estimate) were nonsignicantly lower during the high risk period (28 days: 0.5, 95% CI 0.12 to 2.05; 63 days: 0.47, 95% CI 0.18 to 1.19) while the seizure rates were non-signicantly higher during the same period (28 days: 3.62, 95% CI 0.87 to 15.09; 63 days: 2.38, 95% CI 0.72 to 7.93). The seizures recorded in the rst 28 days of treatment occurred on days 5 and 6 in one individual with no previous history of epilepsy. Of note in this study was that 12 people had been prescribed bupropion despite previous diagnoses of seizure. Allergic reactions have also been reported with bupropion. These include pruritus, hives, angioedema and dyspnoea. Symptoms of this type requiring medical treatment have been reported at a rate of about 1 to 3 per thousand in clinical trials (GlaxoSmithKline), and this is approximately the level at which they are being reported in the national surveillance schemes. There have also been case reports of arthralgia, myalgia, and fever with rash and other symptoms suggestive of delayed hypersensitivity. These symptoms may resemble serum sickness. From the national surveillance schemes it is not possible to calculate the frequency of this outcome. Hypersensitivity reactions are listed as possible rare (occurring at rates less than 1 per 1000) adverse effects in the product data. In the UK, Australia and France, bupropion is licensed only for smoking cessation. In the UK there were four reported suicides, 78 reports of suicidal ideation and ve of suicide attempts/parasuicide between the licensing of bupropion and May 2004 among an estimated 1,000,000 prescriptions (MHRA 2004). In Australia there were 32 reports of suicide/self-injurious ideation from approximately 534,000 prescriptions up to 2004 (TGA 2004). In France there were reports of 22 suicide/attempted suicides and

19 suicidal ideation from 2001 to 2004 amongst approximately 698,000 people exposed (Beyens 2008). In all these populations the risk based on reported events is in the order of 1:10,000. A review of the safety of bupropion was undertaken by the European Agency for the Evaluation of Medicines for Human Use (EMEA 2002). Suicidal ideation had been observed in six out of a total of 4067 participants in clinical trials for smoking cessation, a rate of 1: 677. The rate of suicidal ideation with bupropion was stated to be low compared with the rates found in the general population but no data were presented. It was also stated that there was neither a pharmacological nor a clinical reason for suspecting bupropion to be causally associated with depression or suicide. The committee concluded that the benet/risk balance remained favourable, but made recommendations to strengthen warnings on hypersensitivity, and on depression, by advising clinicians to be aware of the possible emergence of signicant depressive symptoms in patients undergoing a smoking cessation attempt. A follow-up of 136 women exposed to bupropion prescribed for smoking cessation or depression during the rst trimester of pregnancy suggested that bupropion does not increase the rates of major malformations, but there were signicantly more spontaneous abortions (Chun-Fai-Chan 2005). An assessment of potential infant exposure to bupropion and active metabolites in breast milk suggests that the exposure of an infant whose mother was taking a therapeutic dose would be small (Haas 2004). Bupropion is also an inhibitor of CYP2D6 so care is needed when starting or stopping bupropion use in patients taking other medication metabolized by this route (Kotlyar 2005). Although no patient is reported to have died while taking bupropion in trials for smoking cessation, some have died while taking bupropion prescribed for smoking cessation in routine practice. There has been no formal epidemiological analysis of these deaths, but no national reporting scheme has concluded that bupropion caused these deaths. Bupropion may cause adverse effects in overdose. A review of bupropion-only non-therapeutic exposures reported to the US Toxic Exposure Surveillance System for 19981999 identied 3755 exposures to Wellbutrin SR, 2184 to Wellbutrin and 1409 to Zyban (Belson 2002). These non-therapeutic exposures included intentional overdose and unintentional ingestion as well as reports of adverse reactions. Clinical effects related to bupropion exposure developed in 31% of non-therapeutic exposures, with vomiting the most common childhood symptom and tachycardia the most common in teenagers and adults. Six per cent of exposures (19% of symptomatic patients) developed a seizure. Seizures were more common with Wellbutrin exposures (22% of symptomatic patients) compared to bupropion SR (16% of symptomatic) and Zyban (13% of exposures). Moderate or severe outcomes were reported in 17% of Wellbutrin exposures, 12% of Wellbutrin SR exposures and 9% of Zyban exposures. Seventyeight per cent of the moderate and major effects resolved in less than 24 hours. Five deaths all involved suspected suicides and only one in ve involved Zyban or Wellbutrin SR.
14

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

In 2003, post-marketing data from studies of SSRIs for depression in adolescents suggested they may increase the risk for suicidal ideation (Hegerl 2006). Based on this nding, the US FDA issued warnings for several clases of antidepressants including bupropion when used for depression in both children and adults (US FDA 2004). In 2009, the US FDA added new warnings about the risk of serious neuropsychiatric symptoms in patients using bupropion for smoking cessation (US FDA 2009a; US FDA 2009b). The FDA stated these symptoms include changes in behavior, hostility, agitation, depressed mood, suicidal thoughts and behavior, and attempted suicide. The added warnings are based on the continued review of postmarketing adverse event reports for varenicline [a smoking cessation treatment, see Cahill 2008] and bupropion received by the FDA. There were 46 reports of suicidal ideation and 29 of suicidal behaviour for bupropion to November 27 2007 (US FDA 2009a).
Adverse effects of nortriptyline

the USPHS analysis. Also, it could be because the Cochrane analysis was a collation of six within-study randomized comparisons whereas the USPS was an across-study comparison of the results the combination arm in three trials to the results of the patch alone arm in 32 studies. Meta-analysis of the three bupropion trials that compared the recommended dose of 300 mg/day (150 mg twice daily) with a dose of only 150 mg failed to show a signicant long-term benet of the higher dose. Whilst the power of the comparison is not sufcient to establish equivalence, for people with troubling side effects such as insomnia, a reduction in dose to 150mg in the morning would be an alternative to discontinuing pharmacotherapy altogether. There is still insufcient evidence from head to head trials to prefer bupropion over NRT or vice versa. In indirect, across-study comparison the efcacy seems similar. The choice between these two therapies will depend on patient preferences including a consideration of the risks of adverse events. In three trials, participants treated with bupropion were significantly less likely to quit than those treated with varenicline, a partial nicotinic agonist. Although this suggests varenicline should be preferred over bupropion as a rst line therapy, further study is warranted for several reasons. First, the number of studies is small. Second, the three trials used very similar optimal samples, settings and procedures. Whether superiority for varenicline would occur in a more real-world setting is unclear. Finally, given that both bupropion and varenicline block nicotine receptors and increase dopamine, a biological explanation for superior efcacy for varenicline has not been proposed. The evidence for efcacy of varenicline is covered by another Cochrane review (Cahill 2008). Further trials of extended therapy with bupropion for individuals who have recently quit bring the number included to ve, and the pooled estimate only narrowly excludes 1 (RR 1.17; 95% CI 0.99 to 1.39) but the clinical importance of any effect seems likely to be small. Preventing relapse remains a major challenge. Nortriptyline has also been shown to assist cessation; there is an adequate evidence base although the number of trials and the total number of participants is much smaller than for bupropion. As with bupropion there is no evidence that the combination of nortriptyline and NRT is more effective than NRT alone. There are no direct comparisons of nortriptyline with NRT or varenicline. Head to head comparison with bupropion in three trials favour bupropion but do not show a signicant difference. The pooled risk ratios of efcacy of nortriptyline and bupropion appear broadly similar. One argument for considering nortriptyline as a rst line therapy is its lower cost (Wagena 2005a). The main argument against this is based on the potential for serious adverse effects (Hughes 2005). Although not widely tested, the efcacy of bupropion and nortriptyline appear to be independent of a past history of depression
15

The adverse events reported included the well known tricyclic effects of dry mouth, drowsiness, light-headedness and constipation observed in studies treating depression in which doses were often > 150 mg (Khawam 2006). In addition, nortriptyline can be lethal in overdoses. Based on experiences when used to treat depression, nortriptyline would be expected to have the potential for more serious adverse events. In contrast, when used at 75 to 150 mg doses in smokers, drop-out rates in the trials reporting this outcome have ranged from 4% to 12%, with one exception (Wagena 2005). This rate is similar to that for bupropion and NRT. The only serious adverse event in someone treated with nortriptyline was collapse/palpitations thought possibly caused by treatment (Aveyard 2008). Since nortriptyline is not approved for smoking cessation in any country, we are unaware of any post-marketing surveillance data.

DISCUSSION
Thirty-six trials now provide a large evidence base conrming the benet from bupropion used as single pharmacotherapy for smoking cessation. There is no statistical heterogeneity evident and the pooled estimate suggests that bupropion increased long term quitting success by relative factor of 1.5 - 1.9. Treatment effects appear to be comparable in a range of populations, settings and types of behavioural support and in smokers with and without a past history of depression. Clear evidence of an additional benet from adding bupropion to NRT was not demonstrated. The meta-analysis for the updated USPHS clinical practice guideline reported an odds ratio of 1.3 (95% CI 1.0 to 1.8) for a combination versus nicotine patch alone (Fiore 2008 table 6.28). The difference in meta-analytic outcomes may be because the current analysis included several studies of hard-to-treat populations not included in

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

(Hall 1998; Hayford 1999; Hurt 2002) and post-cessation depression (Catley 2005, reporting an analysis of Ahluwalia 2002). This suggests that their efcacy is not due to a traditional antidepressant effect and that they benet those with no history of depression. Although the pharmacological mechanism of action of bupropion is still unclear, recent animal studies suggest that it may act as an antagonist at the nicotine receptor (Cryan 2003; Wiley 2002, Young 2002). How nortriptyline increases cessation is unclear. Although there is considerable research interest in genetic differences that could help predict response to pharmacotherapy (Uhl 2008), there is currently no genetic test that can be used for treatment matching in a clinical setting. There is preliminary evidence that smokers with normal dopamine receptor availability and function might respond better to bupropion (David 2005; Lerman 2006) whilst genotypes that are associated with impaired dopaminergic systems could have relatively better outcomes with NRT (Johnstone 2004). It is also possible that women with particular genotypes may respond differently to bupropion compared with men having the same genotypes (Swan 2005). The rate of metabolism of nicotine has also been suggested as a moderator of treatment effect, with fast metabolisers beneting from bupropion (Collins 2004, reported in Patterson 2008). No seizures were reported in the rst large studies of bupropion for smoking cessation but more recently four studies (Gonzales 2006; Nides 2006; Strayer 2004; Zellweger 2005) report a total of 7 seizures. Since about 8,000 people have been exposed to bupropion in the cessation studies included in this review, the averaged rate is still less than the 1:1000 estimated risk used in product safety information, although the clustering of seizures in a few small studies is unexpected. Some suicides and deaths while taking bupropion have been reported. Currently, like many other antidepressants and varenicline, bupropion has a warning about the possibility of serious mood and behavioral changes. However, it remains unclear whether these outcomes were caused by bupropion effects. In studies in depressed patients nortriptyline sometimes caused sedation, constipation, urinary retention and cardiac problems, and when taken as an overdose could be fatal. Based on the rate of signicant adverse events when used to treat depression, nortriptyline would be expected to have higher rate of drop-outs. This has not been the case in the relatively small number of subjects receiving nortriptyline in the existing studies (about 500), perhaps because the dose of nortriptyline used (75 to 150 mg) is generally smaller than that used for depression and smokers are not acutely ill. However, given this small sample size, the safety of these doses of nortriptyline for smoking cessation is still unclear.

term trials have, somewhat surprisingly, failed to show that this class of antidepressants helps smoking cessation. Some studies have found SSRIs effective in post hoc-determined subgroups (Borrelli 2004; Swan 1999) but this requires verication. The most recent trial (Spring 2007) found that although uoxetine initially increased cessation amongst smokers with a history of depressive disorder, by the end of the study it impaired cessation regardless of depressive history. There is no clear evidence of long term efcacy for monoamine oxidase inhibitors. Two early trials of selegiline suggested a possible benet whilst the most recent trial has not supported this.

Mechanism of action of antidepressants Whether the efcacy of bupropion and nortriptyline is specic to the unique pharmacology of these medications or whether it would occur in all antidepressants has not been completely resolved. The SSRI antidepressants appear not to be efcacious. This suggests serotonin modulation is not important, leaving the dopaminergic or noradrenergic effects of nortriptyline and bupropion to account for their efcacy. Although the efcacy of bupropion was initially thought to be due to its dopaminergic actions, nortriptyline, which is also effective, has relatively weak dopaminergic activity. In addition, bupropion has as much noradrenergic activity as dopaminergic activity. Another possibility, at least for bupropion, is that it acts as a nicotinic receptor blocker (Warner 2005). Whether the same is true for nortriptyline is not clear (Gambassi 1999). If noradrenergic effects are important in treatments for smoking, then monoamine oxidase inhibitors and other tricyclic antidepressants should be effective; however, only a few small trials of these are available.

Comparison with prior reviews and meta-analyses The ndings of this review are in agreement with the conclusions of other reviews and guidelines (Aubin 2002; Haustein 2003; Hughes 2005; Jorenby 2002; Martinez-Raga 2003; McRobbie 2005; RCP 2000; Tonstad 2002; Tracey 2002; Haustein 2003; Martinez-Raga 2003; West 2000; West 2003). Many national smoking cessation guidelines were last updated six years ago. The US guidelines were updated in 2008 (Fiore 2008) and continue to recommend bupropion as a rst line therapy and nortriptyline as a second-line therapy due to possible adverse events. Open uncontrolled trials and observational studies of bupropion have shown real-life quit rates comparable to those found in clinical trials (Holmes 2004; Wilkes 2005; Paluck 2006). Studies of cost-effectiveness also support the utility of bupropion (Bolin 2006; Javitz 2004) and nortriptyline (Hall 2005).

Other antidepressants The six long-term trials of selective serotonin reuptake inhibitors (SSRIs) (uoxetine, paroxetine and sertraline) and other short-

AUTHORS CONCLUSIONS
16

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Implications for practice


The existing evidence supports a role for bupropion and nortriptyline in clinical practice. Nicotine replacement therapy has proven efcacy in over 90 studies (Stead 2008) and has a very benign sideeffect prole. There is insufcient published evidence to conclude either bupropion or nortriptyline has superior efcacy to NRT or vice versa. The condence intervals around the efcacy estimates for bupropion, nortriptyline and NRT overlap. Bupropion and nortriptyline are equally effective in smokers with and without a history of depression and their efcacy does not appear to be mediated by improving post-cessation depression. Although the US Guideline (US DHHS 2000) suggests smokers with depression problems should use bupropion rather than NRT, whether smokers with a previous history of depression or mild current depression would do better with antidepressants than NRT has not been tested. Whether bupropion prevents depressive symptoms or relapse to depression better than NRT has also not been studied. Patient preferences, cost, availability and side-effect prole will all need to be taken into account in choosing among medications. Bupropion and nortriptyline may be helpful in those who fail on nicotine replacement therapy. Recent studies (Gonzales 2006; Jorenby 2006; Nides 2006) comparing bupropion with varenicline have shown higher quit rates with varenicline. All smoking cessation medications can produce clinically signicant adverse effects. When people are initially screened for potential adverse effects, however, fewer than 10% of those on antidepressants for smoking cessation stop taking the medications due to adverse effects. Although bupropion use has been associated with deaths in lay public reports, currently there is insufcient evidence to state that bupropion caused these deaths. There has also been concern about antidepressants such as bupropion being associated with psychiatric disorders including suicidal ideation and suicide attempts. Again, is not clear that there is a causal relationship. Smoking cessation may also precipitate depression (Hughes 2007). Also, although nortriptyline is associated with more side effects when used for depression, in the doses used for smoking cessation this may not be true. Slow release bupropion, under the name Zyban, is licensed for smoking cessation in many parts of the world, including North America, Australia and Europe, but is not available in many other countries. Often, bupropion is available in these countries under the name Wellbutrin SR as a treatment for depression. Nortriptyline is marketed as an antidepressant in many countries but is not currently marketed as a smoking cessation aid in any country. In almost all countries, bupropion and nortriptyline are available only as prescription medications.

Implications for research


More research is needed with different antidepressants to determine which antidepressants or classes of antidepressant are effective in smoking cessation. Determining this could provide insight not only into the mechanism of action of antidepressant efcacy but also into the biological factors controlling nicotine dependence and smoking. Antidepressants of the SSRI category are not effective, which suggests serotonin may not be an important factor. However it is unclear whether dopaminergic, noradrenergic or nicotinic-cholinergic monoaminergic activity or blockage of nicotine receptors is most important for cessation efcacy. Given some suggestive results with selegiline, further trials of this compound and other monoamine oxidase inhibitors (MAOIs), which have mostly adrenergic activity, could be helpful. Similarly, the suggestive ndings that genotype might moderate antidepressant treatment efcacy deserves follow-up. Also, it would be helpful to know whether bupropions efcacy is due to receptor blockade and whether nortriptyline also is a nicotine receptor blocker. Research on the biological and behavioural mediators of the efcacy of bupropion and nortriptyline is needed; e.g. how much of their efcacy is due to craving or withdrawal relief, blocking nicotine reinforcement, or preventing lapses from becoming relapses. Knowledge of whether NRT or antidepressants have more efcacy in decreasing depression post-cessation would help decide whether smokers with a past history of depression should prefer antidepressants over NRT. The use of antidepressants in combination with nicotine replacement therapy, in smokers who have failed with NRT, in smokers with baseline dysphoria, should be further investigated as initial data suggest the combination may add efcacy. Given the concern by some about deaths and psychiatric disorders from antidepressants used for smoking cessation, continued monitoring is indicated.

ACKNOWLEDGEMENTS
Our thanks to Drs Niaura, Borrelli, Spring, Fiore, Hurt, Mizes, Ferry, Schuh, Cinciripini, Hays, Prochazka, Ahluwalia, Mayo, Collins, Novotny, Brown, David & Evins for assistance with additional information or data on studies. JR Hughess contribution is supported by Research Scientist Development Award DA-00490 from the National Institute on Drug Abuse.

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

17

REFERENCES

References to studies included in this review


Ahluwalia 2002 {published data only} Ahluwalia JS, Harris KJ, Catley D, Okuyemi KS, Mayo MS. Sustained-release bupropion for smoking cessation in African Americans: a randomized controlled trial. JAMA 2002;288:46874. Boardman T, Catley D, Mayo MS, Ahluwalia JS. Selfefcacy and motivation to quit during participation in a smoking cessation program. International Journal of Behavioral Medicine 2005;12:26672. Catley D, Harris KJ, Okuyemi KS, Mayo MS, Pankey E, Ahluwalia JS. The inuence of depressive symptoms on smoking cessation among African Americans in a randomized trial of bupropion. Nicotine & Tobacco Research 2005;7:85970. Harris KJ, Ahluwalia JS, Catley D, Okuyemi KS, Mayo MS, Resnicow K. Successful recruitment of minorities into clinical trials: the Kick It at Swope project. Nicotine & Tobacco Research 2003;5:57584. Harris KJ, Okuyemi KS, Catley D, Mayo MS, Ge B, Ahluwalia JS. Predictors of smoking cessation among African-Americans enrolled in a randomized controlled trial of bupropion. Preventive Medicine 2004;38:498502. Okuyemi KS, Ahluwalia JS, Ebersole Robinson M, Catley D, Mayo MS, Resnicow K. Does menthol attenuate the effect of bupropion among African American smokers?. Addiction 2003;98:138793. Thomas JL, Guo H, Lynam IM, Powell JN, Okuyemi KS, Bronars CA, et al.The impact of perceived treatment assignment on smoking cessation outcomes among AfricanAmerican smokers. Journal of General Internal Medicine 2008;23(9):13616. Aubin 2004 {published data only} Aubin HJ, Lebargy F, Berlin I, Bidaut-Mazel C, ChemaliHudry J, Lagrue G. Efcacy of bupropion and predictors of successful outcome in a sample of French smokers: a randomized placebo-controlled trial. Addiction 2004;99: 120618. Lebargy F, Aubin HJ, Lagrue G, Bidaut-Mazel C, ChemaliHudry J, Poulain L. A placebo-controlled, double-blind study of Zyban LP: An effective and well-tolerated aid to smoking cessation - preliminary results (POS4-69). Society for Research on Nicotine and Tobacco 9th Annual Meeting February 19-22 New Orleans, Louisiana. 2003. Aveyard 2008 {published data only} Aveyard P, Johnson C, Fillingham S, Parsons A, Murphy M. Nortriptyline plus nicotine replacement versus placebo plus nicotine replacement for smoking cessation: pragmatic randomised controlled trial.[see comment]. BMJ 2008;336 (7655):12237. Aveyard P, Johnson C, Murphy M, Johnstone E, Walton R, Fillingham S, et al.A pragmatic randomised controlled trial to test the efcacy of nortriptyline plus nicotine replacement therapy (NRT) versus a placebo plus NRT in helping

smokers to stop and testing the role of noradrenergic and dopaminergic genetic variants in smoking cessation [PI-TS02]. Society for Research on Nicotine and Tobacco 8th European Meeting, September 2006; Kusadasi, Turkey. 2006. Berlin 1995 {published data only} Berlin I, Said S, Spreux Varoquaux O, Launay JM, Olivares R, Millet V, et al.A reversible monoamine oxidase A inhibitor (moclobemide) facilitates smoking cessation and abstinence in heavy, dependent smokers. Clinical Pharmacology and Therapeutics 1995;58:44452. Berlin I, Spreux Varoquaux O, Said S, Launay JM. Effects of past history of major depression on smoking characteristics, monoamine oxidase-A and -B activities and withdrawal symptoms in dependent smokers. Drug and Alcohol Dependence 1997;45:317. Biberman 2003 {published data only} Biberman R, Neumann R, Katzir I, Gerber Y. A randomized controlled trial of oral selegiline plus nicotine skin patch compared with placebo plus nicotine skin patch for smoking cessation. Addiction 2003;98:140307. Blondal 1999 {published data only} Blondal T, Gudmundsson LJ, Tomasson K, Jonsdottir D, Hilmarsdottir H, Kristjansson F, et al.The effects of uoxetine combined with nicotine inhalers in smoking cessation - a randomized trial. Addiction 1999;94:100715. Brown 2007 {published data only} Abrantes AM, Strong DR, Lloyd-Richardson EE, Niaura R, Kahler CW, Brown RA. Regular exercise as a protective factor in relapse following smoking cessation treatment. American Journal on Addictions 2009;18(1):1001. Brown RA, Niaura R, Lloyd-Richardson EE, Strong DR, Kahler CW, Abrantes AM, et al.Bupropion and cognitivebehavioral treatment for depression in smoking cessation. Nicotine & Tobacco Research 2007;9:72130. David SP, Brown RA, Papandonatos GD, Kahler CW, Lloyd-Richardson EE, Munafo MR, et al.Pharmacogenetic clinical trial of sustained-release bupropion for smoking cessation. Nicotine & Tobacco Research 2007;9:82133. David SP, Niaura R, Papandonatos GD, Shadel WG, Burkholder GJ, Britt DM, et al.Does the DRD2-Taq1 A polymorphism inuence treatment response to bupropion hydrochloride for reduction of the nicotine withdrawal syndrome?. Nicotine & Tobacco Research 2003;5:93542. David SP, Strong DR, Munafo MR, Brown RA, LloydRichardson EE, Wileyto PE, et al.Bupropion efcacy for smoking cessation is inuenced by the DRD2 Taq1A polymorphism: Analysis of pooled data from two clinical trials. Nicotine & Tobacco Research 2007;9(12):12517. Uhl GR, Liu QR, Drgon T, Johnson C, Walther D, Rose JE, et al.Molecular genetics of successful smoking cessation: convergent genome-wide association study results. Archives of General Psychiatry 2008;65(6):68393.
18

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Cinciripini 2005 {published data only} Cinciripini PM, Tsoh JY, Friedman K, Wetter D, Cinciripini LG, Skaar KL. A placebo controlled evaluation of venlafaxine for smoking cessation: preliminary ndings [Abstract A18]. Society for Research on Nicotine and Tobacco Annual Meeting; Mar 27-29 1998; New Orleans, Louisiana. 1998. Cinciripini PM, Tsoh JY, Wetter DW, Lam C, de Moor C, Cinciripini L, et al.Combined effects of venlafaxine, nicotine replacement, and brief counseling on smoking cessation. Experimental and Clinical Psychopharmacology 2005;13:28292. Cinciripini PM, Wetter D, Minna J, et al.The effects of brief counseling, transdermal nicotine replacement and antidepressant therapy on smoking cessation among smokers carrying the DRD2 A1 allele (PA3A). Society for Research on Nicotine and Tobacco Annual Meeting; Mar 57 1999; San Diego, California. 1999. Cinciripini PM, Wetter DW, Tomlinson GE, Tsoh JY, de Moor CA, Cinciripini LG, et al.The effects of the DRD2 polymorphism on smoking cessation and negative affect: Evidence for a pharmacogenetic effect on mood. Nicotine & Tobacco Research 2004;6:22939. Collins 2004 {published data only} Berrettini WH, Wileyto EP, Epstein L, Restine S, Hawk L, Shields P, et al.Catechol-O-methyltransferase (COMT) gene variants predict response to bupropion therapy for tobacco dependence. Biological Psychiatry 2007;61(1):1118. Collins B, Wileyto P, Patterson F, Rukstalis M, AudrainMcGovern J, Kaufmann V, et al.Gender differences in smoking cessation in a placebo-controlled trial of bupropion with behavioral counseling. Nicotine & Tobacco Research 2004;6:2737. Conti DV, Lee W, Li D, Liu J, Van Den BD, Thomas PD, et al.Nicotinic acetylcholine receptor beta2 subunit gene implicated in a systems-based candidate gene study of smoking cessation. Human Molecular Genetics 2008;17(18): 283448. David SP, Strong DR, Munafo MR, Brown RA, LloydRichardson EE, Wileyto PE, et al.Bupropion efcacy for smoking cessation is inuenced by the DRD2 Taq1A polymorphism: Analysis of pooled data from two clinical trials. Nicotine & Tobacco Research 2007;9(12):12517. Hu J, Redden DT, Berrettini WH, Shields PG, Restine SL, Pinto A, et al.No evidence for a major role of polymorphisms during bupropion treatment. Obesity 2006;14(11):18637. Lee AM, Jepson C, Hoffmann E, Epstein L, Hawk LW, Lerman C, et al.CYP2B6 genotype alters abstinence rates in a bupropion smoking cessation trial. Biological Psychiatry 2007;62(6):63541. Lerman C, Jepson C, Wileyto EP, Epstein LH, Rukstalis M, Patterson F, et al.Role of functional genetic variation in the dopamine D2 receptor (DRD2) in response to bupropion and nicotine replacement therapy for tobacco dependence: results of two randomized clinical trials. Neuropsychopharmacology 2006;31:23142. Lerman C, Niaura R, Collins BN, Wileyto P, Audrain MJ,

Pinto A, et al.Effect of bupropion on depression symptoms in a smoking cessation clinical trial. Psychology of Addictive Behaviors 2004;18:3626. Lerman C, Roth D, Kaufmann V, Audrain J, Hawk L, Liu AY, et al.Mediating mechanisms for the impact of bupropion in smoking cessation treatment. Drug and Alcohol Dependence 2002;67:21923. Lerman C, Shields PG, Wileyto EP, Audrain J, Hawk LH Jr, Pinto A, et al.Effects of dopamine transporter and receptor polymorphisms on smoking cessation in a bupropion clinical trial. Health Psychology 2003;22:5418. Lerman C, Shields PG, Wileyto EP, Audrain J, Pinto A, Hawk L, et al.Pharmacogenetic investigation of smoking cessation treatment. Pharmacogenetics 2002;12:62734. Patterson F, Schnoll RA, Wileyto EP, Pinto A, Epstein LH, Shields PG, et al.Toward personalized therapy for smoking cessation: a randomized placebo-controlled trial of bupropion. Clinical Pharmacology & Therapeutics 2008;84: 3205. Schnoll RA, Epstein L, Audrain J, Niaura R, Hawk L, Shields PG, et al.Can the blind see? Participant guess about treatment arm assignment may inuence outcome in a clinical trial of bupropion for smoking cessation. Journal of Substance Abuse Treatment 2008;34(2):23441. Uhl GR, Liu QR, Drgon T, Johnson C, Walther D, Rose JE, et al.Molecular genetics of successful smoking cessation: convergent genome-wide association study results. Archives of General Psychiatry 2008;65(6):68393. Wileyto EP, Patterson F, Niaura R, Epstein LH, Brown RA, Audrain-McGovern J, et al.Recurrent event analysis of lapse and recovery in a smoking cessation clinical trial using bupropion. Nicotine & Tobacco Research 2005;7:25768. Wileyto P, Patterson F, Niaura R, Epstein L, Brown R, Audrain-McGovern J, et al.Do small lapses predict relapse to smoking behavior under bupropion treatment?. Nicotine & Tobacco Research 2004;6:35766. Covey 2002 {published data only} Covey LS, Glassman AH, Stetner F, Rivelli S. A trial of sertraline for smokers with past major depression. Society for Research on Nicotine and Tobacco Meeting. Arlington, VA (http://www.srnt.org/events/abstracts99/index.htm) 2000. Covey LS, Glassman AH, Stetner F, Rivelli S, Stage K. A randomized trial of sertraline as a cessation aid for smokers with a history of major depression. American Journal of Psychiatry 2002;159:17317. Covey 2007 {published data only} Covey LS, Botello-Harbaum M, Glassman AH, Masmela J, LoDuca C, Salzman V, et al.Smokers response to combination bupropion, nicotine patch, and counseling treatment by race/ethnicity. Ethnicity & Disease 2008;18: 5964. Covey LS, Glassman AH, Jiang H, Fried J, Masmela J, LoDuca C, et al.A randomized trial of bupropion and/ or nicotine gum as maintenance treatment for preventing smoking relapse. Addiction 2007;102:1292302.
19

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Croghan 2007 {published data only} Clark MM, Hurt RD, Croghan IT, Patten CA, Novotny P, Sloan JA, et al.The prevalence of weight concerns in a smoking abstinence clinical trial. Addictive Behaviors 2006; 31:114452. Croghan IT, Hurt RD, Croghan GA, Sloan JA. Comparing nicotine inhaler, bupropion and nicotine inhaler plus bupropion in treating tobacco dependence [abstract]. Nicotine & Tobacco Research 2005;7:6801. Croghan IT, Hurt RD, Dakhil SR, Croghan GA, Sloan JA, Novotny PJ, et al.Randomized comparison of a nicotine inhaler and bupropion for smoking cessation and relapse prevention. Mayo Clinic Proceedings 2007;82:18695. Da Costa 2002 {published data only} Costa C, Younes R, Lourenco M. Smoking cessation: A randomized double-blind study comparing nortriptyline to placebo [abstract]. American Journal of Respiratory and Critical Care Medicine 2001;163(5 Suppl):A354. da Costa CL, Younes RN, Lourenco MT-C. Stopping smoking: a prospective, randomized, double-blind study comparing nortriptyline to placebo. Chest 2002;122:4038. Dalsgar 2004 {published data only} Dalsgar OJ, Vestbo J. A multicenter, randomised, doubleblind, placebo-controlled 6 month trial to evaluate efcacy and tolerability of bupropion hydrochloride sustained release (SR) tablets as treatment for nicotine dependency in healthcare workers and as an aid to smoking cessation (ZYB30009). Poster and oral presentation. European Congress on Tobacco or Health, Warsaw, Poland, 20-22 June 2002. 2002. Dalsgareth OJ, Hansen NC, Ses-Petersen U, Evald T, Hegholm A, Barber J, et al.A multicenter, randomized, double-blind, placebo-controlled, 6-month trial of bupropion hydrochloride sustained-release tablets as an aid to smoking cessation in hospital employees. Nicotine & Tobacco Research 2004;6:5561. Evins 2001 {published data only} Evins AE, Cather C, Rigotti NA, Freudenreich O, Henderson DC, Olm Shipman CM, et al.Two-year follow-up of a smoking cessation trial in patients with schizophrenia: increased rates of smoking cessation and reduction. Journal of Clinical Psychiatry 2004;65:30711. Evins AE, Mays VK, Rigotti NA, Tisdale T, Cather C, Goff DC. A pilot trial of bupropion added to cognitive behavioral therapy for smoking cessation in schizophrenia. Nicotine Tobacco Research 2001;3:397403. Evins 2005 {published data only} Evins AE, Cather C, Culhane M, Freudenreich O, Rigotti NA, Goff DC. Smoking cessation in schizophrenia: A double blind placebo controlled trial of bupropion SR added to cognitive behavioral therapy. Biological Psychiatry 2004;55:806. Evins AE, Cather C, Deckersbach T, Freudenreich O, Culhane MA, Olm-Shipman CM, et al.A double-blind placebo-controlled trial of bupropion sustained-release for

smoking cessation in schizophrenia. Journal of Clinical Psychopharmacology 2005;25:21825. Evins AE, Deckersbach T, Cather C, Freudenreich O, Culhane MA, Henderson DC, et al.Independent effects of tobacco abstinence and bupropion on cognitive function in schizophrenia. Journal of Clinical Psychiatry 2005;66: 118490. Evins 2007 {published data only} Evins AE, Cather C, Culhane M, Birnbaum AS, Horowitz J, Hsieh E, et al.A placebo-controlled study of bupropion SR added to high dose nicotine replacement therapy for smoking cessation or reduction in schizophrenia (POS2104). Society for Research on Nicotine and Tobacco 12th Annual Meeting; February 15-18, Orlando, Florida. 2006. Evins AE, Cather C, Culhane MA, Birnbaum A, Horowitz J, Hsieh E, et al.A 12-week double-blind, placebo-controlled study of bupropion SR added to high-dose dual nicotine replacement therapy for smoking cessation or reduction in schizophrenia. Journal of Clinical Psychopharmacology 2007; 27:3806. Ferry 1992 {published and unpublished data} Ferry LH, Robbins AS, Scariati PD, et al.Enhancement of smoking cessation using the antidepressant bupropion hydrochloride [abstract 2670]. Circulation 1992;86(4 Suppl 1):I671. Ferry 1994 {published and unpublished data} Ferry LH, Burchette RJ. Efcacy of bupropion for smoking cessation in non depressed smokers [Abstract]. Journal of Addictive Diseases 1994;13(4):249. Fossati 2007 {published data only} Ferketich AK, Fossati R, Apolone G. An evaluation of the Italian version of the Fagerstrom Test for Nicotine Dependence. Psychological Reports 2008;102:68794. Fossati R, Apolone G, Negri E, Compagnoni A, La Vecchia C, Mangano S, et al.A double-blind, placebocontrolled, randomized trial of bupropion for smoking cessation in primary care. Archives of Internal Medicine 2007;167:17917. George 2002 {published data only} George TP, Vessicchio JC, Termine A, Bregartner TA, Feingold A, Rounsaville BJ, et al.A placebo controlled trial of bupropion for smoking cessation in schizophrenia. Biological Psychiatry 2002;52:5361. George 2003 {published data only} George TP, Vessicchio JC, Termine A, Jatlow PI, Kosten TR, OMalley SS. A preliminary placebo-controlled trial of selegiline hydrochloride for smoking cessation. Biological Psychiatry 2003;53(2):13643. George 2008 {published data only} George TP, Vessicchio JC, Sacco KA, Weinberger AH, Dudas MM, Allen TM, et al.A placebo-controlled trial of bupropion combined with nicotine patch for smoking cessation in schizophrenia. Biological Psychiatry 2008;63 (11):10926. George TP, Vessicchio JC, Weinberger AH, Sacco KA. Sustained-release bupropion combined with transdermal
20

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

nicotine patch for smoking cessation in schizophrenia (SYM11C). Society for Research on Nicotine and Tobacco 13th Annual Meeting February 21-24, Austin, Texas. 2007. Gonzales 2001 {published data only} Gonzales D, Nides M, Ferry LH, Segall N, Herrero L, Modell J, et al.Retreatment with bupropion SR: results from 12-month follow-up (RP-83). Rapid Communication Poster Abstracts. Society for Research on Nicotine and Tobacco 8th Annual Meeting, February 20-23 Savannah, Georgia. 2002. Gonzales DH, Nides MA, Ferry LH, Kustra RP, Jamerson BD, Segall N, et al.Bupropion SR as an aid to smoking cessation in smokers treated previously with bupropion: A randomized placebo-controlled study. Clinical Pharmacology and Therapeutics 2001;69:43844. Gonzales 2006 {published data only} Gonzales D, Rennard SI, Nides M, Oncken C, Azoulay S, Billing CB, et al.Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs sustained-release bupropion and placebo for smoking cessation: a randomized controlled trial. JAMA 2006;296:4755. Jackson KC, Nahoopii R, Said Q, Dirani R, Brixner D. An employer-based cost-benet analysis of a novel pharmacotherapy agent for smoking cessation. Journal of Occupational & Environmental Medicine 2007;49(4): 45360. West R, Baker CL, Cappelleri JC, Bushmakin AG. Effect of varenicline and bupropion SR on craving, nicotine withdrawal symptoms, and rewarding effects of smoking during a quit attempt. Psychopharmacology 2008;197(3): 3717. Grant 2007 {published data only} Grant KM, Kelley SS, Smith LM, Agrawal S, Meyer JR, Romberger DJ. Bupropion and nicotine patch as smoking cessation aids in alcoholics. Alcohol 2007;41(5):38191. Grecka 2003 {published data only} Grecka D, Bednarek M, Nowinski A, Puscinska E, GoljanGeremek A, Zielinski J. Effect of treatment for nicotine dependence in patients with COPD [Wyniki leczenia uzaleznienia od nikotyny chorych na przewlekla obturacyjna chorobe pluc]. Pneumonologia i Alergologia Polska 2003;71: 4117. Haggstrm 2006 {published data only} Haggstrm FM, Chatkin JM, Sussenbach-Vaz E, Cesari DH, Fam CF, Fritscher CC. A controlled trial of nortriptyline, sustained-release bupropion and placebo for smoking cessation: preliminary results. Pulmonary Pharmacology & Therapeutics 2006;19:2059. Hall 1998 {published data only} Haas AL, Munoz RF, Humeet GL, Reus VI, Hall SM. Inuences of mood, depression history, and treatment modality on outcomes in smoking cessation. Journal of Consulting & Clinical Psychology 2004;72:56370. Hall SM, Gorecki JA, Reus VI, Humeet GL, Munoz RF. Belief about drug assignment and abstinence in treatment of

cigarette smoking using nortriptyline. Nicotine & Tobacco Research 2007;9(4):46771. Hall SM, Reus VI, Munoz RF, Sees KL, Humeet G, Hartz DT, et al.Nortriptyline and cognitive-behavioral therapy in the treatment of cigarette smoking. Archives of General Psychiatry 1998;55:68390. Mooney ME, Reus VI, Gorecki J, Hall SM, Humeet GL, Munoz RF, et al.Therapeutic drug monitoring of nortriptyline in smoking cessation: a multistudy analysis. Clinical Pharmacology & Therapeutics 2008;83:43642. Hall 2002 {published data only} Hall SM, Gorecki JA, Reus VI, Humeet GL, Munoz RF. Belief about drug assignment and abstinence in treatment of cigarette smoking using nortriptyline. Nicotine & Tobacco Research 2007;9(4):46771. Hall SM, Humeet G, Maude-Grifn R, Reus VI, Munoz R, Hartz DT. Nortriptyline versus bupropion and medical management versus psychological intervention in smoking treatment (PA 5A). Society for Research on Nicotine and Tobacco 7th Annual Meeting March 23-23 Seattle, Washington. 2001:31. Hall SM, Humeet GL, Reus VI, Munoz RF, Hartz DT, Maude-Grifn R. Psychological intervention and antidepressant treatment in smoking cessation. Archives of General Psychiatry 2002;59:93036. Hall SM, Lightwood JM, Humeet GL, Bostrom A, Reus VI, Munoz R. Cost-effectiveness of bupropion, nortriptyline, and psychological intervention in smoking cessation. Journal of Behavioral Health Services & Research 2005;32:38192. Mooney ME, Reus VI, Gorecki J, Hall SM, Humeet GL, Munoz RF, et al.Therapeutic drug monitoring of nortriptyline in smoking cessation: a multistudy analysis. Clinical Pharmacology & Therapeutics 2008;83:43642. Hall 2004 Brief {published data only} Hall SM, Humeet GL, Reus VI, Munoz RF, Cullen J. Extended nortriptyline and psychological treatment for cigarette smoking. American Journal of Psychiatry 2004;161: 21007. Mooney ME, Reus VI, Gorecki J, Hall SM, Humeet GL, Munoz RF, et al.Therapeutic drug monitoring of nortriptyline in smoking cessation: a multistudy analysis. Clinical Pharmacology & Therapeutics 2008;83:43642. Hall 2004 Extended {published data only} Hall SM, Humeet GL, Reus VI, Munoz RF, Cullen J. Extended nortriptyline and psychological treatment for cigarette smoking. American Journal of Psychiatry 2004;161: 21007. Hatsukami 2004 {published data only} Hatsukami DK, Rennard S, Patel MK, Kotlyar M, Malcolm R, Nides MA, et al.Effects of sustained-release bupropion among persons interested in reducing but not quitting smoking. American Journal of Medicine 2004;116: 1517. Rennard S, Hatsukami D, Malcolm R E, Patel MK, Jamerson BD, Dozier G. Zyban (bupropion HCL SR) vs placebo as an aid to smoking reduction among smokers
21

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

unwilling and unable to quit smoking (PO4 77). Society for Research on Nicotine and Tobacco 7th Annual Meeting March 23-23 Seattle, Washington. 2001:117. Hays 2001 {published data only} Abel GA, Hays JT, Decker PA, Croghan GA, Kuter DJ, Rigotti NA. Effects of biochemically conrmed smoking cessation on white blood cell count. Mayo Clin Proc 2005; 80:102228. Cox LS, Patten CA, Niaura RS, Decker PA, Rigotti N, Sachs DPL, et al.Efcacy of bupropion for relapse prevention in smokers with and without a past history of major depression. Journal of General Internal Medicine 2004;19: 82834. Durcan MJ, Deener G, White J, Johnston JA, Gonzales D, Niaura R, et al.The effect of bupropion sustainedrelease on cigarette craving after smoking cessation. Clinical Therapeutics 2002;24:54051. Durcan MJ, Johnston JA, White J, Gonzales D, Sachs DP, Rigotti N, Niaura R. Bupropion SR for relapse prevention: a slips-allowed analysis. American Journal of Health Behavior 2004;28(5):45663. Gonzales D, Bjornson W, Durcan MJ, White JD, Johnston JA, Buist AS, et al.Effects of gender on relapse prevention in smokers treated with bupropion SR. American Journal of Preventive Medicine 2002;22:23439. Hays JT, Hurt RD, Rigotti NA, Niaura R, Gonzales D, Durcan MJ, et al.Sustained-release bupropion for pharmacologic relapse prevention after smoking cessation. A randomized, controlled trial. Annals of Internal Medicine 2001;135:42333. Hurt RD, Wolter TD, Rigotti N, Hays JT, Niaura R, Durcan MJ, et al.Bupropion for pharmacologic relapse prevention to smoking - Predictors of outcome. Addictive Behaviors 2002;27(4):493507. Rigotti N, Thorndike AN, Durcan MJ, White JD, Johnston AJ, Niaura R, et al.Attenuation of post-cessation weight gain in smokers taking bupropion: The effect of gender. Abstract Book. Society for Research on Nicotine and Tobacco 6th Annual Meeting; Feb 18-20 2000; Arlington VA. 2000. Hertzberg 2001 {published data only} Hertzberg MA, Moore SD, Feldman ME, Beckham JC. A preliminary study of bupropion sustained-release for smoking cessation in patients with chronic posttraumatic stress disorder. Journal of Clinical Psychopharmacology 2001; 21:948. Holt 2005 {published data only} Holt S, Timu-Parata C, Ryder-Lewis S, Weatherall M, Beasley R. Efcacy of bupropion in the indigenous Maori population in New Zealand. Thorax 2005;60:12023. Hurt 1997 {published and unpublished data} Dale LC, Glover ED, Sachs DP, Schroeder DR, Offord KP, Croghan IT, et al.Bupropion for smoking cessation: predictors of successful outcome. Chest 2001;119: 13571364. Glaxo Wellcome. Presentation for FDA approval of Bupropion sustained release for smoking cessation. Dr J.

Andrew Johnston December 10 1996. Hayford KE, Patten CA, Rummans TA, Schroeder DR, Offord KP, Croghan IT, et al.Efcacy of bupropion for smoking cessation in smokers with a former history of major depression or alcoholism. British Journal of Psychiatry 1999; 174:1738. Hurt RD, Glover ED, Sachs DPL, et al.Bupropion for smoking cessation: A double-blind, placebo-controlled dose response trial [Abstract]. Journal of Addictive Diseases 1996; 15:137. Hurt RD, Sachs DPL, Glover ED, Offord KP, Johnston JA, Dale LC, et al.A comparison of sustained-release bupropion and placebo for smoking cessation. New England Journal of Medicine 1997;337:1195202. Johnston JA, Fiedler-Kelly J, Glover ED, Sachs DP, Grasela TH, DeVeaugh-Geiss J. Relationship between drug exposure and the efcacy and safety of bupropion sustained release for smoking cessation. Nicotine Tob Res 2001;3:13140. Hurt 2003 {published and unpublished data} Hurt RD, Croghan GA, Sloan JA, Krook JE, Silberstein PT. Bupropion for relapse prevention after nicotine patch therapy [PA 5B abstract ]. Society for Research on Nicotine and Tobacco 7th Annual Meeting, March 23-23 2001, Seattle, Washington. 2001:32. Hurt RD, Krook JE, Croghan IT, Loprinzi CL, Sloan JA, Novotny PJ, et al.Nicotine patch therapy based on smoking rate followed by bupropion for prevention of relapse to smoking. Journal of Clinical Oncology 2003;21:91420. Jorenby 1999 {published data only} Durcan MJ, White J, Jorenby DE, Fiore MC, Rennard SI, Leischow SJ, et al.Impact of prior nicotine replacement therapy on smoking cessation efcacy. American Journal of Health Behavior 2002;26:21320. Jamerson BD, Nides M, Jorenby DE, Donahue R, Garrett P, Johnston JA, et al.Late-term smoking cessation despite initial failure: an evaluation of bupropion sustained release, nicotine patch, combination therapy, and placebo. Clinical Therapeutics 2001;23:74452. Jorenby DE, Leischow SJ, Nides MA, Rennard SI, Johnston JA, Hughes AR, et al.A controlled trial of sustained-release bupropion, a nicotine patch, or both for smoking cessation. New England Journal of Medicine 1999; 340:68591. Nielsen K, Fiore MC. Cost-benet analysis of sustainedrelease bupropion, nicotine patch, or both for smoking cessation. Preventive Medicine 2000;30:209216. Smith SS, Jorenby DE, Leischow SJ, Nides MA, Rennard SI, Johnston AJ, et al.Targeting smokers at increased risk for relapse: treating women and those with a history of depression. Nicotine & Tobacco Research 2003;5:99109. Jorenby 2006 {published data only} Jorenby DE, Hays JT, Rigotti NA, Azoulay S, Watsky EJ, Williams KE, et al.Efcacy of varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation: a randomized controlled trial. JAMA 2006;296:5663. West R, Baker CL, Cappelleri JC, Bushmakin AG. Effect
22

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

of varenicline and bupropion SR on craving, nicotine withdrawal symptoms, and rewarding effects of smoking during a quit attempt. Psychopharmacology 2008;197(3): 3717. Killen 2000 {published data only} Killen JD, Fortmann SP, Schatzberg A, Hayward C, Varady A. Onset of major depression during treatment for nicotine dependence. Addictive Behaviors 2003;28:46170. Killen JD, Fortmann SP, Schatzberg AF, Hayward C, Sussman L, Rothman M, et al.Nicotine patch and paroxetine for smoking cessation. Journal of Consulting and Clinical Psychology 2000;68:8839. Killen 2004 {published data only} Killen JD, Robinson TN, Ammerman S, Hayward C, Rogers J, Samuels D. Major depression among adolescent smokers undergoing treatment for nicotine dependence. Addictive Behaviors 2004;29:151726. Killen JD, Robinson TN, Ammerman S, Hayward C, Rogers J, Stone C, et al.Randomized clinical trial of the efcacy of bupropion combined with nicotine patch in the treatment of adolescent smokers. Journal of Consulting and Clinical Psychology 2004;72:72935. Killen 2006 {published data only} Killen JD, Fortmann SP, Murphy GM Jr, Hayward C, Arredondo C, Cromp D, et al.Extended Treatment With Bupropion SR for Cigarette Smoking Cessation. Journal of Consulting and Clinical Psychology 2006;74(2):28694. McCarthy 2008 {published data only} McCarthy DE. Mechanisms of tobacco cessation treatment: Self-report mediators of counseling and bupropion sustained release treatment. Dissertation Abstracts International: Section B: The Sciences and Engineering 2007;67(9-B):5414. McCarthy DE, Piasecki TM, Lawrence DL, Jorenby DE, Shiffman S, Baker TB. Psychological mediators of bupropion sustained-release treatment for smoking cessation. Addiction 2008;103(9):152133. McCarthy DE, Piasecki TM, Lawrence DL, Jorenby DE, Shiffman S, Fiore MC, et al.A randomized controlled clinical trial of bupropion SR and individual smoking cessation counseling. Nicotine & Tobacco Research 2008;10: 71729. McCarthy DE. Piasecki TM, Lawrence DL, Fiore MC, Baker TB. Efcacy of bupropion SR and individual counseling among adults attempting to quit smoking (POS1-041). Society for Research on Nicotine and Tobacco 10th Annual Meeting February 18-21, Phoenix, Arizona. 2004. Muramoto 2007 {published data only} Muramoto ML, Leischow SJ, Sherrill D, Matthews E, Strayer LJ. Randomized, double-blind, placebo-controlled trial of 2 dosages of sustained-release bupropion for adolescent smoking cessation. Archives of Pediatrics & Adolescent Medicine 2007;161:106874. Taren D, Fankem S, Muramoto M. Weight loss in adolescents who quit smoking with bupropion [RP-071]. Society for Research on Nicotine and Tobacco 11th annual

meeting, March 2005; Prague, Czech Republic. Rapid Communications posters. 2005. Myles 2004 {published data only} Myles PS, Leslie K, Angliss M, Mezzavia P, Lee L. Effectiveness of bupropion as an aid to stopping smoking before elective surgery: a randomised controlled trial. Anaesthesia 2004;59:10538. Niaura 2002 {published data only} Borrelli B, Niaura R, Keuthen NJ, Goldstein MG, Depue JD, Murphy C, et al.Development of major depressive disorder during smoking-cessation treatment. Journal of Clinical Psychiatry 1996;57:5348. Borrelli B, Papandonatos G, Spring B, Hitsman B, Niaura R. Experimenter-dened quit dates for smoking cessation: adherence improves outcomes for women but not for men. Addiction 2004;99:37885. Borrelli B, Spring B, Niaura R, Hitsman B, Papandonatos G. Inuences of gender and weight gain on short-term relapse to smoking in a cessation trial. Journal of Consulting and Clinical Psychology 2001;69:51115. Borrelli B, Spring B, Niaura R, Kristeller J, Ockene JK, Keuthen NJ. Weight suppression and weight rebound in exsmokers treated with uoxetine. Journal of Consulting and Clinical Psychiatry 1999;67:12431. Cook JW, Spring B, McChargue DE, Borrelli B, Hitsman B, Niaura R, et al.Inuence of uoxetine on positive and negative affect in a clinic-based smoking cessation trial. Psychopharmacology 2004;173:1539. Doran N, Spring B, Borrelli B, McChargue D, Hitsman B, Niaura R, Hedeker D. Elevated positive mood: a mixed blessing for abstinence. Psychology of Addictive Behaviors 2006;20:3643. Hitsman B, Spring B, Borrelli B, Niaura R, Papandonatos GD. Inuence of antidepressant pharmacotherapy on behavioral treatment adherence and smoking cessation outcome in a combined treatment involving uoxetine.. Experimental & Clinical Psychopharmacology 2001;9: 35562. Mizes JS, Sloan DM, Segraves K, Spring B, Pingatore R, Kristeller J. Fluoxetine and weight-gain in smoking cessation - examination of actual weight-gain and fear of weight-gain [abstract]. Psychopharmacology Bulletin 1996;32:491. Niaura R, Goldstein M, Spring B, Keuthen N, Kristeller J, DePue J, et al.Fluoxetine for smoking cessation: A multicenter randomized double blind dose reponse study. Society for Behavioral Medicine Annual Meeting; April 18 1997; San Francisco, CA. Niaura R, Spring B, Borrelli B, Hedeker D, Goldstein MG, Keuthen N, et al.Multicenter trial of uoxetine as an adjunct to behavioral smoking cessation treatment. Journal of Consulting and Clinical Psychology 2002;70:88796. Swan GE, Jack LM, Niaura R, Borrelli B, Spring B. Subgroups of smokers with different success rates after treatment with uoxetine for smoking cessation [abstract]. Nicotine & Tobacco Research 1999;1:281. Nides 2006 {published data only} Nides M, Oncken C, Gonzales D, Rennard S, Watsky
23

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

EJ, Anziano R, et al.Smoking cessation with varenicline, a selective alpha4beta2 nicotinic receptor partial agonist: Results from a 7-week, randomized, placebo- and bupropion-controlled trial with 1-year follow-up. Archives of Internal Medicine 2006;166:15618. Oncken C, Watsky E, Reeves K, Anziano R. Varenicline is efcacious and well tolerated in promoting smoking cessation: results from a 7-week, randomized, placeboand bupropion-controlled trial. Society for Research on Nicotine and Tobacco 11th Annual Meeting, 20-23 March 2005, Prague, Czech Republic. 2005. Piper 2007 {published data only} Piper ME. Bupropion alone and in combination with nicotine gum: Efcacy, mediation and moderation. Dissertation Abstracts International: Section B: The Sciences and Engineering 2007;67(9-B):5418. Piper ME, Federman EB, McCarthy DE, Bolt DM, Smith SS, Fiore MC, et al.Efcacy of bupropion alone and in combination with nicotine gum. Nicotine & Tobacco Research 2007;9:94754. Piper ME, Federman EB, Smith SS, Fiore MC, Baker TB. Efcacy of bupropion SR alone and combined with 4mg gum (PA2-2). Society for Research on Nicotine and Tobacco 10th Annual Meeting February 18-21, Phoenix, Arizona. 2004:18. Piper ME, Federmen EB, McCarthy DE, Bolt DM, Smith SS, Fiore MC, et al.Using mediational models to explore the nature of tobacco motivation and tobacco treatment effects. Journal of Abnormal Psychology 2008;117:94105. Prochazka 1998 {published data only} Prochazka AV, Weaver MJ, Keller RT, Fryer GE, Licari PA, Lofaso D. A randomized trial of nortriptyline for smoking cessation. Archives of Internal Medicine 1998;158:20359. Prochazka 2004 {published data only} Prochazka AV, Kick S, Steinbrunn C, Miyoshi T, Fryer GE. A randomized trial of nortriptyline combined with transdermal nicotine for smoking cessation. Archives of Internal Medicine 2004;164:222933. Prochazka AV, Reyes R, Steinbrunn C, Miyoshi T. Randomized trial of nortriptyline combined with transdermal nicotine for smoking cessation (PO3 26). Society for Research on Nicotine and Tobacco 7th Annual Meeting, March 23-23 2001, Seattle, Washington. 2001: 73. Rigotti 2006 {published data only} Rigotti N, Thorndike A, Regan S, Pasternak R, Chang Y, McKool K, et al.Safety and efcacy of bupropion for smokers hospitalized with acute cardiovascular disease [abstract]. Nicotine & Tobacco Research 2005;7:682. Rigotti NA, Thorndike AN, Regan S, McKool K, Pasternak RC, Chang Y, et al.Bupropion for smokers hospitalized with acute cardiovascular disease. American Journal of Medicine 2006;119:10807. Thorndike AN, Regan S, McKool K, Pasternak RC, Swartz S, Torres-Finnerty N, et al.Depressive symptoms and smoking cessation after hospitalization for cardiovascular disease. Archives of Internal Medicine 2008;168(2):18691.

Saules 2004 {published and unpublished data} Saules KK, Schuh LM, Arfken CL, Reed K, Kilbey MM, Schuster CR. Double-blind placebo-controlled trial of uoxetine in smoking cessation treatment including nicotine patch and cognitive-behavioral group therapy. American Journal on Addictions 2004;14:43846. Schuh LM, Downey KK, Hopper JA, Tancer M, Schuster CR. Fluoxetine in smoking cessation treatment. College on Problems of Drug Dependence Annual Meeting, San Juan, Puerto Rico 2000. Schmitz 2007 {published data only} Schmitz JM, Stotts AL, Mooney ME, Delaune KA, Moeller GF. Bupropion and cognitive-behavioral therapy for smoking cessation in women.[erratum appears in Nicotine Tob Res. 2007 Jul;9(7):785]. Nicotine & Tobacco Research 2007;9(6):699709. Selby 2003 {unpublished data only} GlaxoSmithKline Clinical Trials Register. Study No: ZYB40001. A randomized, double-blind, placebocontrolled, 12-week smoking cessation trial of Zyban (150 mg bid) in adult smokers previously treated with Zyban. http--ctr.glaxowellcome.co.uk-Summary-bupropionIVZYB40001.pdf (accessed 23rd August 2006). Selby P, Ainslie M, Stepner N, Roberts J. Sustained-release bupropion (Zybanr) is effective in the re-treatment of relapsed adult smokers. Am J Respir Crit Care Med 2003; 167(7):A47. Selby P, Brands B, Stepner N. Retreatment with ZYban SR: 52 week follow-up of a Canadian Multicentre trial (POS3-63). Society for Research on Nicotine and Tobacco 9th Annual Meeting, February 19-22, New Orleans. 2003. Selby P, Brosky G, Baker R, Lertzman M, Dakin P, Roberts J. Zyban is effective in the retreatment of relapsed adult smokers (PO4 68). Society for Research on Nicotine and Tobacco 7th Annual Meeting March 23-23 Seattle Washington. 2001:114. Simon 2004 {published data only} Caplan BJ. The bupropion for smoking cessation trial from a family practice perspective. Archives of Internal Medicine 2005;165:470. Simon JA, Duncan C, Carmody TP, Hudes ES. Bupropion for smoking cessation: a randomized trial. Archives of Internal Medicine 2004;164:1797803. Simon JA, Duncan C, Carmody TP, Hudes ES. Bupropion plus nicotine replacement no better than replacement alone. Journal of Family Practice 2004;53:9534. Simon 2009 {published data only} Simon JA, Duncan C, Huggins J, Solkowitz S, Carmody TP. Sustained-release bupropion for hospital-based smoking cessation: a randomized trial. Nicotine & Tobacco Research 2009;11(6):6639. SMK20001 {unpublished data only} GlaxoSmithKline Clinical Trials Register. Study No: SMK 20001. A Multi-Center, Double-Blind, Double-Dummy, Placebo-Controlled, Randomized, Parallel Group, Dose Response Evaluation of a New Chemical Entity (NCE) and ZYBAN (bupropion hydrochloride) Sustained Release
24

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

(300mg/day) versus Placebo As Aids to Smoking Cessation.. http://www.gsk-clinicalstudyregister.com/les/pdf/812.pdf (accessed 4th August 2009). Spring 2007 {published data only} Carrington A, Doran N, Spring B. Fluoxetine moderates the association between trait-anxiety and smoking status following behavioral treatment for smoking cessation (POS4-81). Society for Research on Nicotine and Tobacco 9th Annual Meeting February 19-22 New Orleans, Louisiana. 2003. Spring B, Doran N, Pagoto S, McChargue D, Cook JW, Bailey K, et al.Fluoxetine, smoking, and history of major depression: A randomized controlled trial. Journal of Consulting & Clinical Psychology 2007;75:8594. Spring B, Doran N, Pagoto S, McChargue DE, Cook JW, Bailey K, et al.Reduced abstinence for smokers previously treated with uoxetine (PA1-1). Society for Research on Nicotine and Tobacco 10th Annual Meeting February 1821, Phoenix, Arizona. 2004. Swan 2003 {published data only} Catz S, Jack LM, Swan GE, McClure J. Adherence to bupropion SR in a smoking cessation effectiveness trial (POS2-77). Society for Research on Nicotine and Tobacco 12th Annual Meeting February 15-18, Orlando, Florida. 2006. Jack LM, Swan GE, Thompson E, Curry SJ, McAfee T, Dacey S, Bergman K. Bupropion SR and smoking cessation in actual practice: methods for recruitment, screening, and exclusion for a eld trial in a managed-care setting. Preventive Medicine 2003;36:58593. Javitz HS, Swan GE, Zbikowski SM, Curry SJ, McAfee TA, Decker DL, et al.Cost-effectiveness of different combinations of bupropion SR dose and behavioral treatment for smoking cessation: a societal perspective. American Journal of Managed Care 2004;10:21726. McAfee T, Zbikowski SM, Bush T, McClure J, Swan G, Jack LM, Curry S. The effectiveness of bupropion SR and phone counseling for light and heavy smokers (PA2-1). Society for Research on Nicotine and Tobacco 10th Annual Meeting February 18-21, Phoenix, Arizona. 2004. Swan GE, Jack LM, Curry S, Chorost M, Javitz H, McAfee T, Dacey S. Bupropion SR and counseling for smoking cessation in actual practice: Predictors of outcome. Nicotine & Tobacco Research 2003;5:91121. Swan GE, Jack LM, Javitz HS, McAfee T, McClure JB. Predictors of 12-month outcome in smokers who received bupropion sustained-release for smoking cessation. Central Nervous System Drugs 2008;22(3):23956. Swan GE, Jack LM, Valdes AM, Ring HZ, Ton CC, Curry SJ, et al.Joint effect of dopaminergic genes on likelihood of smoking following treatment with bupropion SR. Health Psychology 2007;26:3618. Swan GE, Javitz HS, Jack LM, Curry SJ, McAfee T. Heterogeneity in 12-month outcome among female and male smokers. Addiction 2004;99:23750. Swan GE, McAfee T, Curry SJ, Jack LM, Javitz H, Dacey S, Bergman K. Effectiveness of bupropion sustained release

for smoking cessation in a health care setting: a randomized trial. Archives of Internal Medicine 2003;163:233744. Swan GE, Valdes AM, Ring HZ, Khroyan TV, Jack LM, Ton CC, et al.Dopamine receptor DRD2 genotype and smoking cessation outcome following treatment with bupropion SR. Pharmacogenomics Journal 2005;5:219. Tashkin 2001 {published data only} Patel MK, Tashkin DP, Kanner RE, Bailey WC, Buist A, Anderson PJ, et al.A multicenter evaluation of the effects of bupropion hydrochloride sustained release tablets (Bup SR) versus placebo in a population of smokers with chronic obstructive pulmonary disease (PO130). 11th World Conference on Tobacco or Health; Aug 6-11 2000; Chicago, ILL. 2000; Vol. 1:118. Tashkin D, Kanner R, Bailey W, Buist S, Anderson P, Nides M, et al.Smoking cessation in patients with chronic obstructive pulmonary disease: a double-blind, placebocontrolled, randomised trial. Lancet 2001;357:157175. Tonnesen 2003 {published data only} Bolliger CT, Gilljam H, Lebargy F, van Spiegel PI, Edwards J, Hider A, et al.Bupropion hydrochloride (Zyban) is effective and well tolerated as an aid to smoking cessation - a multicountry study. Abstract and presentation at 11th Annual meeting of European Respiratory Society, Berlin, September 22-26 2001. European Respiratory Journal 2001; 18 (Suppl 33):12s. Tonnesen P, Tonstad S, Hjalmarson A, Lebargy F, van Spiegel PI, Hider A, et al.A multicentre, randomized, double-blind, placebo-controlled, 1-year study of bupropion SR for smoking cessation. Journal of Internal Medicine 2003;254:18492. Tonstad S, Aaserud E, Hjalmarson A, Peiffer G, van der Molen T, Hider, et al.Zyban is an effective and well tolerated aid to smoking cessation in a general smoking population - a multi-country study. Society for Research on Nicotine and Tobacco 3rd Europe Conference, September 19-22 2001, Paris, France 2001:46. Tonstad 2003 {published data only} McRobbie H, Brath H, Astbury C, Hider A, Sweet R. Bupropion hydrochloride sustained release (SR) is an effective and well tolerated aid to smoking cessation in smokers with cardiovascular disease 12 month follow-up phase data (ZYB40014). Abstract and presentation at European Respiratory Society meeting, 14-18 September 2002, Stockholm, Sweden. 2002. Tonstad S, Farsang C, Klaene G, Lewis K, Manolis A, Perruchoud AP, Silagy C, van Spiegel PI, Astbury C, Hider A, Sweet R. Bupropion SR for smoking cessation in smokers with cardiovascular disease: a multicentre, randomised study. European Heart Journal 2003;24:94655. van Spiegel PI, Lewis K, Seinost G, Astbury C, Hider A, Sweet R. Bupropion hydrochloride (Zyban) is an effective and well tolerated aid to smoking cessation in smokers with cardiovascular disease - a multicountry study. Abstract and presentation at 11th Annual meeting of European Respiratory Society, Berlin, September 22-26. European Respiratory Journal 2001;18((Suppl 33)):13s.
25

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Uyar 2007 {published data only} Uyar M, Bayram N, Filiz A, Elbek O, Topu A, Dikensoy O, et al.Comparison of nicotine patch and bupropion in treating tobacco dependence. European Respiratory Journal 2005;26(Suppl 49):388s. Uyar M, Filiz A, Bayram N, Elbek O, Herken H, Topcu A, et al.A randomized trial of smoking cessation. Medication versus motivation. Saudi Medical Journal 2007;28(6): 9226. Wagena 2005 {published data only} Wagena EJ, Knipschild PG, Huibers MJ, Wouters EF, van Schayck CP. Efcacy of bupropion and nortriptyline for smoking cessation among people at risk for or with chronic obstructive pulmonary disease. Archives of Internal Medicine 2005;165:228692. Weinberger 2009 {unpublished data only} Weinberger AH, Reutenauer EL, OMalley SS, Potenza MN, George TP. A randomized placebo-controlled clinical trial of selegiline for smoking cessation: Preliminary results (POS5-29). Society for Research on Nicotine and Tobacco 15th Annual Meeting April 27-30, 2009, Dublin, Ireland. Weinberger AH, Reutenauer EL, Solorzano M, OMalley SS, Potenza MN, George TP. A randomized placebo controlled clinical trial of selegiline for smoking cessation (abstract 653). CPDD 71st Annual Meeting, June 20-25 2009, Reno Nevada. Zellweger 2005 {published data only} Puska P, Brath H, Astbury C, Hider AE. Zyban is an effective and well tolerated aid to smoking cessation in a healthcare professionals population - a multi-country study. Society for Research on Nicotine and Tobacco 3rd European Conference, September 2001, Paris, France. 2001:45. Zellweger JP, Blaziene A, Astbury C, Hider A, Hogue S. Bupropion hydrochloride sustained release is an effective and well tolerated aid to smoking cessation in a healthcare professionals population - a multicountry study. Abstract and presentation at 11th Annual meeting of European Respiratory Society, Berlin, September 22-26 2001. European Respiratory Journal 2001;18 (Suppl 33):166s. Zellweger JP, Boelcskei PL, Carrozzi L, Sepper R, Sweet R, Hider AZ. Bupropion SR vs placebo for smoking cessation in health care professionals. American Journal of Health Behavior 2005;29:2409.

Berlin 2005 {published data only} Berlin I, Covey LS, Jiang HP, Hamer D. Lack of effect of D2 dopamine receptor TaqI A polymorphism on smoking cessation. Nicotine & Tobacco Research 2005;7:7258. Bowen 1991 {published data only} Bowen DJ, Spring B, Fox E. Tryptophan and highcarbohydrate diets as adjuncts to smoking cessation therapy. Journal of Behavioral Medicine 1991;14(2):97110. Brauer 2000 {unpublished data only} Brauer LH, Paxton DA, Stock CT, Rose JE. Selegiline and transdermal nicotine for smoking cessation. Society for Research on Nicotine and Tobacco Annual Conference; 2000 Feb 18-20; Arlington VA (http://www.srnt.org/events/ abstracts99/index.htm) 2000. Breitling 2008 {published data only} Breitling LP, Twardella D, Brenner H. High effectiveness of short treatment with bupropion for smoking cessation in general care. Thorax 2008;63:4767. Carro 2007 {published data only} Carrao JL, Moreira LB, Fuchs FD. The efcacy of the combination of sertraline with buspirone for smoking cessation. A randomized clinical trial in nondepressed smokers. European Archives of Psychiatry & Clinical Neuroscience 2007;257:3838. Chan 2005 {published data only} Chan B, Einarson A, Koren G. Effectiveness of bupropion for smoking cessation during pregnancy. Journal of Addictive Diseases 2005;24(2):1923. Cornelius 1997 {published data only} Cornelius JR, Salloum IM, Ehler JG, Jarrett PJ, Cornelius MD, Black A, et al.Double-blind uoxetine in depressed alcoholic smokers. Psychopharmacology Bulletin 1997;33: 16570. Cornelius 1999 {published data only} Cornelius JR, Perkins KA, Salloum IM, Thase ME, Moss HB. Fluoxetine versus placebo to decrease the smoking of depressed alcoholic patients [letter]. Journal of Clinical Psychopharmacology 1999;19:1834. Dalack 1995 {published data only} Dalack GW, Glassman AH, Rivelli S, Covey LS, Stetner F. Mood, major depression, and uoxetine response in cigarette smokers. American Journal of Psychiatry 1995;152: 398403. Dale 2002 {published data only} Dale LC, Ebbert JO, Schroeder DR, Croghan IT, Rasmussen DF, Trautman JA, Cox LS, Hurt RD. Bupropion for the treatment of nicotine dependence in spit tobacco users: a pilot study. Nicotine Tobacco Research 2002;4(3): 26774. Dale 2007 {published data only} Dale LC, Ebbert JO, Glover ED, Croghan IT, Schroeder DR, Severson HH, et al.Bupropion SR for the treatment of smokeless tobacco use. Drug & Alcohol Dependence 2007; 90(1):5663. Thomas JL, Ebbert JO, Patten CA, Dale LC, Bronars CA, Schroeder DR. Measuring nicotine dependence among
26

References to studies excluded from this review


Barnes 2006 {published data only} Barnes J, Barber N, Wheatley D, Williamson EM. A pilot randomised, open, uncontrolled, clinical study of two dosages of St Johns wort (Hypericum perforatum) herb extract (LI-160) as an aid to motivational/behavioural support in smoking cessation. Planta Medica 2006;72(4): 37882. Berlin 2002 {published data only} Berlin I, Aubin HJ, Pedarriosse AM, Rames A, Lancrenon S, Lagrue G. Lazabemide, a selective, reversible monoamine oxidase B inhibitor, as an aid to smoking cessation. Addiction 2002;97:134754.

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

smokeless tobacco users. Addictive Behaviors 2006;31(9): 151121. Edwards 1989 {published data only} Edwards NB, Murphy JK, Downs AD, Ackerman BJ, Rosenthal TL. Doxepin as an adjunct to smoking cessation: a double-blind pilot study. American Journal of Psychiatry 1989;146(3):3736. Murphy JK, Edwards NB, Downs AD, Ackerman BJ, Rosenthal TL. Effects of doxepin on withdrawal symptoms in smoking cessation. American Journal of Psychiatry 1990; 147(10):13537. Elsasser 2002 {published data only} Elsasser GN, Guck TP, Destache CJ, Daher PM, Frey DR, Jones J, Larsen PM. Sustained release bupropion in the treatment of nicotine addiction among teenage smokers (RP-32). Rapid Communication Poster Abstracts. Society for Research on Nicotine and Tobacco 8th Annual Meeting, February 20-23 Savannah, Georgia. 2002. Evins 2005b {published data only} Evins AE, Alpert JE, Pava J, Petersen TJ, Farabaugh AH, Fava M. A double blind placebo controlled trial of bupropion added to nicotine patch and cognitive behavioral therapy in smokers with current or past unipolar depressive disorder. Neuropsychopharmacology 2005;30 Suppl 1:S91. Evins 2008 {published data only} Evins AE, Culhane MA, Alpert JE, Pava J, Liese BS, Farabaugh A, et al.A controlled trial of bupropion added to nicotine patch and behavioral therapy for smoking cessation in adults with unipolar depressive disorders. Journal of Clinical Psychopharmacology 2008;28:6606. Fatemi 2005 {published data only} Fatemi SH, Stary JM, Hatsukami DK, Murphy SE. A double-blind placebo-controlled cross over trial of bupropion in smoking reduction in schizophrenia. Schizophrenia Research 2005;76(2-3):3536. Frederick 1997 {published data only} Frederick SL, Hall SM, Sees KL. The effect of venlafaxine on smoking cessation in subjects with and without a history of depression. NIDA Research Monograph 1997;174:208. Gawin 1989 {published data only} Gawin F, Compton M, Byck R. Buspirone reduces smoking [letter]. Archives of General Psychiatry 1989;46(3):2889. Glover 2002 {published data only} Glover ED, Glover PN, Sullivan CR, Cerullo CL, Hobbs G. A comparison of sustained-release bupropion and placebo for smokeless tobacco cessation. American Journal of Health Behavior 2002;26(5):38693. Gold 2002 {published data only} Gold PB, Rubey RN, Harvey RT. Naturalistic, selfassignment comparative trial of bupropion SR, a nicotine patch, or both for smoking cessation treatment in primary care. American Journal of Addiction 2002;11(4):31531. Hawk 2008 {unpublished data only} Hawk LW, Mahoney MC, Ashare RL, Rhodes JD, Oliver JA, Cummings KM, et al.Preliminary evidence of extinction

of smoking behavior with bupropion (PA9-4). Society for Research on Nicotine and Tobacco 14th Annual Meeting February 26-March 1, Portland, Oregon. 2008. Hitsman 1999 {published data only} Hitsman B, Pingitore R, Spring B, Mahableshwarkar A, Mizes JS, Segraves KA, et al.Antidepressant pharmacotherapy helps some cigarette smokers more than others. Journal of Consulting and Clinical Psychiatry 1999; 67:54754. Hitsman B, Spring B, Borrelli B, Niaura R, Papandonatos G. Adherence to medication versus behavioral therapy as predictors of smoking cessation in combined treatment involving uoxetine [abstract]. Society for Research on Nicotine and Tobacco Annual Conference; 2000 Feb 1820; Arlington VA 2000. Houtsmuller 2002 {published data only} Houtsmuller EJ, Stitzer ML. Selegiline effects on smoking and abstinence [abstract]. CPDD Annual Meeting; 1998; Scottsdale, AZ 1998. Houtsmuller EJ, Thornton JA, Stitzer ML. Effects of selegiline (l-deprenyl) during smoking and short-term abstinence. Psychopharmacology (Berl) 2002;163:21320. Jacobs 1971 {published data only} Jacobs MA, Spilken AZ, Norman MM, Wohlberg GW, Knapp PH. Interaction of personality and treatment conditions associated with success in a smoking control program. Psychosomatic Medicine 1971;33(6):54556. Kalman 2004 {unpublished data only} Kalman D, Engler P, Monti P. Preliminary ndings from a pilot treatment study of smokers in early alcohol recovery (POS1-072). Society for Research on Nicotine and Tobacco 10th Annual Meeting February 18-21, Phoenix, Arizona. 2004. Kotz 2009 {published data only} Kotz D, Wesseling G, Huibers MJ, van Schayck OC. Efcacy of confrontational counselling for smoking cessation in smokers with previously undiagnosed mild to moderate airow limitation: study protocol of a randomized controlled trial. BMC Public Health 2007;7:332. Kotz D, Wesseling G, Huibers MJH, van Schayck OCP. Efcacy of confronting smokers with airow limitation for smoking cessation. European Respiratory Journal 2009;33: 75462. Lawvere 2006 {published data only} Lawvere S, Mahoney MC, Cummings KM, Hyland AJ. St Johns Wort for smoking cessation: twelve months post cessation. Society for Research on Nicotine and Tobacco 11th Annual Meeting, 20-23 March 2005; Prague, Czech Republic. 2005. Lawvere S, Mahoney MC, Cummings KM, Kepner JL, Hyland A, Lawrence DDet al. A Phase II study of St. Johns Wort for smoking cessation. Complementary Therapies in Medicine 2006;14(3):17584. Miller 2003 {published data only} Miller H, Ranger-Moore J, Hingten M. Bupropion SR for smoking cessation in pregnancy: a pilot study [abstract].
27

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

American Journal of Obstetrics and Gynecology 2003;189(6): S133. Monuteaux 2007 {published data only} Monuteaux MC, Spencer TJ, Faraone SV, Wilson AM, Biederman J. A randomized, placebo-controlled clinical trial of bupropion for the prevention of smoking in children and adolescents with attention-decit/hyperactivity disorder. Journal of Clinical Psychiatry 2007;68(7):1094101. Mooney 2008 {published data only} Mooney ME, Poling J, Gonzalez G, Gonsai K, Kosten T, Sofuoglu M. Preliminary study of buprenorphine and bupropion for opioid-dependent smokers. American Journal on Addictions 2008;17(4):28792. Sofuoglu M, Mooney M, Gonzalez G, Gonsai K, Poling J, Kosten T. Buprenorphine and bupropion combination for opioid-dependent smokers. 68th Annual Scientic Meeting of the College on Problems of Drug Dependence. 2006. Naranjo 1990 {published data only} Naranjo CA, Kadlec KE, Sanhueza P, Woodley Remus D, Sellers EM. Fluoxetine differentially alters alcohol intake and other consummatory behaviors in problem drinkers. Clinical Pharmacology and Therapeutics 1990;47:4908. Neumann 2000 {unpublished data only} Neumann JK, Peeples B, East J, Ellis AR. Nicotine reduction: effectiveness of bupropion. British Journal of Psychiatry 2000;177:8788. Neumann 2002 {published data only} Neumann JK, Peeples B, Seneker A. Nicotine reduction and bupropion. Chest 2002;121:1378. Niederhofer 2004 {published data only} Niederhofer H, Huber M. Bupropion may support psychosocial treatment of nicotine- dependent adolescents: Preliminary results. Pharmacotherapy 2004;24(11):15248. Olmstead 1999 {published data only} Olmstead R, Kelly J, Chin C, Iwamoto-Schaap PN, Madsen DC, Huerta L, et al.Combined bupropion and mecamylamine treatment for smoking cessation: a pilot trial Combined bupropion and mecamylamine treatment for smoking cessation: a pilot trial.: 1999.. Society for Research on Nicotine and Tobacco Fifth Annual Meeting March 5-7 San Diego CA. 1999. Paluck 2006 {published data only} Paluck EC, McCormack JP, Ensom MH, Levine M, Soon JA, Fielding DW. Outcomes of bupropion therapy for smoking cessation during routine clinical use. Annals of Pharmacotherapy 2996;40(2):18590. Pomerleau 1991 {published data only} Pomerleau OF, Pomerleau CS, Morrell EM, Lowenbergh JM. Effects of uoxetine on weight gain and food intake in smokers who reduce nicotine intake. Psychoneuroendocrinology 1991;16:43340. Raynor 2005 {published data only} Raynor DA. Adherence to pharmacological smoking cessation treatment among weight-concerned women.

Dissertation Abstracts International: Section B: The Sciences and Engineering 2005;65(8-B):4301. Robinson 1991 {published data only} Robinson MD, Smith WA, Cederstrom EA, Sutherland DE. Buspirone effect on tobacco withdrawal symptoms: a pilot study. Journal of the American Board of Family Practice 1991;4(2):8994. Sellers 1987 {published data only} Sellers EM, Naranjo CA, Kadlec K. Do serotonin uptake inhibitors decrease smoking? Observations in a group of heavy drinkers. Journal of Clinical Psychopharmacology 1987;7:41720. Sherman 2008 {published data only} Sherman SE, Aldana I, Estrada M, York L. Comparing the tolerability and effectiveness of two treatment regimens in a smoking clinic. Military Medicine 2008;173(6):5504. Shiffman 2000 {published data only} Shiffman S, Johnston JA, Khayrallah M, Elash CA, Gwaltney CJ, Paty JA, et al.The effect of bupropion on nicotine craving and withdrawal. Psychopharmacology Berl 2000;148:3340. Shoptaw 2008 {published data only} Shoptaw S, Heinzerling KG, Rotheram-Fuller E, Steward T, Wang J, Swanson AN, et al.Randomized, placebo-controlled trial of bupropion for the treatment of methamphetamine dependence. Drug and Alcohol Dependence 2008;96(3): 22232. Sittipunt 2007 {published data only} Sittipunt C, Kawkitinarong K, Wongtim S, Udompanich V. The effectiveness of nortriptyline plus brief motivation counseling for the treatment of smoking cessation in Thai active smokers [Abstract]. Respirology 2007;12(Suppl 4): A223. Spring 1995 {published data only} Spring B, Wurtman J, Wurtman R, el Khoury A, Goldberg H, McDermott J, et al.Efcacies of dexfenuramine and uoxetine in preventing weight gain after smoking cessation. American Journal of Clinical Nutrition 1995;62(6):11817. Stein 1993 {published data only} Stein RA, Jarvik ME, Gorelick DA. Impairment of memory by uoxetine in smokers. Experimental and Clinical Psychopharmacology 1993;1:18893. Steinberg 2009 {published data only} Steinberg MB, Greenhaus S, Schmelzer AC, Bover MT, Foulds J, Hoover DR, et al.Triple-combination pharmacotherapy for medically ill smokers: a randomized trial. Annals of Internal Medicine 2009;150(7):44754. Strayer 2004 {unpublished data only} Strayer SM, Flusche A, Hodge J, Martindale JR. Effectiveness trial of Zyban for smoking cessation in the outpatient setting (POS1-044). Abstract Book. Society for Research on Nicotine and Tobacco 10th Annual Meeting February 18-21, Phoenix, Arizona. 2004:45.
28

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Swanson 2003 {published data only} Swanson NA, Burroughs CC, Long MA, Lee RW. Controlled trial for smoking cessation in a Navy shipboard population using nicotine patch, sustained-release bupropion, or both. Military Medicine 2003;168:8304. Tidey 2009 {published data only} Tidey JW, Rohsenow DJ. Intention to quit moderates the effect of bupropion on smoking urge. Nicotine & Tobacco Research 2009;11(3):30812. Toll 2007 {published data only} Jatlow P, Toll BA, Leary V, Krishnan-Sarin S, OMalley SS. Comparison of expired carbon monoxide and plasma cotinine as markers of cigarette abstinence. Drug and Alcohol Dependence 2008;98(3):2039. Leeman RF, Mckee SA, Toll BA, Krishnan-Sarin S, Cooney JL, Makuch RW, et al.Risk factors for treatment failure in smokers: Relationship to alcohol use and to lifetime history of an alcohol use disorder. Nicotine & Tobacco Research 2008;10(12):1793809. Toll BA, OMalley SS, Katulak NA, Wu R, Dubin JA, Latimer A, et al.Comparing gain- and loss-framed messages for smoking cessation with sustained-release bupropion: a randomized controlled trial. Psychology of Addictive Behaviors 2007;21(4):53444. Toll BA, Salovey P, OMalley SS, Mazure CM, Latimer A, Mckee SA. Message framing for smoking cessation: the interaction of risk perceptions and gender. Nicotine & Tobacco Research 2008;10(1):195200. Weinberger 2008 {published data only} Weinberger AH, Vessicchio JC, Sacco KA, Creeden CL, Chengappa KN, George TP. A preliminary study of sustained-release bupropion for smoking cessation in bipolar disorder. Journal of Clinical Psychopharmacology 2008;28 (5):5847. Weiner 2001 {published data only} Weiner E, Ball MP, Summerfelt A, Gold J, Buchanan RW. Effects of sustained-release bupropion and supportive group therapy on cigarette consumption in patients with schizophrenia. American Journal of Psychiatry 2001;158(4): 6357. White 2005 {published data only} White WD, Crockford D, Patten S, el Guebaly N. A randomized, open-label pilot comparison of gabapentin and bupropion SR for smoking cessation. Nicotine & Tobacco Research 2005;7(5):80913. Zernig 2008 {published data only} Zernig G, Wallner R, Grohs U, Kriechbaum N, Kemmler G, Saria A. A randomized trial of short psychotherapy versus sustained-release bupropion for smoking cessation. Addiction 2008;103(12):202431. ZYB30011 2002 {unpublished data only} GlaxoSmithKline Clinical Trials Register. A multicentre, randomised, double- blind, placebo controlled study to evaluate the efcacy and tolerability of bupropion hydrochloride (SR) sustained release (2 x 150mg per day) versus placebo as an aid to smoking cessation in smokers

with at least one cardiovascular (CV) risk factor.. http: //www.gsk-clinicalstudyregister.com/les/pdf/730.pdf (accessed 4th August 2009).

References to studies awaiting assessment


Rovina 2003 {unpublished data only} Gratziou C, Rovina N, Athanassa Z, Francis K, Evangelou E, Chiotis D, et al.Evaluation of prolonged bupropion treatment as an aid in smoking cessation [abstract]. European Respiratory Journal 2002;20 Suppl 38:611s. Rovina N, Gratziou C, Nikoloutsou I, Athanassa Z, Francis K, Roussos C. Ideal duration of therapy with bupropion HCL: Comparison between short and long treatment. Society for Research on Nicotine and Tobacco 5th European Meeting November 20-22 2003 Padua: Abstract book. 2003. Rovina N, Gratziou C, Nikoloutsou I, Athanassa Z, Francis K, Roussos C. Short or prolonged treatment with bupropion HCL in smoking cessation therapy. European Respiratory Journal 2003;22 Suppl 45:165s. Schepis 2006 {unpublished data only} Schepis TS, Warren KA, Rao U. Evaluation of a cognitivebehavioral smoking cessation treatment for adolescents and young adults (POS2-53). Society for Research on Nicotine and Tobacco 12th Annual Meeting February 1518, Orlando, Florida. 2006. Schnoll 2005 {unpublished data only} Schnoll R, Lazev A, Sobel M, Tatum K, Butler D, Lerman C. Preliminary results from a randomized trial of bupropion for smoking cessation among cancer patients. Society for Research on Nicotine and Tobacco 11th Annual Meeting, 20-23 March, Prague, Czech Republic. 2005. Sonntag 2003 {published data only} Hoch E, Wittchen HU. Population health perspective on smoking cessation: A randomized controlled trial of different methods in primary health care (RPOS 3-71). Society for Research on Nicotine and Tobacco 12th Annual Meeting February 15-18, Orlando, Florida. 2006. Sonntag H, Hoch E, Jahn B, Spiegel B, Pster H, Wittchen HU. Smoking cessation in primary care: implementation effectiveness and optimized allocation. Suchtmedizin in Forschung und Praxis 2003;5:13741.

References to ongoing studies


Brown 2007b {published data only} Brown RA, Strong DR, Miller IW, Kahler CW, Niaura R, Price LH. Efcacy of sequential vs. concurrent use of uoxetine in smoking cessation for elevated depressive symptom smokers (SYM8D). Society for Research on Nicotine and Tobacco 13th Annual Meeting February 2124, Austin, Texas. 2007. Glover (NCT00439413) {unpublished data only} Selegiline for smoking cessation. Ongoing study June 2007. Kalman (NCT00304707) {unpublished data only} Bupropion treatment for smokers in recovery. Ongoing study April 2005.
29

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Killen (NCT00218647) {unpublished data only} Effectiveness of the selegiline patch in treating nicotine dependent individuals. Ongoing study July 2005. Le Foll (NCT00390923) {unpublished data only} Testing a full substitution therapy approach as treatment of tobacco dependence. Ongoing study July 2007. Sood (NCT00405912) {unpublished data only} St. Johns Wort for tobacco cessation. Ongoing study September 2005.

Chun-Fai-Chan 2005 Chun-Fai-Chan B, Koren G, Fayez I, Kalra S, Voyer-Lavigne S, Boshier A, Shakir S, Einarson A. Pregnancy outcome of women exposed to bupropion during pregnancy: a prospective comparative study. Am J Obstet Gynecol 2005; 192(3):932936. Clarke 2002 Clarke M, Oxman AD, editors. Selection Bias. Cochrane Reviewers Handbook 4.1.5 [updated April 2002]. Section 6.3. In: The Cochrane Library [database on disk and CDROM]. The Cochrane Collaboration. Oxford: Update Software; 2003, issue 1. Cox 2004 Cox LS, Patten CA, Niaura RS, Decker PA, Rigotti N, Sachs DPL, et al.Efcacy of bupropion for relapse prevention in smokers with and without a past history of major depression. Journal of General Internal Medicine 2004;19: 82834. Cryan 2003 Cryan JF, Bruijnzeel AW, Skjei KL, Markou A. Bupropion enhances brain reward function and reverses the affective and somatic aspects of nicotine withdrawal in the rat. Psychopharmacology (Berl) 2003;168:34758. Dale 2001 Dale LC, Glover ED, Sachs DP, Schroeder DR, Offord KP, Croghan IT, et al.Bupropion for smoking cessation: predictors of successful outcome. Chest 2001;119:135764. David 2005 David SP, Papandonatos GD, Munafo MR, McCaffery JM, Lerman C, Lloyd-Richardson EE, et al.DRD2-TAQ1A genotypic moderation of bupropion treatment efcacy for smoking cessation at 6-month follow-up [abstract]. Nicotine & Tobacco Research 2005;7:704. Dunner 1998 Dunner DL, Zisook S, Billow AA, Batey SR, Johnston JA, Ascher JA. A prospective safety surveillance study for bupropion sustained-release in the treatment of depression. Journal of Clinical Psychiatry 1998;59:36673. Durcan 2002 Durcan MJ, White J, Jorenby DE, Fiore MC, Rennard SI, Leischow SJ, et al.Impact of prior nicotine replacement therapy on smoking cessation efcacy. American Journal of Health Behavior 2002;26(3):21320. Ebbert 2007 Ebbert JO, Montori V, Vickers-Douglas KS, Erwin PC, Dale LC, Stead LF. Intervention for smokeless tobacco use cessation. Cochrane Database of Systematic Reviews 2007, Issue 4. [DOI: 10.1002/14651858.CD004306.pub3] Egger 1997 Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315:629634. EMEA 2002 European Agency for the Evaluation of Medicines for Human Use. Committee for Proprietary Medicinal
30

Additional references
Aubin 2002 Aubin HJ. Tolerability and safety of sustained-release bupropion in the management of smoking cessation. Drugs 2002;62 Suppl 2:4552. Belson 2002 Belson MG Kelley TR. Bupropion exposures: clinical manifestations and medical outcome. Journal of Emergency Medicine 2002;23:22330. Benowitz 2000 Benowitz NL, Peng MW. Non-nicotine pharmacotherapy for smoking cessation. CNS Drugs 2000;13:26585. Beyens 2008 Beyens MN, Guy C, Mounier G, Laporte S, Ollagnier M. Serious Adverse Reactions of Bupropion for Smoking Cessation Analysis of the French Pharmacovigilance Database from 2001 to 2004. Drug Safety 2008;31: 101726. Bolin 2006 Bolin K, Lindgren B, Willers S. The cost utility of bupropion in smoking cessation health programs: simulation model results for Sweden. Chest 2006;129:65160. Borrelli 2004 Borrelli B, Papandonatos G, Spring B, Hitsman B, Niaura R. Experimenter-dened quit dates for smoking cessation: adherence improves outcomes for women but not for men. Addiction 2004;99:37885. Boshier 2003 Boshier A, Wilton LV, Shakir SA. Evaluation of the safety of bupropion (Zyban) for smoking cessation from experience gained in general practice use in England in 2000. European Journal of Clinical Pharmacology 2003;59(10):76773. Cahill 2008 Cahill K, Stead LF, Lancaster T. Nicotine receptor partial agonists for smoking cessation. Cochrane Database of Systematic Reviews 2008, Issue 3. [DOI: 10.1002/ 14651858.CD006103.pub3] Catley 2005 Catley D, Harris KJ, Okuyemi KS, Mayo MS, Pankey E, Ahluwalia JS. The inuence of depressive symptoms on smoking cessation among African Americans in a randomized trial of bupropion. Nicotine & Tobacco Research 2005;7(6):859870.

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Products. Opinion following an article 36 referral. Bupropion hydrochloride. http://www.emea.eu.int/pdfs/ human/referral/2761002en.pdf Accessed 29 April 2004. Fiore 2008 Fiore MC, Jan CR, Baker TB, et al.Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. AHRQ publication No. 00-0032. Rockville, MD: US Dept of Health and Human Services. Public Health Services, May 2008. Fryer 1999 Fryer JD, Lukas RJ. Noncompetitive functional inhibition at diverse, human nicotinic acetylcholine receptor subtypes by bupropion, phencyclidine, and ibogaine. Journal of Pharmacology and Experimental Therapeutics 1999;288: 8892. Furberg 2006 Furberg CD, Levin AA, Gross PA, Shapiro RS, Strom BL. The FDA and drug safety: a proposal for sweeping changes. Archives of Internal Medicine 2006;166:193842. Gambassi 1999 Gambassi G, Bernabei R. Antidepressants and smoking cessation [Comment]. Archives of Internal Medicine 1999; 159:12578. Gaszner 2006 Gaszner P, Miklya I. Major depression and the synthetic enhancer substances, (-)-deprenyl and R-(-)1-(benzofuran-2-yl)-2-propylaminopentane. Progress in Neuropsychopharmacology and Biological Psychiatry 2006;30: 514. GlaxoSmithKline GlaxoSmithKline. Zyban(R) bupropion hydrochloride Sustained-Release Tablets. Product Information. www.gsk.com/products/assets/uszyban.pdf (accessed 15/ 11/2006). Goldstein 1998 Goldstein MG. Bupropion sustained release and smoking cessation. Journal of Clinical Psychiatry 1998;59 suppl 4: 6672. Gonzales 2002a Gonzales D, Bjornson W, Durcan MJ, White JD, Johnston JA, Buist AS, et al.Effects of gender on relapse prevention in smokers treated with bupropion SR. American Journal of Preventive Medicine 2002;22(4):23439. Gourlay 1995 Gourlay SG, Forbes A, Marriner T, Pethica D, McNeil JJ. Double blind trial of repeated treatment with transdermal nicotine for relapsed smokers. BMJ 1995;311:3636. Haas 2004 Haas JS, Kaplan CP, Barenboim D, Jacob P, Benowitz NL. Bupropion in breast milk: an exposure assessment for potential treatment to prevent post-partum tobacco use. Tobacco Control 2004;13:526. Hajek 2009 Hajek P, Stead LF, West R, Jarvis M, Lancaster T. Relapse prevention interventions for smoking cessation. Cochrane

Database of Systematic Reviews 2009, Issue 1. [DOI: 10.1002/14651858.CD003999.pub3] Hall 2001 Hall SM, Delucchi KL, Velicer WF, Kahler CW, RangerMoore J, Hedeker D, et al.Statistical analysis of randomized trials in tobacco treatment: longitudinal designs with dichotomous outcome. Nicotine Tobacco Research 2001;3: 193202. Hall 2005 Hall SM, Lightwood JM, Humeet GL, Bostrom A, Reus VI, Munoz R. Cost-effectiveness of bupropion, nortriptyline, and psychological intervention in smoking cessation. Journal of Behavioral Health Services & Research 2005;32:38192. Haustein 2003 Haustein KO. Bupropion: pharmacological and clinical prole in smoking cessation. International Journal of Clinical Pharmacology and Therapeutics 2003;41:5666. Hayford 1999 Hayford KE, Patten CA, Rummans TA, Schroeder DR, Offord KP, Croghan IT, et al.Efcacy of bupropion for smoking cessation in smokers with a former history of major depression or alcoholism. British Journal of Psychiatry 1999; 174:1738. Hegerl 2006 Hegerl U. Antidepressants and suicidiality. European Archives of Psychiatry and Clinical Neuroscience 2006;256: 199200. Higgins 2003 Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analysis. BMJ 2003;327: 55760. Higgins 2008 Higgins JPT, Green S (editors). Section 9.2.2.3 Warning: OR and RR are not the same. Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.1 [updated September 2008]. The Cochrane Collaboration, 2008. Available from www.cochrane-handbook.org, 2008. Holmes 2004 Holmes S, Zwar N, Jimenez-Ruiz CA, Ryan PJ, Browning D, Bergmann L, Johnston JA. Bupropion as an aid to smoking cessation: a review of real-life effectiveness. International Journal of Clinical Practice 2004;58(3): 285291. Hubbard 2005 Hubbard R, Lewis S, West J, Smith C, Godfrey C, Smeeth L, et al.Bupropion and the risk of sudden death: a self-controlled case-series analysis using The Health Improvement Network. Thorax 2005;60(10):84850. Hughes 2005 Hughes JR, Stead LF, Lancaster T. Nortriptyline for smoking cessation: A review. Nicotine & Tobacco Research 2005;7:4919. Hughes 2007 Hughes JR. Depression during tobacco abstinence. Nicotine & Tobacco Research 2007;9:4436.
31

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Hughes 2008 Hughes JR. Smoking and suicide: A brief overview. Drug and Alcohol Dependence 2008;198:16978. Hurt 2002 Hurt RD, Wolter TD, Rigotti N, Hays JT, Niaura R, Durcan MJ, et al.Bupropion for pharmacologic relapse prevention to smoking - Predictors of outcome. Addictive Behaviors 2002;27(4):493507. Javitz 2004 Javitz HS, Swan GE, Zbikowski SM, Curry SJ, McAfee TA, Decker DL, Patterson R, Jack LM. Cost-effectiveness of different combinations of bupropion SR dose and behavioral treatment for smoking cessation: a societal perspective. American Journal of Managed Care 2004;10(3): 21726. Johnstone 2004 Johnstone EC, Yudkin Pl, Hey K, Roberts SJ, Welch SJ, Murphy MF, et al.Genetic variation in dopaminergic pathways and short-term effectiveness of the nicotine patch. Pharmacogenetics 2004;14:8390. Jorenby 2002 Joreby D. Clinical efcacy of bupropion in the management of smoking cessation. Drugs 2002;62 Suppl 2:2535. Khawam 2006 Khawam EA, Laurencic G, Malone DA. Side effects of antidepressants: An overview. Cleveland Clinic Journal of Medicine 2006;73:35161. Kotlyar 2001 Kotlyar M, Golding M, Hatsukami DK, Jamerson BD. Effect of nonnicotine pharmacotherapy on smoking behavior. Pharmacotherapy 2001;21:153048. Kotlyar 2005 Kotlyar M, Brauer LH, Tracy TS, Hatsukami DK, Harris J, Bronars CA, Adson DE. Inhibition of CYP2D6 activity by bupropion. Journal of Clinical Psychopharmacology 2005;25: 2269. Lerman 2002a Lerman C, Roth D, Kaufmann V, Audrain J, Hawk L, Liu AY, Niaura R, Epstein L. Mediating mechanisms for the impact of bupropion in smoking cessation treatment. Drug and Alcohol Dependence 2002;67:21923. Lerman 2002b Lerman C, Shields PG, Wileyto EP, Audrain J, Pinto A, Hawk L, et al.Pharmacogenetic investigation of smoking cessation treatment. Pharmacogenetics 2002;12:62734. Lerman 2004 Lerman C, Niaura R, Collins BN, Wileyto P, Audrain MJ, Pinto A, et al.Effect of bupropion on depression symptoms in a smoking cessation clinical trial. Psychology of Addictive Behaviors 2004;18:3626. Lerman 2006 Lerman C, Jepson C, Wileyto EP, Epstein LH, Rukstalis M, Patterson F, et al.Role of functional genetic variation in the dopamine D2 receptor (DRD2) in response to

bupropion and nicotine replacement therapy for tobacco dependence: results of two randomized clinical trials. Neuropsychopharmacology 2006;31:23142. Mantel 1959 Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. Journal of the National Cancer Institute 1959;22:71948. Martinez-Raga 2003 Martinez-Raga J, Keaney F, Sutherland G, Perez Galvez B, Strang J. Treatment of nicotine dependence with bupropion SR: review of its efcacy, safety and pharmacological prole. Addiction Biology 2003;8:1321. McRobbie 2005 McRobbie H, Lee M, Juniper Z. Non-nicotine pharmacotherapies for smoking cessation. Respiratory Medicine 2005;99:120212. MHRA 2004 Pharmacovigilance Information Unit, Medicines and Healthcare products Regulatory Agency (UK). Personal Communication 29 April 2004. Patterson 2008 Patterson F, Schnoll RA, Wileyto EP, Pinto A, Epstein LH, Shields PG, et al.Toward personalized therapy for smoking cessation: a randomized placebo-controlled trial of bupropion. Clinical Pharmacology & Therapeutics 2008;84: 3205. RCP 2000 Working party of the Royal College of Physicians of London. Non-nicotine medications for treating nicotine addiction. Nicotine Addiction in Britain. London: Royal College of Physicians, 2000:147151. Scharf 2004 Scharf D, Shiffman S. Are there gender differences in smoking cessation, with and without bupropion? Pooledand meta-analyses of clinical trials of Bupropion SR. Addiction 2004;99:146269. Smith 2003 Smith SS, Jorenby DE, Leischow SJ, Nides MA, Rennard SI, Johnston AJ, et al.Targeting smokers at increased risk for relapse: treating women and those with a history of depression. Nicotine & Tobacco Research 2003;5:99109. Stead 2008 Stead LF, Perera R, Bullen C, Mant D, Lancaster T. Nicotine replacement therapy for smoking cessation. Cochrane Database of Systematic Reviews 2008, Issue 3. [DOI: 10.1002/14651858.CD000146.pub3] Swan 1999 Swan GE, Jack LM, Niaura R, Borrelli B, Spring B. Subgroups of smokers with different success rates after treatment with uoxetine for smoking cessation [abstract]. Nicotine & Tobacco Research 1999;1(3):281. Swan 2005 Swan GE, Valdes AM, Ring HZ, Khroyan TV, Jack LM, Ton CC, et al.Dopamine receptor DRD2 genotype and
32

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

smoking cessation outcome following treatment with bupropion SR. Pharmacogenomics Journal 2005;5:219. TGA 2004 Adverse Drugs Reactions Unit, Therapeutic Goods Administration (Australia). Personal Communication 31 March 2004. Tonnesen 1993 Tonnesen P, Norregaard J, Sawe U, Simonsen K. Recycling with nicotine patches in smoking cessation. Addiction 1993; 88:5339. Tonstad 2002 Tonstad S. Use of sustained-release bupropion in specic patient populations for smoking cessation. Drugs 2002;2 Suppl 2:3743. Tracey 2002 Tracey JA. Zyban - is there a cause for concern?. Expert Opinion on Drug Safety 2002;1:3035. Uhl 2008 Uhl GR, Liu QR, Drgon T, Johnson C, Walther D, Rose JE, et al.Molecular genetics of successful smoking cessation: convergent genome-wide association study results. Archives of General Psychiatry 2008;65(6):68393. US DHHS 2000 Fiore MC, Bailey WC, Cohen SJ, et al.Treating Tobacco Use and Dependence. Clinical Practice Guideline. Rockville, MD: U.S. Department of Health and Human Services, Public Health Service, June 2000. US FDA 2004 U.S. Food, Drug Administration. Antidepressant use in children, adolescents and adults. Public Health Advisory, March 22, 2004. www.fda.gov/cder/drug/antidepressants/ default.htm (accessed 19 April 2004). US FDA 2009a Anon. Varenicline and bupropion. Reports of suicidality associated with used of varenicline (marketed as CHANTIX) and bupropion (marketed as Zyban and generics). FDA Drug Safety Newsletter 2009;2(1):14. US FDA 2009b Public Health Advisory: FDA Requires New Boxed Warnings for the Smoking Cessation Drugs Chantix and Zyban. http://www.fda.gov/Drugs/DrugSafety/ PublicHealthAdvisories/ucm169988.htm accessed 30th July 2009. Wagena 2005a Wagena EJ, Knipschild P, Zeegers MP. Should nortriptyline be used as a rst-line aid to help smokers quit? Results from a systematic review and meta-analysis. Addiction 2005;100: 31726. Warner 2005 Warner C, Shoaib M. How does bupropion work as a smoking cessation aid?. Addiction Biology 2005;10(3): 21931.

West 2000 West R, McNeill A, Raw M. Smoking cessation guidelines for health professionals: an update. Thorax 2000;55(12): 98799. West 2003 West R. Bupropion SR for smoking cessation. Expert Opinion on Pharamcotherapy 2003;4:53340. West 2008 West R, Baker CL, Cappelleri JC, Bushmakin AG. Effect of varenicline and bupropion SR on craving, nicotine withdrawal symptoms, and rewarding effects of smoking during a quit attempt. Psychopharmacology 2008;197(3): 3717. Wiley 2002 Wiley JL, Lavecchia KL, Martin BR, Damaj MI. Nicotinelike discriminative stimulus effects of bupropion in rats. Experimental and Clinical Psychopharmacology 2002;10: 129135. Wilkes 2005 Wilkes S, Evans A, Henderson M, Gibson J. Pragmatic, observational study of bupropion treatment for smoking cessation in general practice.. Postgraduate Medical Journal 2005;81:71922. Young 2002 Young R, Glennon RA. Nicotine and bupropion share a similar discriminative stimulus effect. European Journal of Pharmacology 2002;443:113118.

References to other published versions of this review


Hughes 1994 Hughes JR. Non-nicotine pharmacotherapies for smoking cessation. Journal of Drug Development 1994;6:197203. Hughes 2000 Hughes JR, Stead LF, Lancaster T. Anxiolytics and antidepressants for smoking cessation. Cochrane Database of Systematic Reviews 2000, Issue 4. Hughes 2002 Hughes JR, Stead LF, Lancaster T. Antidepressants for smoking cessation. Cochrane Database of Systematic Reviews 2002, Issue 1.[Art. No.: CD000031. DOI: 10.1002/ 14651858.CD000031.pub3] Hughes 2003 Hughes JR, Stead LF, Lancaster T. Antidepressants for smoking cessation. Cochrane Database of Systematic Reviews 2003, Issue 2. [DOI: 10.1002/14651858.CD000031] Hughes 2004 Hughes J, Stead L, Lancaster T. Antidepressants for smoking cessation. Cochrane Database of Systematic Reviews 2004, Issue 4. [DOI: 10.1002/14651858.CD000031.pub2] Indicates the major publication for the study

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

33

CHARACTERISTICS OF STUDIES

Characteristics of included studies [ordered by study ID]


Ahluwalia 2002 Methods BUPROPION Setting: community-based health care centre, USA Recruitment: community volunteers 600 African American smokers, > 10 CPD; 70% F, av. age 44, av. CPD 17, 27% had possible clinical depression (CES-D > 16) 1. Bupropion 300 mg/day for 7 weeks 2. Placebo Both arms: 8 sessions of in-person or telephone counselling & S-H guide Abstinence at 26w (prolonged) Validation: CO <= 10 ppm, discrepancies resolved with cotinine <= 20 mg Continuous abstinence rates shown in Figure 3 of paper. Figures obtained from authors.

Participants

Interventions

Outcomes

Notes Risk of bias Bias

Authors judgement

Support for judgement Randomization codes were generated in blocks of 50 and sent to the pharmaceutical company... Blinded drugs provided to investigator; ... [the pharmaceutical company]... packaged the treatment and then shipped the blinded drug to the investigator. Approximately 32% lost to follow-up in each group; included as smokers.

Random sequence generation (selection Low risk bias)

Allocation concealment (selection bias)

Low risk

Incomplete outcome data (attrition bias) All outcomes

Low risk

Aubin 2004 Methods BUPROPION Setting: 74 cessation outpatient clinics, France Recruitment: volunteers Randomization: computer-generated, blind 504 smokers, >= 10 CPD; 56% F, av age 41, av CPD NS, 16% history of MDD

Participants

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

34

Aubin 2004

(Continued)

Interventions

1. Bupropion 300 mg for 7 weeks 2. Placebo Both arms: motivational support at clinic visits at baseline, w3, w7, w12 & 3 phone calls TQD, 2-3 days later, w5, w18 Abstinence at 26w (continuous from w4) Validation: CO < 10 ppm First included as Lebargy 2003 based on abstract.

Outcomes

Notes Risk of bias Bias

Authors judgement

Support for judgement The computerized randomization schedule, prepared by the sponsor, was inaccessible to the investigator who was provided with a specic set of sequential treatment numbers. Subjects fullling the entry criteria were randomized in a double-blind manner to study treatment in a 2:1 bupropion:placebo ratio.; Blinding was assured by matching the placebo to the bupropion tablets... 26% of the placebo and 27% of the bupropion groups lost; included as smokers.

Random sequence generation (selection Low risk bias)

Allocation concealment (selection bias)

Low risk

Incomplete outcome data (attrition bias) All outcomes

Low risk

Aveyard 2008 Methods NORTRIPTYLINE Setting: National Health Service stop smoking clinics, UK Recruitment: People attending clinics 901 smokers, 10/day; 46% F, av. age 43, av. CPD 21 1. Nortriptyline 75 mg/day, for 8 w including tapering (max dose for 6w) 2. Placebo capsules All participants received free NRT and had behavioural support, the majority attending group sessions run by cessation specialists Abstinence at 12 months (prolonged from day 15 post quit) Validation: CO at 4w, saliva cotinine (collected by post) at 6m & 12m New in 2009 update

Participants Interventions

Outcomes

Notes

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

35

Aveyard 2008

(Continued)

Risk of bias Bias Authors judgement Support for judgement An independent statistician generated the randomisation schedule in Stata. We used block randomisation, with randomly ordered block sizes of two, four, and six, stratied by stop smoking adviser. Study nurses recruited participants, and the study administrator (who had not met the participants) allocated participants in sequence against the list for each adviser. Only the administrator and the pharmacist knew the allocation. 12% I, 17% C lost at 12m, included as smokers. Authors note that majority of losses were already smoking.

Random sequence generation (selection Low risk bias)

Allocation concealment (selection bias)

Low risk

Incomplete outcome data (attrition bias) All outcomes

Low risk

Berlin 1995 Methods MOCLOBEMIDE Setting: clinic, France Recruitment: By adverts in general practices or from occupational medicine depts 88 smokers, >20/day and FTQ>=6. No current major depression or anxiety disorders. 57% had history of MDD 1. Moclobemide 400 mg/day for 1w pre- and 2m post-TQD, 200 mg for 3rd month 2. Placebo (P) No behavioural intervention or counselling Abstinence at 1 year (prolonged) Abstinence veried at all visits up to 6m by plasma cotinine <= 20 ng/ml. 1 year abstinence based on telephone self report by 6m quitters. There were no serious adverse reactions. Insomnia was more common in drug (36%) than P (7%) groups. There were 4 drop-outs for adverse effects/relapse in drug and 2 in P.

Participants

Interventions

Outcomes

Notes

Risk of bias Bias Authors judgement Support for judgement


36

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Berlin 1995

(Continued)

Random sequence generation (selection Unclear risk bias) Allocation concealment (selection bias) Unclear risk

Randomization method not described.

Double-blind, but blinding at allocation not explicit. Relapses and subjects lost from follow-up were considered treatment failures.

Incomplete outcome data (attrition bias) All outcomes Biberman 2003 Methods

Low risk

SELEGILINE Setting: 3 community-based clinic, Israel Recruitment: mailing to members of public health service provider 109 smokers (15+ CPD); 38% F, av. age 42, av. CPD 27-30 1. Selegiline 10 mg/day for 26 weeks, nicotine patch 21 mg for 8 weeks incl tapering 2. Placebo & nicotine patch Both arms: Behavioural support from trained family physician; weekly then fortnightly visits for 12w Abstinence at 52 w, continuous with validation at each visit Validation: negative for urine nicotine, cotinine, 3-hydroxycotinine (Niccheck) Included in 2009 update. No serious AEs, no signicant differences in AEs, 2 selegiline discontinuations.

Participants Interventions

Outcomes

Notes

Risk of bias Bias Authors judgement Support for judgement Four hundred dice-throwing generated a randomized sequence code; 199 containers prepacked with selegiline and 201 containers prepacked with placebo were numbered accordingly. Judged adequate. The code was sealed, kept secretly and was revealed for the rst time when the last participant nished the 12 months of followup. The rst participant who joined the trial after the initial visit run-in phase received the rst bottle from the container set number 001, the second participant from set number 002 and so on. The trial coordinator arranged participants allocation. Judged adequate.
37

Random sequence generation (selection Low risk bias)

Allocation concealment (selection bias)

Low risk

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Biberman 2003

(Continued)

Incomplete outcome data (attrition bias) All outcomes Blondal 1999 Methods

Low risk

19 lost to f-up, included as smokers in MA.

FLUOXETINE Setting: cessation clinic, Iceland Recruitment: community volunteers 100 smokers (excl 5 early withdrawals), > 10 CPD; 62% F, av age 41, av CPD 28, 38% uoxetine/56% placebo had history of depression 1. Nicotine inhaler and uoxetine for 3m, option of continuing for 3m more. Fluoxetine 10 mg/day initiated 16 days before TQD, increased to 20 mg/day on day 6. 2. Nicotine inhaler and placebo Both arms: 5 x 1 hr group behaviour therapy. Advised to use 6-12 inhalers/day for up to 6m. Abstinence at 1 year (sustained from quit day) Validation: CO < 10 ppm at all assessments (6w, 3,6, 12 m)

Participants

Interventions

Outcomes

Notes Risk of bias Bias Authors judgement Support for judgement Computer generated randomization; part of the randomization procedure was performed by the manufacturer at another location where the code was also kept until it was broken in May 1997. ...pill boxes, with either uoxetine or an identical appearing placebo containing the same ingredients except uoxetine, were labelled with numbers ranging from 100 to 210...At the clinic a laboratory technician then dispensed the pill boxes immediately after the baseline interview, usually 3 4 weeks before the quitting day, always delivering the lowest numbered box. Results exclude 5 withdrawals; 3 from uoxetine group due to adverse effects - nervousness and anxiety, 1 from uoxetine due to pregnancy, 1 from placebo who had purchased uoxetine.
38

Random sequence generation (selection Low risk bias)

Allocation concealment (selection bias)

Low risk

Incomplete outcome data (attrition bias) All outcomes

Unclear risk

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Brown 2007 Methods BUPROPION Setting: 2 clinical sites (Butler Hospital, Miriam Hospital) Rhode Island, USA Recruitment: community volunteers 524 smokers >= 10 CPD; 48% F, av. age 44, av. CPD 25, 17.6% with history of MDD single episode, 3.1% recurrent MDD 2 x 2 factorial design. Alternative psychosocial treatments were standard cessation therapy or plus CBT for depression. Both had 12 x 90 min groups twice weekly/ weekly/ monthly for 12w. TQD 5th session. Collapsed in this analysis 1. Bupropion 300 mg/day for 12 weeks 2. Placebo Abstinence at 12m (sustained at 4 visits) Validation: CO <= 10 ppm, saliva cotinine <= 15 ng/ml First included as Brown 2006, part unpublished data. Some genotyping studies combine these participants with those reported in Collins 2004

Participants

Interventions

Outcomes

Notes

Risk of bias Bias Authors judgement Support for judgement Participants were randomly assigned to one of two treatment sites, where they were to receive one of two manualized group treatments ... Participants were then randomly assigned to receive one of two medication conditions, bupropion or placebo, using the urn randomization technique. Whereas we were able to balance the drug and placebo conditions on an individual basis, behavioral treatments were randomized by group and thus were more susceptible to uctuations in recruitment and to the availability at both sites of pairings of a senior and a junior therapist trained in CBTD. Knowledge of behavioural assignment was probably not concealed but seems unlikely to have lead to individual selection bias. 81% provided complete outcome data at all follow ups, not related to treatment condition. All participants included in ITT analyses

Random sequence generation (selection Unclear risk bias)

Allocation concealment (selection bias)

Unclear risk

Incomplete outcome data (attrition bias) All outcomes

Low risk

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

39

Cinciripini 2005 Methods VENLAFAXINE Setting: clinic, USA Recruitment: community volunteers 135 smokers, >= 10 CPD; 50% F, av age 46, av CPD 27 1. Venlafaxine titrated to max of 225 mg/day from 3w before quit day for 21w, including 2w tapering. 2. Placebo Both arms: 6w 22 mg nicotine patch, and 9x 15 min behavioural counselling. Abstinence at 12m (PP) Validation: CO <= 10 ppm and/or saliva cotinine < 15 ng/ul Adverse events/withdrawals: not reported First included as Cinciripini 1999 based on abstract.

Participants Interventions

Outcomes

Notes Risk of bias Bias

Authors judgement

Support for judgement Randomization method not described. Stratication by depression history. Randomization by pharmacy, all study personnel with direct patient contact blind. Unclear how missing data was addressed

Random sequence generation (selection Unclear risk bias) Allocation concealment (selection bias) Low risk

Incomplete outcome data (attrition bias) All outcomes Collins 2004 Methods

Unclear risk

BUPROPION Setting: 2 clinical research sites (Georgetown University Medical Center & State University of New York), USA Recruitment: community volunteers 555 smokers, >= 10 CPD, excluding history of psychiatric disorder including MDD; 57% F, av. age 46, av. CPD 21 1. Bupropion 300 mg/day for 10 w begun 2 w before TQD 2. Placebo Both arms: 7 sessions group behavioural counselling Abstinence at 6m (prolonged from w2, 7 consecutive days of smoking dened as relapse) Validation: saliva cotinine <= 15 ng/ml

Participants

Interventions

Outcomes

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

40

Collins 2004

(Continued)

Notes

Replaces Lerman 2002 which reported subset of data. Denominators supplied by 1st author, excludes 114 who withdrew before intervention. Some study details from Lerman 2006. Some genotyping studies combine these participants with those reported in Brown 2007.

Risk of bias Bias Authors judgement Support for judgement Randomization was determined by a computer-generated randomization scheme operated by a senior data manager; stratication was carried out by study site (Lerman 2006). Centrally generated & allocation concealed from counsellors & assessors. 6% at 6 month follow-up; included as smokers.

Random sequence generation (selection Low risk bias)

Allocation concealment (selection bias)

Low risk

Incomplete outcome data (attrition bias) All outcomes Covey 2002 Methods

Low risk

SERTRALINE Setting: clinic, USA Recruitment: volunteers 134 smokers with a history of past MDD; 65% F, av age 44.5, 47% had history of recurrent MDD 1. Sertraline starting dose 50 mg/day, 200 mg/day by week 4 quit day. 9 day taper. Total duration 10w + 9 day taper, including 1w placebo washout prior to randomization 2. Placebo Both arms: 9 x 45 min individual counselling sessions at clinic visits Abstinence 6m after end of treatment (7 day PP) Validation: serum cotinine < 25 ng/ml

Participants

Interventions

Outcomes

Notes Risk of bias Bias Authors judgement Support for judgement Randomization method not described.

Random sequence generation (selection Unclear risk bias)

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

41

Covey 2002

(Continued)

Allocation concealment (selection bias)

Low risk

Medications were provided in prepared bottles that were numbered according to the randomization schedule and dispensed at each visit. All study staff at the clinic site were blinded to treatment assignment. The subjects lost to follow-up after random assignment were considered treatment failures.

Incomplete outcome data (attrition bias) All outcomes

Unclear risk

Covey 2007 Methods BUPROPION Setting: Cessation clinic, USA Recruitment: community volunteers quit after 8w bupropion & nicotine patch 289 abstainers (excludes 5 withdrawing consent before starting meds); 45% F, av. age 43, av. cigs/day 21 All participants received 8 w open-label bupropion & nicotine patch (21mg with weaning) for 7w from TQD. Transition procedures preserved blinding for RP phase but allowed weaning from bupropion. Individual counselling including CBT techniques, 15 min x6 during open label, x4 during RP, x2 during follow up. 1. Bupropion (300 mg) & nicotine gum (2 mg, use as needed to manage craving) for 16 w 2. Bupropion & placebo gum 3. Nicotine gum & placebo pill (150 mg bupropion for rst week) 4. Double placebo (150 mg bupropion for rst week) Abstinence (no relapse to 7 days of smoking) for 12m (10m after randomization, 6m after EOT) (Primary outcome for study was time to relapse) Validation: CO 8ppm at each visit New for 2009 update Quit rate after open-label treatment was 52% so the nal quit rate of 30% for combination therapy is equivalent to ~16% of people starting treatment

Participants

Interventions

Outcomes

Notes

Risk of bias Bias Authors judgement Support for judgement A statistician who did not participate in the clinical phases of the study provided computer-generated randomization lists that were not accessible to the clinical staff , stratied by gender & depression history.
42

Random sequence generation (selection Low risk bias)

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Covey 2007

(Continued)

Allocation concealment (selection bias)

Low risk

A research nurse who did not have direct contact with participants prepared individual medication kits based on the randomization schedule. 5 randomized participants withdrew before double blind phase. Greater loss to follow up in double placebo, losses included in ITT analysis.

Incomplete outcome data (attrition bias) All outcomes

Low risk

Croghan 2007 Methods BUPROPION Setting: clinics, USA Recruitment: community volunteers for pharmacotherapy cessation & relapse prevention trial 405 abstainers after 3m pharmacotherapy, 74 from inhaler, 141 bupropion, 190 combination. Participant characteristics not presented at start of RP phase In cessation phase participants had been randomized to bupropion (300mg), nicotine inhaler (up to 16 cartridges/day) or combination. Physician advice at entry, brief (<10 min) counselling at monthly study visits (total 12-18 including RP phase) & S-H. Abstainers (7 day PP after 3m therapy) eligible for RP phase. RP intervention randomized single therapy abstainers to continue cessation therapy or placebo for 9m. Combined therapy abstainers randomized to 4 groups: combination, placebo & single therapy, or double placebo Abstinence at 15m (from TQD, 12m from RP start, 3m from EOT) (PP) Validation: CO 8ppm New for 2009 update. All arms with bupropion combined, compared to the respective placebo arms. Cessation rates at end of induction phase were 14% for inhaler, 26% for bupropion and 34% for combination.

Participants

Interventions

Outcomes

Notes

Risk of bias Bias Authors judgement Support for judgement Randomization using a dynamic allocation procedure balancing stratication factors. Randomization procedure makes prior knowlege of allocation unlikely.

Random sequence generation (selection Low risk bias) Allocation concealment (selection bias) Low risk

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

43

Croghan 2007

(Continued)

Incomplete outcome data (attrition bias) All outcomes

Low risk

Losses to follow up post-medication were high and not enumerated by group, but all included in ITT analysis.

Da Costa 2002 Methods NORTRIPTYLINE Setting: cessation clinic, Brazil Recruitment: volunteers to a smokers support group 144 smokers, >= 15 CPD; predominantly female , age, CPD not described, 48% had a history of depression 1. Nortriptyline max 75 mg/day for 6w incl titration period, begun 1w before start of behaviour therapy 2. Placebo Both arms: 6 weekly group cognitive behavioural therapy Abstinence 6m after end of treatment (prolonged) Validation: none

Participants

Interventions

Outcomes

Notes Risk of bias Bias Authors judgement Support for judgement Each patient chose a blind number from a box ... Probably adequate. ... with each number corresponding to a medication kit that was externally undistinguishable. Patients and professionals participating in this study were blindfolded for this distribution. Potentially adequate but difference in numbers in each group not accounted for. Number lost in each group not clear.

Random sequence generation (selection Low risk bias) Allocation concealment (selection bias) Unclear risk

Incomplete outcome data (attrition bias) All outcomes

Unclear risk

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

44

Dalsgar 2004 Methods BUPROPION Setting: 5 hospitals, Denmark Recruitment: hospital staff 335 smokers incl physicians, nurses, other hospital service and admin staff, >= 10 CPD, no history of MDD; 75% F, av. age 43, av. CPD 19 1. Bupropion 300 mg/day for 7 weeks 2. Placebo Both arms: motivational support around TQD, at w3 & 7, and at 12w follow up Abstinence at 6m (prolonged from w4) Validation: CO < 10 ppm

Participants

Interventions

Outcomes

Notes Risk of bias Bias Authors judgement Support for judgement Randomization was computer generated and blinded. Allocation was double-blinded and bupropion and placebo tablets were identical in form and number. 32% of the bupropion group and 43% the placebo group discontinued treatment, included in analysis.

Random sequence generation (selection Low risk bias) Allocation concealment (selection bias) Low risk

Incomplete outcome data (attrition bias) All outcomes

Low risk

Evins 2001 Methods BUPROPION Setting: outpatient clinic, USA Recruitment: volunteers Randomization: no details 18 smokers with stable schizophrenia (excl 1 drop-out prior to medication) 39% F, av age 45.5/42.7, av CPD 38/30 1. Bupropion 300 mg/day for 3m. TQD after w3 2. Placebo Both arms: 9x 1 hr weekly group CBT Abstinence at 6m, (prolonged) Validation: CO < 9 ppm or serum cotinine < 14 ng/mL

Participants

Interventions

Outcomes

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

45

Evins 2001

(Continued)

Notes

2 year follow up also reported (Evins et al 2004). 3 additional quitters, not used in metaanalysis since additional therapy used

Risk of bias Bias Authors judgement Support for judgement Randomization method not described.

Random sequence generation (selection Unclear risk bias) Allocation concealment (selection bias) Low risk

Subjects were randomly assigned to 12 weeks of double-blind bupropion SR, 150 mg/day, or an identical appearing placebo tablet added to their usual medication regimen. Nineteen subjects were enrolled and 18 subjects completed the 6-month smoking cessation trial.

Incomplete outcome data (attrition bias) All outcomes

Low risk

Evins 2005 Methods BUPROPION Setting: clinic, USA Recruitment: volunteers 56 smokers with schizophrenia (>=10 CPD) (excl 6 drop-outs prior to medication); 27% F, av age 45, av CPD 37/26 1. Bupropion 300 mg/day for 3m. 2. Placebo Both arms: 12 session group CBT Abstinence at 6m (7 day PP) Validation: CO < 9 ppm There was a signicant treatment effect at EOT. Originally included as Evins 2003 based on abstracts

Participants

Interventions

Outcomes

Notes

Risk of bias Bias Authors judgement Support for judgement Randomization method not stated.

Random sequence generation (selection Unclear risk bias) Allocation concealment (selection bias) Unclear risk

Allocation concealment not described.


46

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Evins 2005

(Continued)

Incomplete outcome data (attrition bias) All outcomes

Low risk

Only people taking at least one dose of study medication included in analyses in paper. 5 in each group lost to follow-up and included as smokers.

Evins 2007 Methods BUPROPION Setting: community mental health centre, USA Recruitment: outpatients 51 smokers (>=10 CPD) with schizophrenia; av. age 44, av. CPD 28/25 1. Bupropion 300 mg/day for 3m, nicotine patch, 21 mg for 8w incl tapering, 2 mg nicotine gum 2. Placebo + NRT as 1. Both arms: 12 session group CBT, TQD week 4 Abstinence at 12m (from TQD) Validation: CO <= 8 ppm First included as Evins 2006 based on unpublished data Used in bup+NRT vs NRT comparison.

Participants Interventions

Outcomes

Notes

Risk of bias Bias Authors judgement Support for judgement Randomization method not described.

Random sequence generation (selection Unclear risk bias) Allocation concealment (selection bias) Incomplete outcome data (attrition bias) All outcomes Unclear risk Unclear risk

Allocation concealment not described. 20% of the bupropion group and 18% of the placebo group were lost to follow-up at week 12; included as smokers.

Ferry 1992 Methods BUPROPION Setting: clinic, USA Randomization: no details 42 male smokers

Participants

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

47

Ferry 1992

(Continued)

Interventions

1. Bupropion 300 mg/day for 3m 2. Placebo Both arms: group smoking cessation and relapse prevention counselling Abstinence at 6m from end of treatment (sustained) Validation: saliva cotinine Abstract with no further details

Outcomes

Notes Risk of bias Bias

Authors judgement

Support for judgement Randomization method not described.

Random sequence generation (selection Unclear risk bias) Allocation concealment (selection bias) Incomplete outcome data (attrition bias) All outcomes Ferry 1994 Methods BUPROPION Setting: Veterans Medical Centre, USA 190 smokers Unclear risk Unclear risk

Allocation concealment not described. No details given.

Participants Interventions

1. Bupropion 100 mg x 3/day for 12w 2. Placebo Both arms: group smoking cessation and relapse prevention counselling; TQD within rst 4w Abstinence at 12m (prolonged from day 29) Validation: saliva cotinine <= 15 ng/ml at 6m and 12m Abstract with long-term abstinence data supplied by author.

Outcomes

Notes Risk of bias Bias

Authors judgement

Support for judgement Randomization method not described.

Random sequence generation (selection Unclear risk bias) Allocation concealment (selection bias) Unclear risk

Allocation concealment not described.

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

48

Ferry 1994

(Continued)

Incomplete outcome data (attrition bias) All outcomes

Low risk

The most conservative approach to analysis would reclassify all of these individuals as smokers due to protocol violation.

Fossati 2007 Methods BUPROPION Setting: primary care clinics, Italy Recruitment: patients of 71 general practitioners 593 smokers, 10 CPD; 40% F, av. age 49, av. CPD 22 1. Bupropion 300 mg/day for 7 weeks 2. Placebo Both arms: GP visits at enrollment & 4, 7, 26 & 52w, phone calls 1 day pre TQD, 3 days post TQD, 10w post enrollment. Classied as low intensity Abstinence at 12m (continuous from week 4) Validation: CO 10ppm at each visit New for 2009 update

Participants Interventions

Outcomes

Notes Risk of bias Bias

Authors judgement

Support for judgement Randomized; GP assigned them a randomization code. Stated to be double-blind, but not explicit that GPs blind to randomization code. 15% Bupropion & 17% Placebo did not attend 12m f-up, included as smokers.

Random sequence generation (selection Low risk bias) Allocation concealment (selection bias) Unclear risk

Incomplete outcome data (attrition bias) All outcomes

Low risk

George 2002 Methods BUPROPION Setting: mental health clinic, USA Recruitment: outpatients 32 smokers with schizophrenia motivated to quit; 44% F, av. age 41/45, av. CPD 24 1. Bupropion 300 mg/day for 9 weeks. TQD w3 2. Placebo Both arms: 10x 60 min weekly group therapy
49

Participants Interventions

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

George 2002

(Continued)

Outcomes

Abstinence at 6m (7-day PP) Validation: CO < 10 ppm

Notes Risk of bias Bias Authors judgement Support for judgement Randomization method not described.

Random sequence generation (selection Unclear risk bias) Allocation concealment (selection bias) Low risk

Both subjects and research staff were blinded to study medication assignment. Study medications were prepared by research pharmacists at CMHC, using encapsulation of SR bupropion tablets with blue 00 opaque capsules; placebo capsules contained only a dextrose matrix. Subjects who were lost during the trial or at 6-month follow-up were counted as smokers.

Incomplete outcome data (attrition bias) All outcomes

Low risk

George 2003 Methods SELEGILINE Setting: outpatient smoking research clinic, USA Recruitment: community volunteers 40 smokers, CO 10 ppm; 63% F, av. age 49, av. CPD 23, 25% MDD history +ve 1. Selegiline 10 mg/day for 9 weeks (5 mg/day in w1 & w9) 2. Placebo Abstinence at 6m (7 day PP) Validation: CO < 10ppm Included in 2009 The main side effects of SEL were anorexia, gastrointestinal symptoms, and insomnia. None of the differences in adverse event ratings were signicant in the SEL compared with the PLA group, and the drug was well tolerated compared with the placebo group. Reports of anxiety/agitation in both the SEL and PLA groups during the trial were high.

Participants Interventions

Outcomes

Notes

Risk of bias Bias Authors judgement Support for judgement


50

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

George 2003

(Continued)

Random sequence generation (selection Unclear risk bias) Allocation concealment (selection bias) Unclear risk

Randomization method not described.

Method not described. Subjects and raters were blinded to medication assignment. 29/40 not assessed at 6m. Greater loss to fup in placebo, exact data not reported.

Incomplete outcome data (attrition bias) All outcomes

Low risk

George 2008 Methods BUPROPION Setting: Mental Health CentreUSA Recruitment: Outpatients 58 smokers with schizophrenia or schizoaffective disorder (excludes 1 receiving no study medication); 40% F, av. age 40, av. CPD ~23 1. Bupropion 300 mg/day for 9w, begun 7 days pre-TQD 2. Placebo Both arms: Nicotine patch (21mg/24hrs) for 8w from TQD & group behaviour therapy 10 weekly sessions Abstinence at 6m, PP Validation: CO <10 ppm New for 2009. Bupropion as adjunct to NRT

Participants

Interventions

Outcomes

Notes Risk of bias Bias

Authors judgement

Support for judgement Randomization method not described.

Random sequence generation (selection Unclear risk bias) Allocation concealment (selection bias) Unclear risk

Double blind but no additional details given. 6/29 intervention & 10/29 control did not complete trial, included as smokers.

Incomplete outcome data (attrition bias) All outcomes

Low risk

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

51

Gonzales 2001 Methods BUPROPION Setting: 16 clinical trial centres, USA Recruitment: volunteers who had previously failed to quit using bupropion 450 smokers, >= 15 CPD, who had previously used bupropion for at least 2w without adverse effects; 55% F (Placebo), 48% F (Bup); av. age 45, av. CPD not specied, no details of depression history 1. Bupropion 300 mg/day for 12w, begun 7 days pre-TQD. 2. Placebo Both arms: brief individual counselling at visits w1-7, 9, 12, + telephone counselling at 4 and 5m Abstinence at 12m, prolonged from w4 Validation: CO <= 10 ppm at each visit 6m data published. 12m data presented in a poster used since 2003 update

Participants

Interventions

Outcomes

Notes Risk of bias Bias

Authors judgement

Support for judgement Participants who satised the inclusion criteria were randomized to the treatment phase and received either bupropion SR ... or matching placebo. Eligible participants were assigned a protocol-specic treatment number on the basis of a randomization code provided by GlaxoWellcome. Although a double-blind study, allocation concealment method not described ...all participants who stopped participating in the study during the treatment phase were considered to be smokers.

Random sequence generation (selection Low risk bias)

Allocation concealment (selection bias)

Unclear risk

Incomplete outcome data (attrition bias) All outcomes

Unclear risk

Gonzales 2006 Methods BUPROPION Setting: 19 clinical trial centres, USA Recruitment: community volunteers 1025 smokers of >= 10 CPD (673 in relevant arms), recent MDD excluded, prior exposure to bupropion excluded; 46% F, av. age 42, av. CPD 21, no details of depression history

Participants

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

52

Gonzales 2006

(Continued)

Interventions

1. Bupropion 300 mg/day for 12w, begun 7 days pre-TQD 2. Varenicline 2mg/day 3. Placebo All arms: Brief (<10 min) standardized individual counselling at 12 weekly visits during drug phase and 11 clinic/phone visits during follow up, problem solving and relapse prevention Abstinence at 1 year (sustained from w4) Validation: CO <= 10 ppm at each visit Bupropion was an active control for varenicline. Bupropion vs placebo and bupropion vs varenicline comparisons contribute to review.

Outcomes

Notes

Risk of bias Bias Authors judgement Support for judgement predened ... computer-generated randomization sequence, 1:1:1, using block size of 6, stratied by centre. Central allocation. Loss to follow-up similar across conditions; 44% bupropion, 39.5% varenicline, 46% placebo, all included in analyses.

Random sequence generation (selection Low risk bias)

Allocation concealment (selection bias) Incomplete outcome data (attrition bias) All outcomes

Low risk Low risk

Grant 2007 Methods BUPROPION Setting: 2 substance use disorder clinics, USA Recruitment: Alcoholics in residential or outpatient treatment programmes 58 alcoholic smokers (20+ CPD); 84% M, av. age 40, av. CPD 25 1. Bupropion 300 mg for 60 days + nicotine patch 21 mg for 8 weeks incl tapering 2. Placebo & nicotine patch Both arms: 1 hour cessation group (& 4 weekly assessment visits) Abstinence at 6m, 7 day PP Validation: no biochemical val, collaterals contacted, inconsistent, adjusted rates not reported. New for 2009 update

Participants Interventions

Outcomes

Notes Risk of bias

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

53

Grant 2007

(Continued)

Bias

Authors judgement

Support for judgement Randomization method not described.

Random sequence generation (selection Unclear risk bias) Allocation concealment (selection bias) Unclear risk

Double-blind, but not explicit who was blinded. Higher loss in bupropion (40%) than placebo (21%). ITT analysis.

Incomplete outcome data (attrition bias) All outcomes

Low risk

Grecka 2003 Methods BUPROPION Setting: Smokers clinic, Poland Recruitment: smokers with a diagnosis of COPD and failure to stop smoking with advice alone 70 smokers with COPD 43% F, av age 56, av CPD 24 1. Bupropion 300 mg/day for 7w 2. Nicotine patch (15mg) for 8w Common components: support at clinic visits at baseline, 2w, EOT Abstinence at 1 year (sustained) Validation: CO < 10ppm

Participants

Interventions

Outcomes

Notes Risk of bias Bias Authors judgement Support for judgement Randomization method not described.

Random sequence generation (selection Unclear risk bias) Allocation concealment (selection bias) Incomplete outcome data (attrition bias) All outcomes Unclear risk Unclear risk

Allocation concealment not described. Not described.

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

54

Haggstrm 2006 Methods BUPROPION & NORTRIPTYLINE Setting: Smoking cessation clinic, Brazil Recruitment: community volunteers. 156 smokers, FTND at least 4; 70% F placebo & nortrip, 59% Bup, av. age 44, av. CPD NS 1. Bupropion 300 mg/day for 60 days, placebo nortriptyline, TQD during week 2 2. Nortripytyline 75 mg/day for 60 days, placebo bupropion 3. Double placebo All arms: 6x 15-min individual CBT, weekly then bi-weekly. Abstinence at 6m (continuous from TQD) Validation: CO <= 10 ppm at 3 & 6m

Participants

Interventions

Outcomes

Notes Risk of bias Bias Authors judgement Support for judgement Randomization method not described.

Random sequence generation (selection Unclear risk bias) Allocation concealment (selection bias) Incomplete outcome data (attrition bias) All outcomes Hall 1998 Methods Unclear risk Unclear risk

Allocation concealment not described. Numbers lost to follow-up not reported, all included as smokers.

NORTRIPTYLINE Setting: clinic, USA Recruitment: community volunteers. Exclusion criteria included MDD within 3m of baseline 199 smokers of >= 10 CPD, 33% had history of MDD 55% F, av age 40, av CPD 21-25 2 x 2 factorial design. Alternative psychological Rxs were 10 sessions of CBT or 5 sessions of health education control. Collapsed in this analysis 1. Nortriptyline titrated to therapeutic levels - usually 75-100 mg/day, 12w 2. Placebo Abstinence at 1 year post-EOT, prolonged. PP rates also reported. Validation: CO at weeks 12, 24, 39 and 64 There were no signicant main or intervention effects for MDD category so these are pooled.
55

Participants

Interventions

Outcomes

Notes

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Hall 1998

(Continued)

Risk of bias Bias Authors judgement Support for judgement Computer randomization, after stratication on history of MDD and number of cigarettes smoked. Allocation generated at enrollment. 30% did not complete treatment in placebo and 17% in active groups. Analyses with missing =smoking given.

Random sequence generation (selection Low risk bias)

Allocation concealment (selection bias) Incomplete outcome data (attrition bias) All outcomes

Low risk Low risk

Hall 2002 Methods BUPROPION & NORTRIPTYLINE Setting: cessation research centre, USA Recruitment: community volunteers 220 smokers, >= 10 CPD; 40-47% F, av. age 37-43, av. CPD 20-23, 33% had history of MDD 3 x 2 factorial design. Alternative psychological interventions were Medical Management (MM, physician advice, S-H, 10-20 min 1st visit, 5 minds at 2,6,11 weeks) or Psychosocial Intervention (PI, as MM plus 5x 90 min group sessions at 4,5,7,11w) Pharmacotherapy: 1. Bupropion 300 mg/day, 12w 2. Nortriptyline titrated to therapeutic levels, 12w 3. Placebo Abstinence at 1 year (47w post quit date), prolonged. PP also reported Validation: CO <= 10 ppm, urine cotinine <= 60 ng/mL No signicant interaction between pharmacotherapy and behaviour therapy, so BT arms collapsed in main analysis. Bupropion & nortriptyline compared to placebo and headto-head. Levels of support compared for bupropion only, PP rates used.

Participants

Interventions

Outcomes

Notes

Risk of bias Bias Authors judgement Support for judgement Participants were stratied by number of cigarettes smoked, sex and history of depression vs no history, and randomly assigned to 1 of the 6 experimental cells.

Random sequence generation (selection Unclear risk bias)

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

56

Hall 2002

(Continued)

Allocation concealment (selection bias)

Low risk

We encapsulated both drugs to maintain the patency of the bupropion formulation and to provide a blinded drug. All participants received capsules that were identical in number and appearance but blinding of allocation not explicit. 19% lost to f-up at 52 w. No signicant difference across conditions. Included as smokers in analyses.

Incomplete outcome data (attrition bias) All outcomes

Low risk

Hall 2004 Brief Methods NORTRIPTYLINE Setting: clinic, USA Recruitment: community volunteers. 81 smokers of >= 10 CPD 41% F, av age 36/39, av CPD 19, 23% MDD history +ve 2 x 2 factorial design. Nortriptyline vs placebo and brief vs extended treatment. Rx length subgroups entered as separate studies 1. Nortriptyline titrated to 50-150 ng/ml (~75-100 mg) for 12w, quit date week 5 2. Placebo Both arms received nicotine patch for 8w from quit date, & 5 group counselling sessions, total 7.5 hrs Abstinence at 52w, repeated PP at 24, 36, 52w. Validation: CO <= 10 ppm and urine cotinine <= 50 ng/ml at each point. Factorial design, entered in meta-analysis as two trials

Participants

Interventions

Outcomes

Notes Risk of bias Bias

Authors judgement

Support for judgement Randomization stratied on CPD, prior NRT use, MDD history; method not specied. Allocation concealment not described. 9% lost at week 52, included as smokers.

Random sequence generation (selection Unclear risk bias)

Allocation concealment (selection bias) Incomplete outcome data (attrition bias) All outcomes

Unclear risk Low risk

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

57

Hall 2004 Extended Methods NORTRIPTYLINE See Hall 2004 Brief 79 smokers of >= 10 CPD 42% F, av age 39/40, av CPD 19, 18% MDD history +ve First 12w treatment as for Hall 2004 Brief , 1. Nortriptyline extended treatment, same dose continued to week 52 then tapered. Individual counselling every 4w, total 3-4.5 hrs. Phone counselling, total 40-80 mins. 2. Placebo extended treatment, same behavioural support. Participants could choose to discontinue pharmacotherapy before 52w. See Hall 2004 Brief In the active extended treatment arm participants were still receiving nortriptyline at the time of nal follow up.

Participants

Interventions

Outcomes Notes

Hatsukami 2004 Methods BUPROPION Setting: 12 clinical trial sites, USA Recruitment: community volunteers 594 smoker of >= 20 CPD wanting to reduce amount smoked. Not quit for > 3m in prev year, at least 2 failed quit attempts including 1 with NRT, not currently depressed, 6% had history of MDD. Excludes 15 who took no study medication. Not a cessation trial 1. Bupropion 300 mg/day, 26w 2. Placebo Both arms: written materials suggesting reduction techniques, monthly brief individual counselling, telephone contact 2 days, 12 days, 5w after target reduction date. Participants indicating a willingness to quit at any time were enrolled in a 7w cessation programme with weekly visits followed by 19w of follow up Abstinence 6m after quit date (denominator 594; 214 entered cessation phase Validation: urine cotinine Not used in main analysis 38% of bupropion and 34% of placebo group entered cessation phase. Median time to attempting cessation shorter in bupropion group

Participants

Interventions

Outcomes

Notes

Risk of bias Bias Authors judgement Support for judgement Subjects were assigned randomly using a computer-generated schedule...

Random sequence generation (selection Low risk bias)

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

58

Hatsukami 2004

(Continued)

Allocation concealment (selection bias) Incomplete outcome data (attrition bias) All outcomes

Unclear risk Low risk

Allocation concealment not described. For cessation analyses, subjects who dropped out were considered to have resumed smoking [after withdrawal date].

Hays 2001 Methods BUPROPION Setting: 5 clinical trial centres, USA Recruitment: 784 community volunteers 429 smokers of >= 15 CPD who quit after 7 weeks open label bupropion; 51% F, av age 46, av CPD 26, 19% history of MDD 1. Bupropion 300 mg/day for 45 weeks 2. Placebo Both arms: physician advice, S-H materials and brief individual counselling at followup visits. Abstinence at 2 years (1 year after end of pharmacotherapy), prolonged Validation: CO <= 10 ppm Relapse prevention trial

Participants

Interventions

Outcomes

Notes Risk of bias Bias

Authors judgement

Support for judgement Randomization to the placebo or bupropion groups was computer generated at a central location;... ...the investigators did not know the patient assignments. All bupropion and placebo pills were identical in shape, size, and color. Participants who dropped out were considered to have relapsed to smoking, but information on other important factors, such as weight gain, was not collected and therefore could not be included in the analysis. Approximately 26% of the bupropion group and 27% of the placebo group did not complete the study.

Random sequence generation (selection Low risk bias)

Allocation concealment (selection bias)

Low risk

Incomplete outcome data (attrition bias) All outcomes

Low risk

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

59

Hertzberg 2001 Methods BUPROPION Setting: Veterans Affairs Medical Centre (VAMC), USA Recruitment: VAMC outpatient volunteers 15 male veterans with Post Traumatic Stress Disorder, av age 50, av CPD 33 1. Bupropion 300 mg/day, 12w begun at least 1w before TQD. 2. Placebo Both arms: individual counselling pre-quit, weeks 1,2,4,8,12. Abstinence at 6m, prolonged, validated at weeks 2, 8, 12. Validation: CO <= 10ppm Paper includes as abstinent one person with a slip at week 12 2 of the successful quitters were taking bupropion at 6m, prescribed after end of study.

Participants Interventions

Outcomes

Notes Risk of bias Bias

Authors judgement

Support for judgement Randomization method not described.

Random sequence generation (selection Unclear risk bias) Allocation concealment (selection bias) Incomplete outcome data (attrition bias) All outcomes Unclear risk Low risk

Allocation concealment not described. 30% of the participants receiving bupropion SR did not complete the full 12-week trial; 80% of the placebo group failed to complete the trial and were considered to have resumed smoking.

Holt 2005 Methods BUPROPION Setting: Cessation clinic, New Zealand Recruitment: Maori community volunteers aged 16-70 134 smokers, >=10 CPD; 72% F, av age 42/38 1. Bupropion 300mg/day for 7w 2. Placebo Both arms: counselling at 3 clinic visits during medication & 3 monthly follow ups, motivational phone call 1 day before & 2 days after TQD Abstinence at 12m (continuous, undened) Validation: CO at each visit

Participants Interventions

Outcomes

Notes
Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 60

Holt 2005

(Continued)

Risk of bias Bias Authors judgement Support for judgement Randomization using a computer generated code. Neither the study team nor the participant was aware of which treatment had been allocated until the end of the 12 month study period. 36% lost in bupropion group and 52% in placebo at 12 months. Participants who were lost to follow up were categorised as smokers ... often this was conrmed by family members or friends.

Random sequence generation (selection Low risk bias) Allocation concealment (selection bias) Low risk

Incomplete outcome data (attrition bias) All outcomes

Low risk

Hurt 1997 Methods BUPROPION Setting: multi-centre, USA Recruitment: community volunteers 615 smokers, > 15 CPD, without current depression; 55% F, av. age 44, av. CPD 27, 3% had a history of major depression and alcoholism, 15% depression alone, 7% alcoholism alone. 1. Bupropion 100 mg/day for 7 weeks 2. Bupropion 150 mg/day 3. Bupropion 300 mg/day 4. Placebo All arms: physician advice, S-H materials, and brief individual counselling by study assistant at each visit Abstinence at 12m (prolonged from day 22, data provided by Glaxo Wellcome) (continuous abstinence to week 6 and 7 day PP abstinence at 12m reported in paper) Validation: expired CO <= 10ppm 300 mg compared with placebo in main analysis There was no evidence that history of major depression or alcoholism interacted with treatment condition or was associated with poorer outcomes. Prolonged abstinence rates at 12m as supplied by Glaxo Welcome: 300 mg 21; 150 mg 23; Placebo 15

Participants

Interventions

Outcomes

Notes

Risk of bias Bias Authors judgement Support for judgement

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

61

Hurt 1997

(Continued)

Random sequence generation (selection Unclear risk bias) Allocation concealment (selection bias) Incomplete outcome data (attrition bias) All outcomes Unclear risk Unclear risk

Randomized, stratied by site, method not described. Allocation concealment not described. Subjects who missed a follow-up visit were considered to be smoking.... The rate of completion of the study increased with the dose and was 57 percent, 65 percent, 64 percent, and 71 percent for the placebo, 100-mg, 150-mg, and 300-mg groups, respectively...

Hurt 2003 Methods BUPROPION Setting: multi-centre 14 North Central Cancer Treatment Group sites, USA Recruitment: community volunteers. 578 smokers recruited to rst stage of study: >= 15 CPD; 57% F, av age 42, 21% history of MDD 176 smokers abstinent after 8w nicotine patch treatment randomized to relapse prevention intervention 194 non-abstinent smokers randomized to bupropion as second line therapy (All participants rst received nicotine patch for 8w, dose based on cig consumption) Relapse prevention arm: 1. Bupropion for 26w 2. Placebo Second line therapy arm: 1. Bupropion for 8w 2. Placebo Relapse prevention arm: Abstinence at 12m, (PP, 6m after end of therapy). Second line therapy arm: Abstinence at 6m (4m after end of therapy) Validation: CO < 8 ppm Does not contribute to primary analysis. Long-term follow up for 2nd line Rx arm from authors.

Participants

Interventions

Outcomes

Notes

Risk of bias Bias Authors judgement Support for judgement Randomized using dynamic allocation.

Random sequence generation (selection Low risk bias)

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

62

Hurt 2003

(Continued)

Allocation concealment (selection bias)

Unclear risk

Double-blind, but allocation concealment not described. Patients lost to follow-up considered to be smoking.

Incomplete outcome data (attrition bias) All outcomes

Unclear risk

Jorenby 1999 Methods BUPROPION Setting: multi-centre clinical trial units, USA Recruitment: community volunteers 893 smokers, > 15 CPD, no current major depressive episode, 15-20% had history of MDD 52% F, av age 43 av CPD 25 1. Nicotine patch (24 hr, 21 mg for 6w, tapered for 2w) and sustained release bupropion 300 mg for 9w from 1w before quit day 2. Bupropion 300 mg and placebo patch 3. Nicotine patch and placebo tablets 4. Placebo patch and placebo tablets All arms: Brief (< 15 min) individual counselling session at each weekly assessment. One telephone call 3 days after quit day Abstinence at 12m, (continuous) Validation: Expired CO < 10ppm at each clinic visit Primary outcome for study was PP abstinence; this analysis uses continuous abstinence since quit day.

Participants

Interventions

Outcomes

Notes

Risk of bias Bias Authors judgement Support for judgement The subjects were randomly assigned to one of four treatments with use of an unequal-cell design...[but] Randomization was not balanced within sites. Allocation concealment method unclear. Bupropion and placebo tablets looked identical. All subjects who discontinued treatment early or who were lost to follow-up were classied as smokers. Approximately 20% left the study and provided no additional information. 15% stopped taking medica63

Random sequence generation (selection Low risk bias)

Allocation concealment (selection bias)

Unclear risk

Incomplete outcome data (attrition bias) All outcomes

Low risk

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Jorenby 1999

(Continued)

tion but participated in follow-up assessments. Jorenby 2006 Methods BUPROPION Setting: multi-centre clinical trial units, USA Recruitment: community volunteers 683 smokers (in relevant arms) >=10 CPD, no recent treatment for MDD, prior exposure to bupropion excluded; 41% F, av. age 42, av. CPD 22 1. Bupropion 300mg for 12 w +placebo varenicline 2. Varenicline 2mg for 12 w +placebo bupropion 3. Placebo bupropion + placebo varenicline All arms: Brief (< 10 min) individual counselling at each weekly assessment for 12w & 5 follow-up visits. One telephone call 3 days after quit day Abstinence at 12m, (sustained from week 9) Validation: Expired CO < 10 ppm at each clinic visit Bupropion was an active control for varenicline. Bupropion vs placebo and bupropion vs varenicline comparisons contribute to review.

Participants

Interventions

Outcomes

Notes

Risk of bias Bias Authors judgement Support for judgement Randomization was completed centrally by using a computer-generated list and sites used an electronic system to assign participants to treatment. Folders [containing medication or placebo] for all participants (regardless of treatment assignment) were identical throughout the treatment phase including a period of dose titration (week 1) and treatment at the target dose (weeks 2-12). Over the period of treatment and follow-up 14% of those receiving varenicline were lost to follow-up; 14% randomized to bupropion lost to follow-up; 16% of the placebo group were lost to follow-up. Participants whose smoking status was unknown or whose carbon monoxide
64

Random sequence generation (selection Low risk bias)

Allocation concealment (selection bias)

Low risk

Incomplete outcome data (attrition bias) All outcomes

Low risk

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Jorenby 2006

(Continued)

level was higher than 10 ppm were classied as smoking during both the treatment phase and follow-up.

Killen 2000 Methods PAROXETINE Setting: clinic, USA Recruitment: Advertisements 224 smokers, > 10 CPD, no current major depression. 12-25% had history of MDD; 46% F, av age 46, av CPD 26 1. Nicotine patch (24 hr, 21 mg, 8w) + 40 mg paroxetine (9w incl tapering) 2. Patch as 1 + 20 mg paroxetine 3. Patch as 1 + placebo paroxetine All arms: S-H manual and 15 min behavioural counselling at weeks 1 & 4. Abstinence at 6m (7 day PP at 10 & 26w) Validation: CO < 9 ppm and saliva cotinine < 20 ng/ml at each visit. 40 mg & 20 mg dose pooled in MA from 2009. 20/75 quit on 40mg, 15/75 on 20mg

Participants

Interventions

Outcomes

Notes Risk of bias Bias

Authors judgement

Support for judgement Randomization method not described.

Random sequence generation (selection Unclear risk bias) Allocation concealment (selection bias) Unclear risk

Double-blind but allocation concealment not explicitly described. Those failing to provide conrmation [of smoking status] were reclassied as smokers.

Incomplete outcome data (attrition bias) All outcomes

Unclear risk

Killen 2004 Methods BUPROPION Setting: continuation high schools, USA Recruitment: adolescents at schools 211 adolescent smokers, >= 10 CPD, at least 1 failed quit attempt; 31% F, av. age 17, av. CPD 15

Participants

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

65

Killen 2004

(Continued)

Interventions

1. Bupropion 150mg for 9w from 1w before TQD, Nicotine patch for 8w 2. Placebo & nicotine patch Both arms: Weekly 45 min group sessions, skills training Abstinence at 6m (7 day PP) Validation: Saliva cotinine < 20 ng/ml at 6m (CO at EOT) Low compliance with both bupropion & patch therapy

Outcomes

Notes Risk of bias Bias

Authors judgement

Support for judgement Randomization method not described.

Random sequence generation (selection Unclear risk bias) Allocation concealment (selection bias) Incomplete outcome data (attrition bias) All outcomes Unclear risk Low risk

Allocation concealment not described. 38% bupropion & 35% placebo lost at 6 months, included in analysis.

Killen 2006 Methods BUPROPION Setting: clinics, USA Recruitment: community volunteers 362 smokers >=10 CPD, no current major depression; 46% F, av age 45, av CPD 20, 25% previous bupropion use Extended treatment for relapse prevention after successful quitting. All received open label combination pharmacotherapy of bupropion 300 mg for 11w, nicotine patch for 10w. TQD day 7, 30 min individual relapse prevention skills training at 6 clinic visits. 1. Bupropion 150 mg for 14w 2. 2w tapering bupropion then placebo. Both arms had 4 further clinic visits during extended therapy Abstinence at 12m (continuous). PP and 7day relapse-free outcomes also reported. Validation: CO (10 people not required to provide samples) Relapse prevention, does not contribute to main analysis. PP outcomes favour placebo but no outcomes showed signicant effects

Participants

Interventions

Outcomes

Notes

Risk of bias Bias Authors judgement Support for judgement

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

66

Killen 2006

(Continued)

Random sequence generation (selection Low risk bias)

Centrally generated pre-assigned random sequence stratied by gender, prior to open label phase. Centrally assigned. 8% bupropion & 13% placebo lost at 12 months, included in analysis.

Allocation concealment (selection bias) Incomplete outcome data (attrition bias) All outcomes

Low risk Low risk

McCarthy 2008 Methods BUPROPION Setting: Cessation clinic, USA Recruitment: community volunteers 463 smokers; 50% F, av. age 36-41 across arms, av. CPD 22 Factorial trial 1. Bupropion SR 300mg for 8 weeks 2. Placebo Counselling conditions: 1. Counselling; 8 x10min session, 2 prequit, TQD, 5 over 4 wks 2. Psychoeducation about medication, support & encouragement. Same no. of sessions, 80mins less contact time Abstinence at 12m (7 day PP). Prolonged self-reported abstinence also assessed Validation: CO 10ppm New for 2009. Counselling conditions collapsed in main analysis, entered separately in subgroup analysis by intensity, condition 2 classied as low intensity

Participants Interventions

Outcomes

Notes

Risk of bias Bias Authors judgement Support for judgement Random number table.

Random sequence generation (selection Low risk bias) Allocation concealment (selection bias) Low risk

Staff who screened and enrolled participants were unaware of the experimental condition to be assigned. 171 (37%) failed to attend quit date visit or lost to follow up, similar across groups, included in ITT analysis.

Incomplete outcome data (attrition bias) All outcomes

Low risk

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

67

Muramoto 2007 Methods BUPROPION Setting: research clinic, USA Recruitment: adolescent community volunteers 312 adolescents (14 to 17) smoking 6 CPD; 46% F, median age 16, median CPD 11 1. Bupropion 300 mg for 7w 2. Bupropion 150 mg 3. Placebo All arms: Brief (10-20 min) individual counselling session pre quit and at each weekly assessment. Abstinence at 6m (7 day PP; 30 day PP abstinence assessed but not reported) Validation: CO <10ppm (cotinine at weeks 2 & 6 only) New for 2009 300 mg arm contributes to main analysis. 2/105 quit in 150mg group

Participants Interventions

Outcomes

Notes

Risk of bias Bias Authors judgement Support for judgement Active study medication and identical-appearing placebo were prepackaged into 3 sets of identical-appearing blister cards in accordance with a computer-generated randomization list. ... a research assistant assigned the subject the next treatment number (and associated blister cards) in sequence. Study subjects and researchers remained blind to treatment group assignment throughout the study. Slightly higher lost to f-up/ declined further participation in placebo group (30%) than active arms (18%). ITT analysis.

Random sequence generation (selection Low risk bias)

Allocation concealment (selection bias)

Low risk

Incomplete outcome data (attrition bias) All outcomes

Low risk

Myles 2004 Methods BUPROPION Setting: preoperative clinic, Australia Recruitment: Smokers awaiting surgery 47 smokers expected to undergo surgery within 8-14w 34% F, av age 45/40, 49% smoked 21-30 CPD

Participants

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

68

Myles 2004

(Continued)

Interventions

1. Bupropion 300 mg for 7w 2. Placebo Both arms: Advice at baseline, 1 phone call 2-4 days after TQD. Low intensity Abstinence at 6m (28 day PP - classied as sustained) Validation CO <= 10 ppm New 2007 More drop-outs in placebo group. Only 20 had surgery.

Outcomes

Notes

Risk of bias Bias Authors judgement Support for judgement Patients were randomly allocated from a table of random numbers into one of two groups: active (bupropion) or placebo (identical appearance). Double-blind but not clear that random number table concealed at allocation. 17% lost to follow-up in the bupropion group; 9%b lost to follow-up in the placebo group. Patients lost to follow-up were assumed to still be smoking.

Random sequence generation (selection Low risk bias)

Allocation concealment (selection bias)

High risk

Incomplete outcome data (attrition bias) All outcomes

Unclear risk

Niaura 2002 Methods FLUOXETINE Setting: 16 clinical trial centres, USA Recruitment: Community volunteers 989 non-depressed smokers, no history of bipolar or current psychiatric disorder 61% F, av age 42 av CPD 28 1. Fluoxetine 30 mg for 10w, starting 2w before TQD 2. Fluoxetine 60 mg for 10w, starting 2w before TQD 3. Placebo All arms: 9 sessions (60-90 mins) individual CBT. Included coping skills, stimulus control techniques and relapse prevention. Abstinence at 32w from TQD, multiple PP Validation: saliva cotinine < 20 ng/mL at each visit Originally based on abstract and data from authors. From 2002 based on full report. Numbers quit derived from rounded quit rates (10% quit in each group).
69

Participants

Interventions

Outcomes

Notes

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Niaura 2002

(Continued)

Risk of bias Bias Authors judgement Support for judgement Randomization method not described.

Random sequence generation (selection Unclear risk bias) Allocation concealment (selection bias) Unclear risk

Double-blind, but blinding of allocater not explicit. Missing data in treatment phase addressed, but unclear whether missing data in followup phase addressed.

Incomplete outcome data (attrition bias) All outcomes

Unclear risk

Nides 2006 Methods BUPROPION Setting: 5 clinical sites, USA Recruitment: Volunteers (phase II study) 638 smokers (255 in relevant arms, incl 2 bupropion & 4 placebo who did not start medication). No major depression in past year 51% F, av age 41, av CPD 20. 13-20% had used bupropion 1. Bupropion 300 mg for 7w 2. Varenicline 2 mg for 7w (other dose regimens not used in reivew 3. Placebo All arms: Up to 10 mins counselling at 7 weekly clinic visits, 12 & 24w. Abstinence at 12m (continuous from week 4) Validation: CO Bupropion was an active control for varenicline. Bupropion vs placebo and bupropion vs 2mg varenicline comparisons contribute to review. Inclusion of 6 pretreatment drop-outs has minimal effect on OR.

Participants

Interventions

Outcomes

Notes

Risk of bias Bias Authors judgement Support for judgement ...a randomization list was computer generated using a method of randomly permuted blocks and a pseudorandom number generator.

Random sequence generation (selection Low risk bias)

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

70

Nides 2006

(Continued)

Allocation concealment (selection bias)

Low risk

Investigators assigned medication to subjects in numerical order of acceptance into the study. Subjects who dropped out for any reason were considered to be smokers at all subsequent time points. 9.5% of varenicline tartarate 0.3 mg, once daily; 7% of varenicline tartarate 1.0 mg, once daily; 11 % of varenicline tartarate 1.0 mg, twice daily; 6% of bubpropion hydrochloride 150 mg, twice daily and 13% of the placebo group were lost to follow up.

Incomplete outcome data (attrition bias) All outcomes

Low risk

Piper 2007 Methods BUPROPION Setting: USA Recruitment: volunteers Randomization: method not stated 608 smokers of 10 CPD; 58% F, av. age 42, av CPD 22, no details of depression history 1. Nicotine gum (4 mg) and bupropion (300 mg) (not used in this review) 2. Placebo gum and bupropion 3. Double placebo All arms: 3x 10 min counselling over 3 weeks Abstinence at 12m (PP) Validation: CO or blood cotinine First included with 6m data as Piper 2004 based on abstract

Participants

Interventions

Outcomes

Notes Risk of bias Bias

Authors judgement

Support for judgement Randomization was conducted in doubleblind fashion using blocked randomization within each of the 10 [orientation session] cohorts. Double blind at randomization.

Random sequence generation (selection Low risk bias)

Allocation concealment (selection bias)

Low risk

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

71

Piper 2007

(Continued)

Incomplete outcome data (attrition bias) All outcomes

Low risk

32% of bupropion & 36% of placebo groups lost at 12 months. Participants who could not be reached at follow-up were considered to be smoking for the purposes of follow-up analyses.

Prochazka 1998 Methods NORTRIPTYLINE Setting: VAMC & Army Medical Centre, USA Recruitment: outpatient clinics and campus advertisements 214 smokers, >10 CPD (Excludes 29 early drop-outs); 38% F, av age 47, av CPD 21,12% had a history of depression 1. Nortriptyline max 75 mg/day from 10 days pre-quit date to 8w after, tapered for 2w. 2. Placebo capsules. Both arms: 2 behavioural group sessions prior to drug therapy. During treatment individual support was provided by the study nurse. Abstinence at 6m (prolonged) Validation: CO =< 9 ppm at each visit and urine cotinine < 50 ng/mL at 6m.

Participants

Interventions

Outcomes

Notes Risk of bias Bias Authors judgement Support for judgement Randomization method not described.

Random sequence generation (selection Unclear risk bias) Allocation concealment (selection bias) Unclear risk

An unblinded research pharmacist recommended dosage reductions for those above the therapeutic range and dosage increases for those who were subtherapeutic. To maintain blinding, dose reductions and increases on an equal number of randomly selected placebo-treated subjects were also recommended...our blinding was only partially effective. Because of the high frequency of dry mouth, the nurse and subjects were often able to identify the active drug. 75% drop-out rate in placebo, 61% in drug group, majority classied as ineffec72

Incomplete outcome data (attrition bias) All outcomes

Low risk

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Prochazka 1998

(Continued)

tive therapy.

Prochazka 2004 Methods NORTRIPTYLINE Setting: clinic, USA Recruitment: outpatient clinic & community volunteers 158 smokers, > 10 CPD, excluding current depression; 54% F, av. CPD 22, 6% history of depression 1. Nortriptyline max 75 mg/day for 14w, from 2w before TQD tapered for 2w + nicotine patch 8w from TQD 2. Placebo capsules + active nicotine patch. All arms: brief counselling from nurse at weekly visits Abstinence at 6m (prolonged) Validation: CO 9 ppm at each visit, cotinine < 50 ng/ml at 6 months First included based on unpublished data, Prochazka 2001. One fewer nortriptyline quitter in published paper

Participants

Interventions

Outcomes

Notes

Risk of bias Bias Authors judgement Support for judgement Subjects were stratied by history of previous major depression and randomized by means of a computer-generated random number list that was held by the Research Pharmacy Service of the Denver Veterans Affairs Medical Center. Once a patient was enrolled, the Research Pharmacy Service randomized the subject according to the randomization list. Judged adequate. Subjects who dropped out were counted as smokers. Number of dropouts not given.

Random sequence generation (selection Low risk bias)

Allocation concealment (selection bias)

Low risk

Incomplete outcome data (attrition bias) All outcomes

Low risk

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

73

Rigotti 2006 Methods BUPROPION Setting: hospitals, USA Recruitment: volunteers 248 smokers hospitalised with cardiovascular disease (excludes 3/3 dropped prior to treatment & 2 placebo deaths during follow up) 31% F, av age 56, av CPD 23/21. 30%/20% had prior use of bupropion, 54%/56% prior use of NRT 1. Bupropion 300 mg for 12w 2. Placebo Both arms: Multicomponent CBT cessation & relapse prevention programme, motivational interviewing approach, Begun in hospital, 30-45 mins, 5 X10 min post-discharge contacts (2 days,1,3,8, 12w), S-H, chart prompt for physician. Total time 80-95 mins Abstinence at 12m (sustained at multiple follow ups) Validation: saliva cotinine at 12 & 52w, CO at 2 & 4w

Participants

Interventions

Outcomes

Notes Risk of bias Bias Authors judgement Support for judgement Using a computer program, the study statistician generated a sequence of randomly-permuted blocks of 4 within strata formed by study site and daily cigarette consumption (10 vs 10). The study pharmacist used this sequence, concealed from enrollment staff, to assign participants to study arm. Subjects and study personnel, except the statistician and pharmacist, were blind to treatment assignment. Subjects were considered smokers if they were lost to follow-up...; 23% lost to follow up in the bupropion group and 23% in the placebo group (Figure 1).

Random sequence generation (selection Low risk bias)

Allocation concealment (selection bias)

Low risk

Incomplete outcome data (attrition bias) All outcomes

Low risk

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

74

Saules 2004 Methods FLUOXETINE Setting: cessation clinic, USA Recruitment: volunteers 150 smokers, 20% history of MDD; 55% F, av. age 40 1. Fluoxetine 40 mg for 14w, nicotine patch for 10w 2. Fluoxetine 20 mg for 14w, nicotine patch for 10w 3. Placebo & nicotine patch All arms: TQD end of w4, CBT 6 sessions starting 2w before TQD, 11 clinic visits Abstinence at 12m (not dened) Validation: CO < 10 ppm Authors provided quit numbers by treatment group

Participants Interventions

Outcomes

Notes Risk of bias Bias

Authors judgement

Support for judgement Randomzation method not described.

Random sequence generation (selection Unclear risk bias) Allocation concealment (selection bias) Unclear risk

Double-blind, but allocation concealment not explicit. Subjects who dropped out of the study or lost to follow-up were considered to be smoking again.

Incomplete outcome data (attrition bias) All outcomes

Unclear risk

Schmitz 2007 Methods BUPROPION Setting: Research clinic, USA Recruitment: Community volunteers 154 women smokers >20 CPD; av. age 48, av. CPD 21 Factorial trial of bupropion and 2 group therapies 1. Bupropion 300 mg/day for 7 weeks 2. Placebo Both arms: either CBT based on relapse prevention model, or group support therapy, both 7 weekly 60 min meetings, TQD morning of 1st session, 10 days after start of meds Abstinence at 12m (7 day PP) Validation: CO 10ppm, saliva cotinine < 15ng/ml New for 2009. Group therapy variants collapsed in main analysis
75

Participants Interventions

Outcomes

Notes

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Schmitz 2007

(Continued)

Risk of bias Bias Authors judgement Support for judgement Urn procedure, balancing on a range of outcome-related variables. Investigators and research staff blind to randomization codes? 14 enrollment failures who did not receive any treatment are excluded from analyses. Other non-completers and losses to follow up included in ITT analysis.

Random sequence generation (selection Low risk bias) Allocation concealment (selection bias) Low risk

Incomplete outcome data (attrition bias) All outcomes

Low risk

Selby 2003 Methods BUPROPION Setting: 15 clinical centres, Canada Recruitment: community volunteers 284 smokers previously exposed to bupropion for at least 2w, not quit for more than 24 hours in previous month 1. Bupropion 300mg for 12w 2. Placebo Behavioural support not described Abstinence at 12m (PP) Validation: CO <= 10 ppm at treatment visits Based on abstract

Participants

Interventions

Outcomes

Notes Risk of bias Bias

Authors judgement

Support for judgement Randomization method not described.

Random sequence generation (selection Unclear risk bias) Allocation concealment (selection bias) Incomplete outcome data (attrition bias) All outcomes Unclear risk Unclear risk

No details given. No details given.

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

76

Simon 2004 Methods BUPROPION Setting: VAMC outpatient units, USA Recruitment: outpatients Randomization: computer-generated, personnel blind 244 smokers, 79% veterans; 5% F, av. age 50, av. CPD 24, 17% history of depression. 1. Bupropion 300 mg for 7w, nicotine patch for 2m 2. Placebo bupropion, nicotine patch for 2m Both arms: 3m CBT counselling, S-H materials and telephone follow-up counselling Abstinence at 12m (sustained at multiple follow ups) Validation: saliva cotinine Used in bupropion+NRT vs NRT comparison. 2 placebo & 3 bupropion deaths excluded from denominators Originally based on abstract, now uses published data and sustained quitting outcome.

Participants Interventions

Outcomes

Notes

Risk of bias Bias Authors judgement Support for judgement We assigned participants to the 2 study arms by using a computer algorithm to generate a random list of treatment assignments. Double-blind, but allocation concealment not explicit. Of the 244 participants enrolled, 3 (1%) were lost to follow-up (all randomized to the placebo arm)...Participants lost to follow-up were considered smokers.

Random sequence generation (selection Low risk bias)

Allocation concealment (selection bias)

Unclear risk

Incomplete outcome data (attrition bias) All outcomes

Low risk

Simon 2009 Methods BUPROPION Setting: VAMC hospital, USA Recruitment: hospitalised volunteers 83 inpatients smoking at least 5 CPD in previous year, smoking in week before admission, in contemplation or preparation stage of change; 1. Bupropion 300 mg for 7w 2. Placebo Both arms: Individual cognitive behavioural 30-60 min during hospital stay + 5 phone calls at w1, w3, w5, w8, w12, recycling encouraged.
77

Participants

Interventions

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Simon 2009

(Continued)

Outcomes

Abstinence at 6m, continuous at each assessment Validation: saliva cotinine <15 ng/ml New for 2009. 1 death in bupropion, 1 in placebo excluded from analyses

Notes Risk of bias Bias

Authors judgement

Support for judgement computer algorithm to generate a random list of treatment assignments. All study personnel engaged in providing interventions to participants were blinded to treatment assignment but not explicit that this included enrollment staff. 5 withdrawals, 1 lost to f-up, 1 death in placebo, 2 withdrawals, 1 lost, 1 death in bupropion. All except deaths included in MA

Random sequence generation (selection Low risk bias) Allocation concealment (selection bias) Unclear risk

Incomplete outcome data (attrition bias) All outcomes

Low risk

SMK20001 Methods BUPROPION Setting: 6 clinical trial centres, USA Recruitment: volunteers for phase II trial 286 smokers >=15 CPD, no prior use of bupropion 48% F, av age 42, av CPD NS 1. Bupropion 300 mg for 7w & placebo novel therapy 2. Double placebo No information about behavioural support Abstinence at 12m (continuous) Validation: CO <= 10 ppm Identied from GSK trials website. Also included a novel cessation aid

Participants

Interventions

Outcomes

Notes Risk of bias Bias

Authors judgement

Support for judgement Randomization method not specied.

Random sequence generation (selection Unclear risk bias)

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

78

SMK20001

(Continued)

Allocation concealment (selection bias) Incomplete outcome data (attrition bias) All outcomes Spring 2007 Methods

Unclear risk Low risk

Allocation concealment not described. 34% lost in bupropion, 29% placebo, included as smokers.

FLUOXETINE Setting: clinic, USA Recruitment: community volunteers 247 smokers, >= 10 CPD; 54% F, av. age 44, av. CPD 23, 44% history of MDD 1. Fluoxetine 60 mg (titrated up over 2 w) for 12 weeks 2. Placebo Both arms: group behavioural counselling, 9 meetings over 12 weeks Abstinence at 6m (prolonged from 2 w after quit date) Validation: CO < 10 ppm, urine cotinine < 20 ng/ml First included as Spring 2004 with unpublished data. Full publication reports sustained abstinence

Participants Interventions

Outcomes

Notes

Risk of bias Bias Authors judgement Support for judgement The study pharmacist stratied participants by depression history and used computer- generated random numbers to assign them to drug or placebo. Research staff and participants were blinded to medication status. Withdrawals/lost to follow-up 40% for uoxetine, 48% placebo. Authors report similar results from missing assumed smoking and GEE analyses. All participants included in MA.

Random sequence generation (selection Low risk bias)

Allocation concealment (selection bias)

Low risk

Incomplete outcome data (attrition bias) All outcomes

Low risk

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

79

Swan 2003 Methods BUPROPION Setting: HMO, USA Recruitment: volunteers from Group Health Co-op membership 1524 smokers >= 10 CPD; 57% F, av age 45, av CPD 23, 44% history of depression Factorial design crossing 2 drug doses with 2 intensities of behavioural counselling: Bupropion 300 mg/day versus 150 mg/day Free & Clear proactive telephone counselling (4 brief calls), access to quitline and S-H materials vs Zyban Advantage Program (ZAP) tailored S-H materials, single telephone call after TQD, access to Zyban support line Prescription was mailed. No face-to-face contact during enrolment or Rx Abstinence at 12m (7-day PP) Validation: none Based on published data from 2004 No dose/behavioural treatment interaction at 12m so arms collapsed to compare 300 vs 150 Effects differed at 3 and 12m. Effect of higher dose disappeared and additional support aided recycling.

Participants Interventions

Outcomes

Notes

Risk of bias Bias Authors judgement Support for judgement Open-label randomized trial...The computer code for the procedure calculated probabilities of group assignment that were dynamically modied based on the number of members in each group so that nal group sizes were equal. No restrictions such as stratication or blocking were used as part of the randomization process. Procedure built into study database. Nonresponders treated as smoking.

Random sequence generation (selection Low risk bias)

Allocation concealment (selection bias) Incomplete outcome data (attrition bias) All outcomes Tashkin 2001 Methods

Low risk Low risk

BUPROPION: Setting: multi-centre, USA Recruitment: advertisements for volunteers

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

80

Tashkin 2001

(Continued)

Participants

404 smokers with mild to moderate COPD. (Excludes 7 early drop-outs who did not take any study medication); 45% F, av. age 53-54, av. CPD 28, 18% in Bupropion group and 23% in Placebo had a history of depression. 1. Bupropion SR 300 mg/day for 12w from 1w before TQD 2. Placebo All participants had brief face-to-face counselling at each clinic visit (weeks 1-7, 10, 12) , telephone counselling 3 days after TQD Abstinence at 52w, sustained from w4 (unpublished data from GSK, Lancet paper reports 6m data) Validation: CO =< 10 ppm at each visit 12m unpublished data used from 2003/2. ITT population dened as those taking at least one dose of study medication.

Interventions

Outcomes

Notes

Risk of bias Bias Authors judgement Support for judgement Randomised as per code provided by Glaxo Wellcome, using block sizes of four stratied by centre. Within each block of four, two participants were assigned placebo and two bupropion SR. The randomisation codes were kept at the study sites during the trial and we instructed investigators to break the code only for a medical emergency. Double-blind study. Investigators did not know how the subjects were randomised. All participants who withdrew from the study were taken to be smokers thereafter.

Random sequence generation (selection Low risk bias)

Allocation concealment (selection bias)

Low risk

Incomplete outcome data (attrition bias) All outcomes

Low risk

Tonnesen 2003 Methods BUPROPION: Setting: 28 clinical trial centres in 8 European countries, Australia, NZ Recruitment: community volunteers 710 smokers >= 10 CPD; 51% F, av. age 42, median CPD 20, no details of depression history

Participants

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

81

Tonnesen 2003

(Continued)

Interventions

1. Bupropion SR 300 mg/day for 7w 2. Placebo Both arms: brief motivational support at weekly clinic visits and telephone support during follow up. 11 clinic visits and 10 phone calls scheduled. Abstinence at 52w (prolonged from w4) Validation: CO <= 10 ppm First included 2003 as Tonstad 2001. ITT population dened as those taking at least one dose of study medication excludes 3 randomized participants

Outcomes

Notes

Risk of bias Bias Authors judgement Support for judgement GlaxoSmithKline created a randomization schedule in a 3 : 1 bupropion: placebo ratio. Each centre received a list with treatment numbers and subjects were consecutively assigned a treatment number at the baseline visit. Double-blind; GlaxoSmithKline supplied bupropion SR 150 mg and placebo-tomatch tablets for oral administration as white, lm-coated tablets. 9% of bupropion SR and 12% placebo were lost to follow-up.

Random sequence generation (selection Low risk bias)

Allocation concealment (selection bias)

Low risk

Incomplete outcome data (attrition bias) All outcomes

Low risk

Tonstad 2003 Methods BUPROPION Setting: 28 clinical trial centres in 10 countries incl Europe, Australia, NZ Recruitment: volunteers with CVD 629 smokers with stable cardiovascular disease (CVD), >= 10 CPD; 23% F, av. age 55, av. CPD 25, 49% had history of MI, no details of depression history 1. Bupropion SR 300 mg/day for 7w, begun 1-2w before TQD 2. Placebo Both arms: brief motivational support at weekly clinic visits and telephone support during follow up. 9 clinic visits and 10 phone calls scheduled. Abstinence at 12m (prolonged from w4) Validation: CO <= 10 ppm
82

Participants

Interventions

Outcomes

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Tonstad 2003

(Continued)

Notes

First included 2003 as McRobbie 2003. ITT population = 626 dened as those taking at least one dose of study medication.

Risk of bias Bias Authors judgement Support for judgement Randomization method not described.

Random sequence generation (selection Unclear risk bias) Allocation concealment (selection bias) Unclear risk

Double-blind but allocation concealment method not described. Subjects with missing investigator assessments were assumed to be smokers at that visit.

Incomplete outcome data (attrition bias) All outcomes

Unclear risk

Uyar 2007 Methods BUPROPION Setting: cessation clinic, Turkey Recruitment: cessation clinic patients 131 smokers; 81% M, av. age 36 1. Bupropion 300mg for 7 weeks 2. Nicotine patch 21mg for 6 weeks incl tapering 3. Advice and follow up only All arms: Brief counselling on consequences of smoking with follow up for 24 weeksmore than low intensity Abstinence at 24w (not dened) Validation: CO < 10 ppm First included based on abstract. Contributes to bupropion vs control and bupropion vs nicotine patch

Participants Interventions

Outcomes

Notes

Risk of bias Bias Authors judgement Support for judgement Randomly allocated, method not described, unclear why fewer in control condition. Allocation concealment not described.

Random sequence generation (selection Unclear risk bias)

Allocation concealment (selection bias)

Unclear risk

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

83

Uyar 2007

(Continued)

Incomplete outcome data (attrition bias) All outcomes Wagena 2005 Methods

Unclear risk

No mention of any losses to f-up.

BUPROPION & NORTRIPTYLINE Setting: university medical centre, Netherlands Recruitment: community volunteers 255 smokers (>= 10 CPD) with or at risk of COPD; 51% F, av. age 51, av. CPD 23, 20% had possible depression, 7% previous use of bupropion 1. Bupropion SR 300 mg/day for 12w 2. Nortriptyline 75 mg/day for 12w 3. Placebo bupropion or placebo nortriptyline All arms: Individual counselling 10-20 mins at baseline, 1w & 3w post TQD (TQD typically day 11). Telephone support TQD, 2, 4, 6, 8, 11w. Abstinence at 26w (prolonged puff-free from w4) Validation: Urine cotinine <= 60 ng/ml at 4, 12 & 26w

Participants

Interventions

Outcomes

Notes Risk of bias Bias Authors judgement Support for judgement Computer-generated by pharmacist, stratied by COPD severity, block size 33. Research staff blinded throughout study. 10 (12%) bupropion, 13 (16%) nortriptyline, 12 (13%) lost or withdrawn. All included in ITT analysis.

Random sequence generation (selection Low risk bias) Allocation concealment (selection bias) Incomplete outcome data (attrition bias) All outcomes Low risk Low risk

Weinberger 2009 Methods SELEGILINE Setting: clinics, USA Recruitment: community volunteers 101 smokers (excludes 2 taking no medication), 50% F, av. age 47, av. CPD 22, 28% had history of MDD

Participants

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

84

Weinberger 2009

(Continued)

Interventions

1. Selegiline 10 mg/day for 9 weeks (5 mg/day in w1 & w9) 2. Placebo Both arms; brief weekly counselling Abstinence at 6m (7-day PP) Validation: CO & cotinine New for 2009 based on conference abstract

Outcomes

Notes Risk of bias Bias

Authors judgement

Support for judgement Randomization method not described.

Random sequence generation (selection Unclear risk bias) Allocation concealment (selection bias) Incomplete outcome data (attrition bias) All outcomes Unclear risk Unclear risk

No information in abstract. 27.5% selegiline, 42% placebo lost at 6 months. Including all participants is less conservative.

Zellweger 2005 Methods BUPROPION Setting: 26 clinical trial centres in 12 European countries Recruitment: volunteers, healthcare professionals (qualied practising physician or nurse) 667 smokers (>= 10 CPD) (excludes 1 centre enrolling 20 people, and 3 people who took no medication) 64% F, Av age 40, av CPD 23. 32% doctor, 68% nurse, no details of depression history 1. Bupropion SR 300 mg/day for 7w 2. Placebo Both arms: Brief (10-15 min) motivational support at weekly clinic visits and telephone support one day before TQD, 3 days after TQD, monthly during follow up Abstinence at 52w (prolonged from w4) Validation: CO <= 10 ppm Continuous abstinence rates and information on adverse events from GlaxoSmithKline data. One centre excluded

Participants

Interventions

Outcomes

Notes

Risk of bias Bias Authors judgement Support for judgement


85

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Zellweger 2005

(Continued)

Random sequence generation (selection Unclear risk bias) Allocation concealment (selection bias) Unclear risk

Randomization method not described.

Double-blind but allocation concealment method not described. Participants with missing assessments or drop-outs considered to be smoking.

Incomplete outcome data (attrition bias) All outcomes

Unclear risk

av: average AE: adverse event CBT: cognitive behavioural therapy CES-D: Center for Epidemiologic Studies Depression Scale CO: carbon monoxide (in exhaled breath) COPD: chronic obstructive pulmonary disease CPD: cigarettes per day CVD: cardiovascular disease EOT: end of treatment f-up: follow up F: female FTND: Fagerstrom Test for Nicotine Dependence FTQ: Fagerstrom Tolerance Questionnaire ITT: intention to treat m: month/s MA: meta-analysis MDD: Major depressive disorder MI: myocardial infarction NRT: nicotine replacement therapy NS: not stated P: Placebo PP: Point Prevalence abstinence RP: relapse prevention Rx: Treatment S-H: self-help TQD: Target quit date VAMC: Veterans Affairs Medical Center w: week/s

Characteristics of excluded studies [ordered by study ID]

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

86

Study Barnes 2006 Berlin 2002 Berlin 2005

Reason for exclusion St Johns Wort - pilot study comparing two doses of St Johns Wort, no quitters at 12 months. Lazabemide (monoamine oxidase-B inhibitor) - short follow up Beoxatone (reversible monoamine oxidase-B inhibitor) - data not published, treatment reported to have had no effect on abstinence rates. Tryptophan - short follow up Tryptophan 50 mg/kg/day, with high-carbohydrate low protein diet (7/1 ratio), vs placebo and low carbohydrate high protein diet (1/1 ratio) for two weeks. Selegiline - only preliminary short-term results available. Six month follow up planned Trial of practitioner education and nancial incentives, or cessation drug costs reimbursement Sertraline - combined with buspirone so effect of sertraline could not be isolated Bupropion - case control study in pregnant women Fluoxetine - Cessation not an outcome. Fluoxetine reduced the amount smoked by depressed alcoholic smokers. Fluoxetine - short-term outcome in a study of depressed alcoholic patients not attempting to quit. Fluoxetine - refers to but does not report on a cessation study. Bupropion - used for smokeless tobacco cessation not smoking cessation. Bupropion - for smokeless tobacco cessation, see Ebbert 2007 Doxepin - short follow up (2 months) Bupropion - only 12 week follow up reported to date. 17 teenage (14-19) smokers treated. Bupropion as adjunct to nicotine patch. Long-term results not published. Large loss to follow up at 12 months. Bupropion - long term results not presented due to high loss to follow-up Bupropion - short-term crossover trial Venlafaxine - short follow up (8 weeks) Buspirone - open trial. Bupropion - used for smokeless tobacco cessation not smoking cessation.

Bowen 1991

Brauer 2000 Breitling 2008 Carro 2007 Chan 2005 Cornelius 1997 Cornelius 1999 Dalack 1995 Dale 2002 Dale 2007 Edwards 1989 Elsasser 2002 Evins 2005b Evins 2008 Fatemi 2005 Frederick 1997 Gawin 1989 Glover 2002

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

87

(Continued)

Gold 2002 Hawk 2008 Hitsman 1999

Bupropion - non random assignment, patient preference Bupropion - short follow-up (12 weeks). Compares 1 week to 4 week prequit use. Fluoxetine - the majority of patients in this study were also part of the multi-centre trial reported in Niaura 2002. Selegiline - short term laboratory study Imipramine - short follow up. Outcome was reduction in smoking to less than 10% of baseline Bupropion - short follow up (12 weeks). Nortriptyline - pharmacotherapy was confounded with additional counselling from nurse (control group 1), compared to usual care St Johns Wort - uncontrolled study Bupropion - short follow up (8 weeks) Bupropion - participants were adolescent non smokers, not for cessation Bupropion - short follow-up, bupropion for opioid and tobacco dependence Fluoxetine - study of short-term smoking behaviour. Bupropion - smokers randomized to 1 or 2 months of medication (300 mg/day). 91/165 randomized were not included in the analysis, including some 1-month group participants who requested further medication. Bupropion - short-term follow up. Comparison of 300 mg and 150 mg doses Bupropion - short-term. 22 adolescents followed up during 90 days of treatment Bupropion - all participants received bupropion. Short-term follow up. Bupropion - uncontrolled prospective observational study. Fluoxetine - no cessation data reported. Bupropion - short (90 day) follow up. Sub-study within a larger trial with long-term follow up, not yet published. Buspirone - case series. Zimelidine or citalopram (SSRIs) - placebo-controlled crossover design study of smoking behaviour and alcohol use in non-depressed heavy drinkers. Bupropion - trial of NRT as adjunct to bupropion
88

Houtsmuller 2002 Jacobs 1971 Kalman 2004 Kotz 2009

Lawvere 2006 Miller 2003 Monuteaux 2007 Mooney 2008 Naranjo 1990 Neumann 2000

Neumann 2002 Niederhofer 2004 Olmstead 1999 Paluck 2006 Pomerleau 1991 Raynor 2005 Robinson 1991 Sellers 1987

Sherman 2008

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

(Continued)

Shiffman 2000

Bupropion - placebo-controlled short-term study of effects on craving and withdrawal in patients not wanting to quit smoking permanently. Trial of bupropion for methamphetamine dependence. Reduction in smoking was a secondary outcome. Only 48/73 participants smoked, quitting not reported. Nortriptyline - only 3-month follow-up Fluoxetine - 6-month cessation not reported. Primarily a study of post-cessation weight gain. Fluoxetine - does not report outcomes from a double-blind study. Bupropion - confounded with nicotine inhaler and treatment duration in comparison with nicotine patch alone Bupropion - all participants prescribed bupropion. Test of behavioural interventions, not bupropion. Adverse event data from author used. Bupropion +/- nicotine patch. Unable to conrm correct denominators. Bupropion - laboratory study, outcomes included urge to smoke, not cessation Bupropion - all participants had same pharmacotherapy Bupropion for people with bipolar disorder. Short follow-up (8 weeks). Only 5 participants. Bupropion - no control group. Bupropion versus gabapentin - Short follow up (6 weeks). Bupropion - used as an active control to a psychosocial intervention, cannot estimate pharmacotherapy effect. Bupropion - only follow up to end of treatment (7 weeks).

Shoptaw 2008

Sittipunt 2007 Spring 1995 Stein 1993 Steinberg 2009 Strayer 2004

Swanson 2003 Tidey 2009 Toll 2007 Weinberger 2008 Weiner 2001 White 2005 Zernig 2008 ZYB30011 2002

Characteristics of ongoing studies [ordered by study ID]


Brown 2007b Trial name or title Methods Participants Interventions Sequential use of uoxetine for smokers with elevated depressive symptoms Randomized, Double Blind (Subject, Investigator), Parallel Assignment, Efcacy Study Regular smokers with elevated depressive symptoms Fluoxetine 20mg , begun 8 weeks prior to and extended throughout brief (behavioral) standard smoking cessation treatment with transdermal nicotine patch vs placebo

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

89

Brown 2007b

(Continued)

Outcomes Starting date Contact information Notes

Biochemically validated abstinence at 1 year April 2008 richardbrown@brown.edu ClinicalTrials.gov identier: NCT00578669

Glover (NCT00439413) Trial name or title Methods Participants Interventions Outcomes Starting date Contact information Notes Selegiline for smoking cessation Randomized, double blind, placebo control, phase II 246 smokers of over 15 CPD, motivated to quit Transdermal selegiline or placebo Smoking cessation at 26 weeks June 2007 Elbert Glover/ NIDA Record accessed 4th August 2009, last updated January 26 2009

Kalman (NCT00304707) Trial name or title Methods Bupropion treatment for smokers in recovery Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Factorial Assignment, Efcacy Study 236 smokers Bupropion or placebo for 8 weeks as adjunct to 7 weeks nicotine patch & counselling Smoking cessation at 24 weeks April 2005 david.kalman@va.gov Record accessed 4th August 2009, last updated February 18 2009

Participants Interventions Outcomes Starting date Contact information Notes

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

90

Killen (NCT00218647) Trial name or title Methods Participants Interventions Outcomes Starting date Contact information Notes Effectiveness of the selegiline patch in treating nicotine dependent individuals Randomized, double blind, placebo control, phase II 230 smokers of over 20 CPD Selegiline transdermal patch 20 mg/day or placebo Smoking cessation at 52 weeks July 2005 Joel Killen, Stanford University Record accessed 4th August 2009, last updated July 9 2008

Le Foll (NCT00390923) Trial name or title Methods Participants Interventions Outcomes Starting date Contact information Notes Testing a full substitution therapy approach as treatment of tobacco dependence Randomized, double blind, placebo control 40 smokers of at least 15 CPD Selegiline 10 mg/day for 8 weeks Smoking cessation at six months July 2007 Bernard Le Foll, Centre for Addiction and Mental Health, Toronto Record accessed 4th August 2009, last updated November 4 2008

Sood (NCT00405912) Trial name or title Methods Participants Interventions St. Johns Wort for tobacco cessation Randomized, Double-Blind, Placebo Control, Parallel Assignment, Safety/Efcacy Study 120 smokers 12-week course of St Johns Wort in two different oral doses of 300 mg or 600 mg three times a day compared to placebo Abstinence at end of treatment (primary) and at 6 months (2ndry)
91

Outcomes

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Sood (NCT00405912)

(Continued)

Starting date Contact information Notes

September 2005 Amit Sood, Mayo Clinic Trial completed but not yet published

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

92

DATA AND ANALYSES

Comparison 1. Bupropion. Abstinence at 6m or greater follow-up

Outcome or subgroup title 1 Bupropion versus placebo/control. Subgroups by length of follow-up 1.1 Twelve month follow-up 1.2 Six month follow-up 2 Bupropion versus placebo/control. Subgroups by clinical/recruitment setting 2.1 Community volunteers 2.2 People recruited from health care settings 2.3 Health care professionals/ hospital staff 2.4 People with a previously unsuccessful quit attempt using bupropion 3 Bupropion versus placebo. Subgroups by level of behavioural support 3.1 Multisession group behavioural support 3.2 Multisession individual counselling 3.3 Low intensity support 4 Bupropion dose response. 300 mg/day versus 150 mg/day 5 Bupropion and NRT versus NRT alone 6 Bupropion for relapse prevention 7 Bupropion versus nicotine patch 8 Bupropion versus varenicline 9 Bupropion for harm reduction 9.1 Reduction in cotinine >50% from baseline at 1y 9.2 Cessation at 6m 10 Bupropion adverse events. No report =no information, None occurred =explicit statement

No. of studies 36

No. of participants 11440

Statistical method Risk Ratio (M-H, Fixed, 95% CI)

Effect size 1.69 [1.53, 1.85]

22 14 36

8628 2812 11440

Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)

1.64 [1.46, 1.84] 1.81 [1.51, 2.16] 1.69 [1.53, 1.85]

18 14 2 2

6663 3041 1002 734

Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)

1.66 [1.47, 1.87] 1.86 [1.53, 2.25] 1.32 [0.98, 1.78] 2.25 [1.29, 3.90]

33

10724

Risk Ratio (M-H, Fixed, 95% CI)

1.70 [1.54, 1.88]

8 24 1 3 6 5 3 3 1 1 1

1574 9103 47 2042 1106 1587 657 1622

Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Other data

1.62 [1.30, 2.03] 1.72 [1.54, 1.91] 2.88 [0.32, 25.68] 1.08 [0.93, 1.26] 1.23 [0.67, 2.26] 1.17 [0.99, 1.39] 1.26 [0.73, 2.18] 0.66 [0.53, 0.82] Totals not selected 0.0 [0.0, 0.0] 0.0 [0.0, 0.0] No numeric data

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

93

Comparison 2. Nortriptyline

Outcome or subgroup title 1 Long term abstinence (6-12m) 1.1 Nortriptyline versus placebo. No other pharmacotherapy 1.2 Nortriptyline and NRT versus NRT alone 2 Nortriptyline vs placebo adverse events. No report =no information, None occurred =explicit statement

No. of studies 10 6

No. of participants

Statistical method Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)

Effect size Subtotals only 2.03 [1.48, 2.78]

975

1219

Risk Ratio (M-H, Fixed, 95% CI) Other data

1.29 [0.97, 1.72] No numeric data

Comparison 3. Bupropion versus nortriptyline

Outcome or subgroup title 1 Long term abstinence

No. of studies 3

No. of participants 417

Statistical method Risk Ratio (M-H, Fixed, 95% CI)

Effect size 1.30 [0.93, 1.82]

Comparison 4. Selective Serotonin Reuptake Inhibitors (SSRIs) versus placebo

Outcome or subgroup title 1 Fluoxetine. Long term abstinence 1.1 Fluoxetine versus placebo 1.2 Fluoxetine & NRT versus placebo and NRT 2 Paroxetine. Long term abstinence 3 Sertraline. Long term abstinence

No. of studies 4 2 2 1 1

No. of participants 1486 1236 250 224 134

Statistical method Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)

Effect size 0.92 [0.68, 1.24] 0.92 [0.65, 1.30] 0.92 [0.53, 1.61] 1.08 [0.64, 1.82] 0.71 [0.30, 1.64]

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

94

Comparison 5. Monoamine oxidase inhibitors (MAOIs) versus placebo

Outcome or subgroup title 1 Long term abstinence 1.1 Moclobemide versus placebo 1.2 Selegiline versus placebo

No. of studies 4 1 3

No. of participants 338 88 250

Statistical method Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)

Effect size 1.49 [0.92, 2.41] 1.57 [0.67, 3.68] 1.45 [0.81, 2.61]

Comparison 6. Venlafaxine versus placebo

Outcome or subgroup title 1 Long term abstinence

No. of studies 1

No. of participants

Statistical method Risk Ratio (M-H, Fixed, 95% CI)

Effect size Subtotals only

Analysis 1.1. Comparison 1 Bupropion. Abstinence at 6m or greater follow-up, Outcome 1 Bupropion versus placebo/control. Subgroups by length of follow-up.
Review: Antidepressants for smoking cessation

Comparison: 1 Bupropion. Abstinence at 6m or greater follow-up Outcome: 1 Bupropion versus placebo/control. Subgroups by length of follow-up

Study or subgroup

Treatment n/N

Control n/N

Risk Ratio M-H,Fixed,95% CI

Weight

Risk Ratio M-H,Fixed,95% CI

1 Twelve month follow-up Brown 2007 Ferry 1992 Ferry 1994 Fossati 2007 Gonzales 2001 Gonzales 2006 Hall 2002 Holt 2005 38/255 10/23 13/95 101/400 20/226 53/329 13/73 19/88 27/269 0/22 6/95 26/193 5/224 29/344 7/73 5/46
0.1 0.2 0.5 1 2 5 10

4.4 % 0.1 % 1.0 % 5.9 % 0.8 % 4.8 % 1.2 % 1.1 %

1.48 [ 0.93, 2.36 ] 20.13 [ 1.25, 324.00 ] 2.17 [ 0.86, 5.46 ] 1.87 [ 1.26, 2.78 ] 3.96 [ 1.51, 10.38 ] 1.91 [ 1.25, 2.93 ] 1.86 [ 0.79, 4.39 ] 1.99 [ 0.79, 4.98 ]

Favour control

Favours treatment

(Continued . . . )
Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 95

(. . .
Study or subgroup Treatment n/N Hurt 1997 Jorenby 1999 Jorenby 2006 McCarthy 2008 Nides 2006 Piper 2007 Rigotti 2006 Schmitz 2007 Selby 2003 SMK20001 Tashkin 2001 Tonnesen 2003 Tonstad 2003 Zellweger 2005 21/156 45/244 50/342 48/229 8/128 42/224 25/124 7/78 18/141 26/143 21/204 111/527 68/313 117/501 Control n/N 15/153 9/160 35/341 32/234 6/127 21/156 17/127 13/76 12/143 20/143 17/200 20/180 29/313 36/166 Risk Ratio M-H,Fixed,95% CI 2.6 % 1.8 % 5.9 % 5.4 % 1.0 % 4.2 % 2.8 % 2.2 % 2.0 % 3.4 % 2.9 % 5.0 % 4.9 % 9.1 % Weight

Continued) Risk Ratio

M-H,Fixed,95% CI 1.37 [ 0.74, 2.56 ] 3.28 [ 1.65, 6.52 ] 1.42 [ 0.95, 2.14 ] 1.53 [ 1.02, 2.31 ] 1.32 [ 0.47, 3.70 ] 1.39 [ 0.86, 2.26 ] 1.51 [ 0.86, 2.65 ] 0.52 [ 0.22, 1.24 ] 1.52 [ 0.76, 3.04 ] 1.30 [ 0.76, 2.22 ] 1.21 [ 0.66, 2.23 ] 1.90 [ 1.21, 2.96 ] 2.34 [ 1.56, 3.52 ] 1.08 [ 0.77, 1.50 ]

Subtotal (95% CI)

4843

3785

72.7 %

1.64 [ 1.46, 1.84 ]

Total events: 874 (Treatment), 387 (Control) Heterogeneity: Chi2 = 31.61, df = 21 (P = 0.06); I2 =34% Test for overall effect: Z = 8.56 (P < 0.00001) 2 Six month follow-up Ahluwalia 2002 Aubin 2004 Collins 2004 Dalsgar 2004 Evins 2001 Evins 2005 George 2002 Haggstrm 2006 Hertzberg 2001 Muramoto 2007 Myles 2004 Simon 2009 Uyar 2007 Wagena 2005 37/300 85/340 93/285 40/221 1/9 1/27 3/16 22/53 3/10 9/104 3/24 6/41 13/50 24/86 19/300 21/164 52/270 8/114 0/9 1/29 1/16 11/51 1/5 6/103 1/23 9/42 5/31 13/89
0.1 0.2 0.5 1 2 5 10

3.2 % 4.8 % 9.0 % 1.8 % 0.1 % 0.2 % 0.2 % 1.9 % 0.2 % 1.0 % 0.2 % 1.5 % 1.0 % 2.2 %

1.95 [ 1.15, 3.31 ] 1.95 [ 1.26, 3.03 ] 1.69 [ 1.26, 2.28 ] 2.58 [ 1.25, 5.32 ] 3.00 [ 0.14, 65.16 ] 1.07 [ 0.07, 16.33 ] 3.00 [ 0.35, 25.87 ] 1.92 [ 1.04, 3.55 ] 1.50 [ 0.20, 11.00 ] 1.49 [ 0.55, 4.02 ] 2.88 [ 0.32, 25.68 ] 0.68 [ 0.27, 1.75 ] 1.61 [ 0.64, 4.08 ] 1.91 [ 1.04, 3.50 ]

Favour control

Favours treatment

(Continued . . . )
Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 96

(. . .
Study or subgroup Treatment n/N Control n/N Risk Ratio M-H,Fixed,95% CI Weight

Continued) Risk Ratio

M-H,Fixed,95% CI

Subtotal (95% CI)

1566

1246

27.3 %

1.81 [ 1.51, 2.16 ]

Total events: 340 (Treatment), 148 (Control) Heterogeneity: Chi2 = 6.37, df = 13 (P = 0.93); I2 =0.0% Test for overall effect: Z = 6.53 (P < 0.00001)

Total (95% CI)

6409

5031

100.0 %

1.69 [ 1.53, 1.85 ]

Total events: 1214 (Treatment), 535 (Control) Heterogeneity: Chi2 = 39.12, df = 35 (P = 0.29); I2 =11% Test for overall effect: Z = 10.72 (P < 0.00001) Test for subgroup differences: Chi2 = 0.83, df = 1 (P = 0.36), I2 =0.0%

0.1 0.2

0.5

10

Favour control

Favours treatment

Analysis 1.2. Comparison 1 Bupropion. Abstinence at 6m or greater follow-up, Outcome 2 Bupropion versus placebo/control. Subgroups by clinical/recruitment setting.
Review: Antidepressants for smoking cessation

Comparison: 1 Bupropion. Abstinence at 6m or greater follow-up Outcome: 2 Bupropion versus placebo/control. Subgroups by clinical/recruitment setting

Study or subgroup

Treatment n/N

Control n/N

Risk Ratio M-H,Fixed,95% CI

Weight

Risk Ratio M-H,Fixed,95% CI

1 Community volunteers Aubin 2004 Brown 2007 Collins 2004 Gonzales 2006 Haggstrm 2006 Hall 2002 Holt 2005 Hurt 1997 Jorenby 1999 Jorenby 2006 85/340 38/255 93/285 53/329 22/53 13/73 19/88 21/156 45/244 50/342 21/164 27/269 52/270 29/344 11/51 7/73 5/46 15/153 9/160 35/341
0.1 0.2 0.5 1 2 5 10

4.8 % 4.4 % 9.0 % 4.8 % 1.9 % 1.2 % 1.1 % 2.6 % 1.8 % 5.9 %

1.95 [ 1.26, 3.03 ] 1.48 [ 0.93, 2.36 ] 1.69 [ 1.26, 2.28 ] 1.91 [ 1.25, 2.93 ] 1.92 [ 1.04, 3.55 ] 1.86 [ 0.79, 4.39 ] 1.99 [ 0.79, 4.98 ] 1.37 [ 0.74, 2.56 ] 3.28 [ 1.65, 6.52 ] 1.42 [ 0.95, 2.14 ]

Favours control

Favours treatment

(Continued . . . )

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

97

(. . .
Study or subgroup Treatment n/N McCarthy 2008 Muramoto 2007 Nides 2006 Piper 2007 Schmitz 2007 SMK20001 Tonnesen 2003 Wagena 2005 48/229 9/104 8/128 42/224 7/78 26/143 111/527 24/86 Control n/N 32/234 6/103 6/127 21/156 13/76 20/143 20/180 13/89 Risk Ratio M-H,Fixed,95% CI 5.4 % 1.0 % 1.0 % 4.2 % 2.2 % 3.4 % 5.0 % 2.2 % Weight

Continued) Risk Ratio

M-H,Fixed,95% CI 1.53 [ 1.02, 2.31 ] 1.49 [ 0.55, 4.02 ] 1.32 [ 0.47, 3.70 ] 1.39 [ 0.86, 2.26 ] 0.52 [ 0.22, 1.24 ] 1.30 [ 0.76, 2.22 ] 1.90 [ 1.21, 2.96 ] 1.91 [ 1.04, 3.50 ]

Subtotal (95% CI)

3684

2979

62.0 %

1.66 [ 1.47, 1.87 ]

Total events: 714 (Treatment), 342 (Control) Heterogeneity: Chi2 = 15.36, df = 17 (P = 0.57); I2 =0.0% Test for overall effect: Z = 8.15 (P < 0.00001) 2 People recruited from health care settings Ahluwalia 2002 Evins 2001 Evins 2005 Ferry 1992 Ferry 1994 Fossati 2007 George 2002 Hertzberg 2001 Myles 2004 Rigotti 2006 Simon 2009 Tashkin 2001 Tonstad 2003 Uyar 2007 37/300 1/9 1/27 10/23 13/95 101/400 3/16 3/10 3/24 25/124 6/41 21/204 68/313 13/50 19/300 0/9 1/29 0/22 6/95 26/193 1/16 1/5 1/23 17/127 9/42 17/200 29/313 5/31 3.2 % 0.1 % 0.2 % 0.1 % 1.0 % 5.9 % 0.2 % 0.2 % 0.2 % 2.8 % 1.5 % 2.9 % 4.9 % 1.0 % 1.95 [ 1.15, 3.31 ] 3.00 [ 0.14, 65.16 ] 1.07 [ 0.07, 16.33 ] 20.13 [ 1.25, 324.00 ] 2.17 [ 0.86, 5.46 ] 1.87 [ 1.26, 2.78 ] 3.00 [ 0.35, 25.87 ] 1.50 [ 0.20, 11.00 ] 2.88 [ 0.32, 25.68 ] 1.51 [ 0.86, 2.65 ] 0.68 [ 0.27, 1.75 ] 1.21 [ 0.66, 2.23 ] 2.34 [ 1.56, 3.52 ] 1.61 [ 0.64, 4.08 ]

Subtotal (95% CI)

1636

1405

24.3 %

1.86 [ 1.53, 2.25 ]

Total events: 305 (Treatment), 132 (Control) Heterogeneity: Chi2 = 11.75, df = 13 (P = 0.55); I2 =0.0% Test for overall effect: Z = 6.33 (P < 0.00001) 3 Health care professionals/ hospital staff Dalsgar 2004 Zellweger 2005 40/221 117/501 8/114 36/166
0.1 0.2 0.5 1 2 5 10

1.8 % 9.1 %

2.58 [ 1.25, 5.32 ] 1.08 [ 0.77, 1.50 ]

Favours control

Favours treatment

(Continued . . . )

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

98

(. . .
Study or subgroup Treatment n/N Control n/N Risk Ratio M-H,Fixed,95% CI Weight

Continued) Risk Ratio

M-H,Fixed,95% CI

Subtotal (95% CI)

722

280

10.9 %

1.32 [ 0.98, 1.78 ]

Total events: 157 (Treatment), 44 (Control) Heterogeneity: Chi2 = 4.75, df = 1 (P = 0.03); I2 =79% Test for overall effect: Z = 1.83 (P = 0.067) 4 People with a previously unsuccessful quit attempt using bupropion Gonzales 2001 Selby 2003 20/226 18/141 5/224 12/143 0.8 % 2.0 % 3.96 [ 1.51, 10.38 ] 1.52 [ 0.76, 3.04 ]

Subtotal (95% CI)

367

367

2.9 %

2.25 [ 1.29, 3.90 ]

Total events: 38 (Treatment), 17 (Control) Heterogeneity: Chi2 = 2.56, df = 1 (P = 0.11); I2 =61% Test for overall effect: Z = 2.87 (P = 0.0041)

Total (95% CI)

6409

5031

100.0 %

1.69 [ 1.53, 1.85 ]

Total events: 1214 (Treatment), 535 (Control) Heterogeneity: Chi2 = 39.12, df = 35 (P = 0.29); I2 =11% Test for overall effect: Z = 10.72 (P < 0.00001) Test for subgroup differences: Chi2 = 4.65, df = 3 (P = 0.20), I2 =35%

0.1 0.2

0.5

10

Favours control

Favours treatment

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

99

Analysis 1.3. Comparison 1 Bupropion. Abstinence at 6m or greater follow-up, Outcome 3 Bupropion versus placebo. Subgroups by level of behavioural support.
Review: Antidepressants for smoking cessation

Comparison: 1 Bupropion. Abstinence at 6m or greater follow-up Outcome: 3 Bupropion versus placebo. Subgroups by level of behavioural support

Study or subgroup

Treatment n/N

Control n/N

Risk Ratio M-H,Fixed,95% CI

Weight

Risk Ratio M-H,Fixed,95% CI

1 Multisession group behavioural support Brown 2007 Collins 2004 Evins 2001 Evins 2005 Ferry 1992 Ferry 1994 George 2002 Schmitz 2007 38/255 93/285 1/9 1/27 10/23 13/95 3/16 7/78 27/269 52/270 0/9 1/29 0/22 6/95 1/16 13/76 4.8 % 9.7 % 0.1 % 0.2 % 0.1 % 1.1 % 0.2 % 2.4 % 1.48 [ 0.93, 2.36 ] 1.69 [ 1.26, 2.28 ] 3.00 [ 0.14, 65.16 ] 1.07 [ 0.07, 16.33 ] 20.13 [ 1.25, 324.00 ] 2.17 [ 0.86, 5.46 ] 3.00 [ 0.35, 25.87 ] 0.52 [ 0.22, 1.24 ]

Subtotal (95% CI)

788

786

18.4 %

1.62 [ 1.30, 2.03 ]

Total events: 166 (Treatment), 100 (Control) Heterogeneity: Chi2 = 10.89, df = 7 (P = 0.14); I2 =36% Test for overall effect: Z = 4.23 (P = 0.000023) 2 Multisession individual counselling Ahluwalia 2002 Aubin 2004 Dalsgar 2004 Fossati 2007 Gonzales 2001 Gonzales 2006 Haggstrm 2006 Hertzberg 2001 Holt 2005 Hurt 1997 Jorenby 1999 Jorenby 2006 McCarthy 2008 37/300 85/340 40/221 101/400 20/226 53/329 22/53 3/10 19/88 21/156 45/244 50/342 24/116 19/300 21/164 8/114 26/193 5/224 29/344 11/51 1/5 5/46 15/153 9/160 35/341 17/113
0.1 0.2 0.5 1 2 5 10

3.4 % 5.1 % 1.9 % 6.3 % 0.9 % 5.1 % 2.0 % 0.2 % 1.2 % 2.7 % 2.0 % 6.3 % 3.1 %

1.95 [ 1.15, 3.31 ] 1.95 [ 1.26, 3.03 ] 2.58 [ 1.25, 5.32 ] 1.87 [ 1.26, 2.78 ] 3.96 [ 1.51, 10.38 ] 1.91 [ 1.25, 2.93 ] 1.92 [ 1.04, 3.55 ] 1.50 [ 0.20, 11.00 ] 1.99 [ 0.79, 4.98 ] 1.37 [ 0.74, 2.56 ] 3.28 [ 1.65, 6.52 ] 1.42 [ 0.95, 2.14 ] 1.38 [ 0.78, 2.42 ]

Favour control

Favours treatment

(Continued . . . )

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

100

(. . .
Study or subgroup Treatment n/N McCarthy 2008 Muramoto 2007 Nides 2006 Piper 2007 Rigotti 2006 Simon 2009 Tashkin 2001 Tonnesen 2003 Tonstad 2003 Uyar 2007 Wagena 2005 Zellweger 2005 24/113 9/104 8/128 42/224 25/124 6/41 21/204 111/527 68/313 13/50 24/86 117/501 Control n/N 15/121 6/103 6/127 21/156 17/127 9/42 17/200 20/180 29/313 5/31 13/89 36/166 Risk Ratio M-H,Fixed,95% CI 2.6 % 1.1 % 1.1 % 4.5 % 3.0 % 1.6 % 3.1 % 5.4 % 5.2 % 1.1 % 2.3 % 9.8 % Weight

Continued) Risk Ratio

M-H,Fixed,95% CI 1.71 [ 0.95, 3.10 ] 1.49 [ 0.55, 4.02 ] 1.32 [ 0.47, 3.70 ] 1.39 [ 0.86, 2.26 ] 1.51 [ 0.86, 2.65 ] 0.68 [ 0.27, 1.75 ] 1.21 [ 0.66, 2.23 ] 1.90 [ 1.21, 2.96 ] 2.34 [ 1.56, 3.52 ] 1.61 [ 0.64, 4.08 ] 1.91 [ 1.04, 3.50 ] 1.08 [ 0.77, 1.50 ]

Subtotal (95% CI)

5240

3863

81.4 %

1.72 [ 1.54, 1.91 ]

Total events: 988 (Treatment), 395 (Control) Heterogeneity: Chi2 = 27.14, df = 24 (P = 0.30); I2 =12% Test for overall effect: Z = 9.62 (P < 0.00001) 3 Low intensity support Myles 2004 3/24 1/23 0.2 % 2.88 [ 0.32, 25.68 ]

Subtotal (95% CI)


Total events: 3 (Treatment), 1 (Control) Heterogeneity: not applicable Test for overall effect: Z = 0.95 (P = 0.34)

24

23

0.2 %

2.88 [ 0.32, 25.68 ]

Total (95% CI)

6052

4672

100.0 %

1.70 [ 1.54, 1.88 ]

Total events: 1157 (Treatment), 496 (Control) Heterogeneity: Chi2 = 38.53, df = 33 (P = 0.23); I2 =14% Test for overall effect: Z = 10.55 (P < 0.00001) Test for subgroup differences: Chi2 = 0.41, df = 2 (P = 0.81), I2 =0.0%

0.1 0.2

0.5

10

Favour control

Favours treatment

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

101

Analysis 1.4. Comparison 1 Bupropion. Abstinence at 6m or greater follow-up, Outcome 4 Bupropion dose response. 300 mg/day versus 150 mg/day.
Review: Antidepressants for smoking cessation

Comparison: 1 Bupropion. Abstinence at 6m or greater follow-up Outcome: 4 Bupropion dose response. 300 mg/day versus 150 mg/day

Study or subgroup

300 mg/day bupropion n/N

150 mg/day bupropion n/N 23/153 2/105 210/763

Risk Ratio M-H,Fixed,95% CI

Weight

Risk Ratio M-H,Fixed,95% CI

Hurt 1997 Muramoto 2007 Swan 2003

21/156 9/104 224/761

9.9 % 0.8 % 89.3 %

0.90 [ 0.52, 1.55 ] 4.54 [ 1.01, 20.52 ] 1.07 [ 0.91, 1.25 ]

Total (95% CI)

1021

1021

100.0 %

1.08 [ 0.93, 1.26 ]

Total events: 254 (300 mg/day bupropion), 235 (150 mg/day bupropion) Heterogeneity: Chi2 = 3.96, df = 2 (P = 0.14); I2 =49% Test for overall effect: Z = 1.01 (P = 0.31)

0.1 0.2

0.5

10

Favours 150mg dose

Favours 300mg dose

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

102

Analysis 1.5. Comparison 1 Bupropion. Abstinence at 6m or greater follow-up, Outcome 5 Bupropion and NRT versus NRT alone.
Review: Antidepressants for smoking cessation

Comparison: 1 Bupropion. Abstinence at 6m or greater follow-up Outcome: 5 Bupropion and NRT versus NRT alone

Study or subgroup

Treatment n/N

Control n/N 2/26 0/29 8/28 24/244 8/108 23/120

Risk Ratio M-H,Random,95% CI

Weight

Risk Ratio M-H,Random,95% CI

Evins 2007 George 2008 Grant 2007 Jorenby 1999 Killen 2004 Simon 2004

3/25 4/29 5/30 55/245 8/103 18/119

9.1 % 3.9 % 17.2 % 26.9 % 18.0 % 24.8 %

1.56 [ 0.28, 8.56 ] 9.00 [ 0.51, 159.94 ] 0.58 [ 0.22, 1.57 ] 2.28 [ 1.46, 3.56 ] 1.05 [ 0.41, 2.69 ] 0.79 [ 0.45, 1.38 ]

Total (95% CI)

551

555

100.0 %

1.23 [ 0.67, 2.26 ]

Total events: 93 (Treatment), 65 (Control) Heterogeneity: Tau2 = 0.31; Chi2 = 13.66, df = 5 (P = 0.02); I2 =63% Test for overall effect: Z = 0.66 (P = 0.51)

0.1 0.2

0.5

10

Favours control

Favours treatment

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

103

Analysis 1.6. Comparison 1 Bupropion. Abstinence at 6m or greater follow-up, Outcome 6 Bupropion for relapse prevention.
Review: Antidepressants for smoking cessation

Comparison: 1 Bupropion. Abstinence at 6m or greater follow-up Outcome: 6 Bupropion for relapse prevention

Study or subgroup

Treatment n/N

Control n/N 32/143 40/164 56/215 13/88 43/181

Risk Ratio M-H,Fixed,95% CI

Weight

Risk Ratio M-H,Fixed,95% CI

Covey 2007 Croghan 2007 Hays 2001 Hurt 2003 Killen 2006

45/146 40/167 62/214 19/88 51/181

17.5 % 21.9 % 30.3 % 7.0 % 23.3 %

1.38 [ 0.93, 2.03 ] 0.98 [ 0.67, 1.44 ] 1.11 [ 0.82, 1.51 ] 1.46 [ 0.77, 2.77 ] 1.19 [ 0.84, 1.68 ]

Total (95% CI)

796

791

100.0 %

1.17 [ 0.99, 1.39 ]

Total events: 217 (Treatment), 184 (Control) Heterogeneity: Chi2 = 2.05, df = 4 (P = 0.73); I2 =0.0% Test for overall effect: Z = 1.83 (P = 0.067)

0.1 0.2

0.5

10

Favours control

Favours treatment

Analysis 1.7. Comparison 1 Bupropion. Abstinence at 6m or greater follow-up, Outcome 7 Bupropion versus nicotine patch.
Review: Antidepressants for smoking cessation

Comparison: 1 Bupropion. Abstinence at 6m or greater follow-up Outcome: 7 Bupropion versus nicotine patch

Study or subgroup

Bupropion n/N

NRT n/N 8/38 24/244 13/50

Risk Ratio M-H,Random,95% CI

Weight

Risk Ratio M-H,Random,95% CI

Grecka 2003 Jorenby 1999 Uyar 2007

5/31 45/244 13/50

20.3 % 45.7 % 34.0 %

0.77 [ 0.28, 2.11 ] 1.88 [ 1.18, 2.98 ] 1.00 [ 0.52, 1.94 ]

Total (95% CI)

325

332

100.0 %

1.26 [ 0.73, 2.18 ]

Total events: 63 (Bupropion), 45 (NRT) Heterogeneity: Tau2 = 0.11; Chi2 = 3.91, df = 2 (P = 0.14); I2 =49% Test for overall effect: Z = 0.84 (P = 0.40)

0.1 0.2

0.5

10

Favour NRT

Favours bupropion

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

104

Analysis 1.8. Comparison 1 Bupropion. Abstinence at 6m or greater follow-up, Outcome 8 Bupropion versus varenicline.
Review: Antidepressants for smoking cessation

Comparison: 1 Bupropion. Abstinence at 6m or greater follow-up Outcome: 8 Bupropion versus varenicline

Study or subgroup

Treatment n/N

Control n/N 77/352 79/344 18/127

Risk Ratio M-H,Fixed,95% CI

Weight

Risk Ratio M-H,Fixed,95% CI

Gonzales 2006 Jorenby 2006 Nides 2006

53/329 50/342 8/128

43.4 % 46.0 % 10.6 %

0.74 [ 0.54, 1.01 ] 0.64 [ 0.46, 0.88 ] 0.44 [ 0.20, 0.98 ]

Total (95% CI)

799

823

100.0 %

0.66 [ 0.53, 0.82 ]

Total events: 111 (Treatment), 174 (Control) Heterogeneity: Chi2 = 1.50, df = 2 (P = 0.47); I2 =0.0% Test for overall effect: Z = 3.77 (P = 0.00016)

0.1 0.2

0.5

10

Favours control

Favours treatment

Analysis 1.9. Comparison 1 Bupropion. Abstinence at 6m or greater follow-up, Outcome 9 Bupropion for harm reduction.
Review: Antidepressants for smoking cessation

Comparison: 1 Bupropion. Abstinence at 6m or greater follow-up Outcome: 9 Bupropion for harm reduction

Study or subgroup

Treatment n/N

Control n/N

Risk Ratio M-H,Fixed,95% CI

Risk Ratio M-H,Fixed,95% CI

1 Reduction in cotinine >50% from baseline at 1y Hatsukami 2004 2 Cessation at 6m Hatsukami 2004 20/295 16/299 1.27 [ 0.67, 2.40 ] 3/153 8/174 0.43 [ 0.12, 1.58 ]

0.1 0.2

0.5

10

Favours control

Favours treatment

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

105

Analysis 1.10. Comparison 1 Bupropion. Abstinence at 6m or greater follow-up, Outcome 10 Bupropion adverse events. No report =no information, None occurred =explicit statement. Bupropion adverse events. No report =no information, None occurred =explicit statement

Study Ahluwalia 2002

Serious events No seizures occurred No serious adverse events reported.

Other adverse events

Withdrawal due to AE

Insomnia (29.3 vs 20.7%) more No information common with bupropion. Dry mouth (28% vs 24%) 61% on bupropion and 45% on 10% bupropion & 5% placebo placebo experienced at least one AE withdrew due to AEs Sleep disorder 33% bupropion vs 19% placebo

Aubin 2004

No seizures occurred 5 bupropion and 1 placebo serious AE during treatment, 2 bupropion during f-up. 1 chest pain, tremor & sweating & 1 depressive syndrome after end of treatment considered possibly due to bupropion. Not reported in paper

Collins 2004 Covey 2007

Not reported in paper

Not reported in paper

One seizure during open label phase The number of reported side effects None reported (before randomization to relapse (e.g. nervousness, constipation, insomnia, stomachprevention) ache, depressed mood) was low (mean = 0.43, SD = 0.91), and did not vary by treatment group (P = 0.69) No seizures occurred No serious adverse event during treatment phase. 3 events during follow-up not considered to be drug related including 1 death in bupropion group, No seizures occurred Insomnia (28% vs 18%), dizziness 12% bupropion & 8% placebo (8% vs 1%) and skin problems (15% withdrew due to adverse event. vs 7%) signicantly more common with bupropion. Major depression more common in placebo (1% vs 5%), No information (only 19 partici- No information pants) Not reported in abstract Not reported in abstract No information from abstract

Dalsgar 2004

Evins 2001

Evins 2005 Ferry 1992

Not reported in abstract

No seizures occurred (data from No information from abstract FDA submission) No seizures occurred (data from No information from abstract FDA submission)

Ferry 1994

3% bupropion & 3% placebo withdrew due to adverse experience (data from FDA submission)

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

106

Bupropion adverse events. No report =no information, None occurred =explicit statement

(Continued)

Fossati 2007

No seizures occurred 8 serious adverse events in bupropion group, of which 1 thought to be medication related (suspected cholangitis) No seizures occurred

Dry mouth (6.3% vs 2.1%), Insom- ~14% bupropion & 7% placebo nia (17.3% vs 6.2%), and constipa- withdrew due to AEs tion (11.0% vs 3.6%) signicantly more common on bupropion

George 2002

Dry mouth (62.5% vs 25.0%) , 2 bupropion & 5 placebo withdrew headache (56.3% vs 37.5%), in- during treatment, no reasons given somnia (43.8% vs 27.8%), memory problems (50.0% vs 31.3%), blurred vision (50.0% vs 25.0%, irregular heartbeat (37.5% vs 12.5%), nausea/vomiting (43.8% vs 18.8%) diarrhoea (50.0% vs 25.0%), anxiety/agitation (50.0% vs 25.0%), tremor (31.3% vs 12.5%) There were signicant (p <.05) No information on AE related withgroup differences on concentration, drawals jitteriness, lightheadedness, muscle stiffness, and frequent nocturnal awakening No signicant differences between bupropion & placebo. 72% on bupropion reported adverse event vs 58% placebo. Most common adverse events insomnia (24% vs 11%) , viral infections (13% vs 19%) dry mouth (13% vs 9%), headache (8% vs 13%), 30 people discontinued medication due to adverse event, 11 (5%) placebo, 19 (8%) bupropion. For patients on bupropion most common events were anxiety (4), dry mouth (3) and rash (3)

George 2008

No seizures occurred. Three serious adverse events (SAEs) involved psychotic decompensation, 2 placebo, 1 bupropion. All deemed unrelated to study medications No seizures occurred. One serious adverse event (rash with pruritus and edema) in the bupropion group was assessed as being due to study medication

Gonzales 2001

Gonzales 2006

1 seizure after 20 days of bupropion. Dry mouth (8.8% vs 5.5%, NS), 9.0% placebo, 15.2% bupropion No other serious events assessed as nausea (12.5% vs 8.4%, NS), in- discontinued medication due to medication somnia (21.9% vs 12.8%) No seizures occurred Insomnia (37% vs 7%) 10 (33%) discontinued bupropion vs 3 (11%) placebo

Grant 2007

Haggstrm 2006

No seizures or other serious adverse Insomnia (50.9% vs 17.6%), dry No report events occurred mouth (50.9% vs 31.4%), diarrhoea (11.0% vs 3.9%) No seizures occurred No signicant differences between No report bupropion & placebo 60 people discontinued medication due to adverse events, 22 (7%)
107

Hall 2002

Hatsukami 2004

No seizures occurred. 8 serious AEs No details in bupropion, 3 placebo. One case of

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Bupropion adverse events. No report =no information, None occurred =explicit statement

(Continued)

chest pain thought to be treatment related. Hays 2001

placebo, 38 (13%) bupropion.

No seizures occurred. No serious ad- No signicant differences between 41 people discontinued medication verse events assessed as being caused bupropion and placebo. Most com- due to adverse events, 17 (8%) by study medication mon adverse events during 45 week placebo, 24 (11%) bupropion. double blind medication phase insomnia (10% vs 7%) and headache (24% vs 17%) also rhinitis, inuenza URI and accidental injury. No seizures occurred. One patient No details receiving bupropion suffered ataxia, headache and jitteriness. No seizures or serious adverse events Insomnia 26% vs 9% One bupropion (ataxia, headache and jitteriness)

Hertzberg 2001

Holt 2005

Three discontinued bupropion due to a rash. 37 people discontinued medication due to adverse events; 6 (5%) placebo; 9 (6%) 100mg; 7 (5%) 150mg; 13 (8%) 300mg. Tremor, headaches, rash and urticaria were the most common reasons for stopping treatment.

Hurt 1997

No seizures occurred. One of three serious adverse events could have been associated with bupropion; extreme irritability restlessness, anger, anxiety and craving in a man who stopped smoking.

Bupropion 300mg was associated with signicantly more insomnia (34.6% vs 20.9%) and dry mouth (12.8% vs 4.6%) than placebo.

Hurt 2003

No seizures occurred

No signicant differences. Not stated. Anxiety (16% vs 9%) and nervousness (13% vs 6%) more common in bupropion group. Insomnia less common (10% vs 17%). Bupropion was associated with more insomnia (42.4% vs 19.5%) and dry mouth (10.7% vs 4.4%) than placebo. 79 people discontinued medication due to adverse events; 6 (3.8%) placebo; 16 (6.6%) patch; 29 (11.9%) bupropion and 28 (11.4%) combined treatment group. 20% dropped out of study, and 35% were lost to follow-up at 12 months. 16 (4.7%) bupropion vs 13 (3.8%) placebo discontinued study due to AEs. 12.6% vs 7.3% discontinued medication.

Jorenby 1999

No seizures occurred. Three serious adverse events were attributed to bupropion, all consisted of rash and pruritus, one with shortness of breath and chest tightness. All had full resolution of symptoms

Jorenby 2006

No seizures occurred Bupropion was associated with more 1 serious adverse event attributed to insomnia (21.2% vs 12.4%), sleep bupropion; angioedema. disorder (6.8% vs 2.6%), constipation (6.5% vs 1.5%), dry mouth (7.6% vs 3.2%).

Killen 2004

No seizures occurred. 22 (21%) reported severe AEs in None reported No adverse effects judged to be se- bupropion & patch group vs 25 vere by study physician (23%) in placebo & patch.
108

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Bupropion adverse events. No report =no information, None occurred =explicit statement

(Continued)

24 (23%) vs 35 (32%) reported moderate AEs Killen 2006 1 seizure during open-label phase 2 other serious adverse events during open label phase (oedema, depression) and 2 during extended treatment (diagnosis of hyperthyroidism in bupropion group, onset of immune thrombocytopenia purpura in placebo group). During open-label phase 53% reported insomnia, 47% dry mouth, 44% vivid dreams, 23% nausea, 22% headache, 17% racing heart rate, 12% skin rash and 7% irregular heart rate. 30 (8%) discontinued medication during open-label phase. 1 bupropion and 2 placebo discontinued during extended treatment phase.

Muramoto 2007

No seizures occurred. 1 hospitalisa- Headache and cough were commontion (150 mg/d group) for deliber- est reported AEs. No others signiate ingestion of Datura innoxia for cantly different. recreational purposes. 1 hospitalisation (150 mg/d group) for intentional overdose of study medication, other drugs & alcohol.

Eight subjects discontinued medication early because of the following adverse events: feeling depressed, irritable, or angry; sleep disturbance; headache; urticaria; anxiety; heart palpitations; suicide attempt; anticholinergic crisis related to recreational drug use; and pregnancy.

Nides 2006

Two seizures, 2 other serious AEs in bupropion (persistent intermittent bloody diarrhoea, syncope) all considered to be possibly related to bupropion

90% of bupropion and 88% on 16% bupropion & 10% placebo displacebo experienced at least one AE. continued medication Insomnia 45% bupropion vs 22% placebo, constipation 14% bupropion vs 4% placebo, dry mouth 12% bupropion vs 6% placebo. 4.7% of adverse avents was insom- Not reported nia, not reported by condition Withdrawals not reported

Piper 2007

No report of seizures

Rigotti 2006

No report of seizures. Two deaths in Not reported placebo group. Non cardiac serious adverse events; 37% bupropion vs 31% placebo, ns Rate of new cardiovascular events did not differ signicantly at 3 months or 1 year. After 30 days off drug more bupropion group sustained a cardiovascular event, borderline signicance after adjustment for cardiac risk factors.

Simon 2004

No report of seizures or other serious Frequency of insomnia and abnor- Withdrawals not reported AE mal dreams similar in both groups. Dry mouth 22% bupropion vs 8%
109

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Bupropion adverse events. No report =no information, None occurred =explicit statement

(Continued)

placebo, gastrointestinal upset 9% bupropion vs 1% placebo Simon 2009 No seizures occurred. 1 death in 11 (26%) bupropion vs 4 (9%) in each group, causes not given (hospi- the placebo reported any AEs. Hytal population) peractivity and insomnia reported solely in bupropion group No seizures or deaths occurred. 7 pa- Overall rate of reporting of adverse 7% vs 1% withdrew due to AEs tients (bupropion 4, placebo 3) ex- events 90% vs 83%. Sleep disorders perienced a serious AE, none con- 46% vs 27% sidered related to medication. No seizures or deaths occurred. No Higher dose associated with more 26% discontinued medication in serious AEs reported difculty sleeping (48% vs 41%) 150 mg group and 31% in 300 mg , difculty concentrating (35% group vs 28%), gastrointestinal problems (27% vs 20%) and shakiness/tremor (24% vs 17%) than lower dose. No seizures occurred. 6 patients (placebo 5, bupropion 1) experienced a serious adverse event. One event (transient ischaemic attack) in placebo group thought to be related to study treatment. No seizures occurred 7 patients (bupropion 6, placebo 1) experienced serious AEs within a week of ending treatment. A reasonable possibility that SAEs in 3 bupropion patients related to study medication (fainting due to insomnia, urticaria/angioedema (2). In addition one bupropion patient delivered twin girls 4 weeks after treatment termination, one still born. No seizures occurred. Five serious adverse events during treatment, all on bupropion. Only 1 (lupus disseminatus) considered related to medication. None led to medication discontinuation. Three SAEs within a week of treatment, none related to bupropion use. 36 patients (Bupropion 24, placebo 14) reported cardiovascular adverse Bupropion associated with more insomnia (24% vs 12%). Rates for headache (6% vs 6%) and dry mouth (6% vs 5%) similar in 2 groups. 27 people discontinued medication, bupropion 14 (7%), placebo 13 (6.5%). Commonest reasons in bupropion group were anxiety (5), insomnia (4)

SMK20001

Swan 2003

Tashkin 2001

Tonnesen 2003

Bupropion associated with more in- 8% on bupropion and 6% on somnia (24% vs 15%), dry mouth placebo withdrew due to adverse (13% vs 5%) headache (13% vs events. 10%) sleep disorder (10% vs 7%), constipation (6% vs 1%) and dizziness (7% vs 4%)

Tonstad 2003

Bupropion associated with more in- 5% on bupropion and 6% on somnia (24% vs 12%), dry mouth placebo withdrew due to adverse (18% vs 10%), nausea (13% vs 6%) events. , dizziness (8% vs 5%). 11% in each group reported headache. No evidence of any effect on vital signs in CVD patients.

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

110

Bupropion adverse events. No report =no information, None occurred =explicit statement

(Continued)

events. 4 deaths (2, 2) during follow-up phase, none related to study medication. Uyar 2007 No seizures occurred 56% on bupropion reported dry 4 (8%) discontinued bupropion due mouth, 44% headache, 40% insom- to adverse effects nia. Sleep disturbance rates signicantly higher than control (38% vs 9.6%). No signicant differences between 15% on bupropion and 9% on bupropion & placebo. Insomnia placebo discontinued medication 34% vs 24%, Dry mouth 28% vs 20%, diarrhoea or constipation 34% vs 26% Bupropion associated with more insomnia (39% vs 22%). Similar rates of dry mouth (12% vs 10%), agitation (10% vs 11%), nausea (10% vs 7%). 9% on bupropion and 5% on placebo withdrew due to adverse events, most commonly due to nervous system events in both groups.

Wagena 2005

No seizures occurred One death in placebo group, previously hospitalised with dermatological reactions

Zellweger 2005

Two seizures occurred in bupropion group. One patient had a possible familial predisposition and the other was sleep deprived. 1 patient on placebo suffered a transient ischemic attack and 1 a pulmonary sequestration

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

111

Analysis 2.1. Comparison 2 Nortriptyline, Outcome 1 Long term abstinence (6-12m).


Review: Antidepressants for smoking cessation

Comparison: 2 Nortriptyline Outcome: 1 Long term abstinence (6-12m)

Study or subgroup

Treatment n/N

Control n/N

Risk Ratio M-H,Fixed,95% CI

Weight

Risk Ratio M-H,Fixed,95% CI

1 Nortriptyline versus placebo. No other pharmacotherapy Da Costa 2002 Haggstrm 2006 Hall 1998 Hall 2002 Prochazka 1998 Wagena 2005 14/68 16/52 24/99 7/73 15/108 20/80 4/76 11/51 12/100 6/73 3/106 13/89 7.8 % 23.1 % 24.8 % 12.5 % 6.3 % 25.6 % 3.91 [ 1.35, 11.31 ] 1.43 [ 0.73, 2.77 ] 2.02 [ 1.07, 3.81 ] 1.17 [ 0.41, 3.30 ] 4.91 [ 1.46, 16.46 ] 1.71 [ 0.91, 3.21 ]

Subtotal (95% CI)

480

495

100.0 %

2.03 [ 1.48, 2.78 ]

Total events: 96 (Treatment), 49 (Control) Heterogeneity: Chi2 = 5.96, df = 5 (P = 0.31); I2 =16% Test for overall effect: Z = 4.38 (P = 0.000012) 2 Nortriptyline and NRT versus NRT alone Aveyard 2008 Hall 2004 Brief Hall 2004 Extended Prochazka 2004 49/445 6/39 17/40 18/79 40/456 10/40 13/41 8/79 56.3 % 14.1 % 18.3 % 11.4 % 1.26 [ 0.84, 1.87 ] 0.62 [ 0.25, 1.53 ] 1.34 [ 0.75, 2.38 ] 2.25 [ 1.04, 4.87 ]

Subtotal (95% CI)

603

616

100.0 %

1.29 [ 0.97, 1.72 ]

Total events: 90 (Treatment), 71 (Control) Heterogeneity: Chi2 = 4.57, df = 3 (P = 0.21); I2 =34% Test for overall effect: Z = 1.78 (P = 0.076)

0.1 0.2

0.5

10

Favours control

Favours treatment

Analysis 2.2. Comparison 2 Nortriptyline, Outcome 2 Nortriptyline vs placebo adverse events. No report =no information, None occurred =explicit statement. Nortriptyline vs placebo adverse events. No report =no information, None occurred =explicit statement

Study Aveyard 2008

Serious events 2 admissions to hospital (1 intervention, 1 control) with collapse or palpitations judged possibly caused by treatment

Other adverse events

Withdrawal due to AE

Dry mouth (80% vs more than No report half, OR 6.67, 5.12 to 8.69), Constipation (OR 2.06, 1.66 to 2.56) and Sweating (OR 1.37, 1.11 to 1.68) signicantly more common

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

112

Nortriptyline vs placebo adverse events. No report =no information, None occurred =explicit statement

(Continued)

Da Costa 2002

None occurred

No signicant differences between No report groups. Dry mouth 44% vs 24%, constipation 29% vs 12%, irritation 18% vs 24%, anxiety 18% vs 28%. Dry mouth (67.3% vs 31.4%) and No report drowsiness (19.2% vs 11.8%) signicantly more common with nortriptyline Constipation (15.4% vs 9.8%) NS Dry mouth (78% vs 33%), lightheadedness (49% vs 22%), shaky hands (23% vs 11%) and blurry vision (16% vs 6%) were signicantly more common. 4 (4%) dropouts due to side effects in drug and 1 (1%) in placebo group. Total dropout rates 30% in drug and 17% in placebo groups

Haggstrm 2006

None occurred

Hall 1998

None occurred

Hall 2002

None occurred

Dry mouth (72% vs 33%) and con- No report stipation ( 32% vs 14%) significantly more common with nortriptyline (Includes data for all Hall 2004 participants) Dry mouth (85% vs 40%), lightheadedness (44% vs 22%), shaky hands (30% vs 14%) constipation (38% vs 15%), blurry vision (23% vs 7%), difculty urinating (13% vs 2%), all p<0.01. Sexual difculties (19% vs 2% p <0.02) 4 (10%) in active brief treatment, 10 (25%) in active extended treatment, 9 (11%) in placebo stopped medication due to adverse effects (active vs placebo p=0.18, Fishers exact test)

Hall 2004 Brief

None occurred

Hall 2004 Extended

None occurred

During weeks 12-52, skin redness See Hall 2004 Brief (2.5% vs 0%, p=0.03, Fishers exact test). Sexual difculties (8.9% vs 1.2% p=0.03, Fishers exact test) Dry mouth (64% vs 23%), dysgeu- 10 (9%) treatment withdrawal due sia (20% vs 8%), GI upset (41% to adverse events in nortriptyline vs 24%), drowsiness (24% vs 8%) group, vs 3 (3%) in placebo group. signicantly more common Dry mouth (38% vs 8%) & se- 10 (13%) discontinued nortriptydation (20% vs 3%) signicantly line including 1 subject with a normore common. mal baseline ECG who developed asymptomatic prolongation of QT interval, vs 1 placebo
113

Prochazka 1998

None occurred

Prochazka 2004

None occurred

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Nortriptyline vs placebo adverse events. No report =no information, None occurred =explicit statement

(Continued)

Wagena 2005

One death in placebo group, pre- Dry mouth (61% vs 20%), di- 24% discontinued nortriptyline vs viously hospitalised with dermato- arrhoea or constipation (48% vs 9% placebo logical reactions 26%) and fatigue (20% vs 9%) signicantly more common in nortriptyline group

Analysis 3.1. Comparison 3 Bupropion versus nortriptyline, Outcome 1 Long term abstinence.
Review: Antidepressants for smoking cessation

Comparison: 3 Bupropion versus nortriptyline Outcome: 1 Long term abstinence

Study or subgroup

Bupropion n/N

Nortriptyline n/N 16/52 7/73 20/80

Risk Ratio M-H,Fixed,95% CI

Weight

Risk Ratio M-H,Fixed,95% CI

Haggstrm 2006 Hall 2002 Wagena 2005

22/53 12/73 24/86

36.8 % 16.0 % 47.2 %

1.35 [ 0.80, 2.26 ] 1.71 [ 0.72, 4.11 ] 1.12 [ 0.67, 1.86 ]

Total (95% CI)

212

205

100.0 %

1.30 [ 0.93, 1.82 ]

Total events: 58 (Bupropion), 43 (Nortriptyline) Heterogeneity: Chi2 = 0.75, df = 2 (P = 0.69); I2 =0.0% Test for overall effect: Z = 1.52 (P = 0.13)

0.1 0.2

0.5

10

Favours nortiptyline

Favours bupropion

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

114

Analysis 4.1. Comparison 4 Selective Serotonin Reuptake Inhibitors (SSRIs) versus placebo, Outcome 1 Fluoxetine. Long term abstinence.
Review: Antidepressants for smoking cessation

Comparison: 4 Selective Serotonin Reuptake Inhibitors (SSRIs) versus placebo Outcome: 1 Fluoxetine. Long term abstinence

Study or subgroup n/N 1 Fluoxetine versus placebo Niaura 2002 Spring 2007 64/656 11/124

Control n/N

Risk Ratio M-H,Fixed,95% CI

Weight

Risk Ratio M-H,Fixed,95% CI

33/333 15/123

54.8 % 18.9 %

0.98 [ 0.66, 1.47 ] 0.73 [ 0.35, 1.52 ]

Subtotal (95% CI)


Total events: 75 (), 48 (Control)

780

456

73.7 %

0.92 [ 0.65, 1.30 ]

Heterogeneity: Chi2 = 0.50, df = 1 (P = 0.48); I2 =0.0% Test for overall effect: Z = 0.47 (P = 0.63) 2 Fluoxetine % NRT versus placebo and NRT Blondal 1999 Saules 2004 10/48 14/102 12/52 7/48 14.4 % 11.9 % 0.90 [ 0.43, 1.90 ] 0.94 [ 0.41, 2.18 ]

Subtotal (95% CI)


Total events: 24 (), 19 (Control)

150

100

26.3 %

0.92 [ 0.53, 1.61 ]

Heterogeneity: Chi2 = 0.01, df = 1 (P = 0.94); I2 =0.0% Test for overall effect: Z = 0.29 (P = 0.77)

Total (95% CI)


Total events: 99 (), 67 (Control)

930

556

100.0 %

0.92 [ 0.68, 1.24 ]

Heterogeneity: Chi2 = 0.51, df = 3 (P = 0.92); I2 =0.0% Test for overall effect: Z = 0.56 (P = 0.58) Test for subgroup differences: Chi2 = 0.00, df = 1 (P = 1.00), I2 =0.0%

0.1 0.2

0.5

10

Favours control

Favours treatment

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

115

Analysis 4.2. Comparison 4 Selective Serotonin Reuptake Inhibitors (SSRIs) versus placebo, Outcome 2 Paroxetine. Long term abstinence.
Review: Antidepressants for smoking cessation

Comparison: 4 Selective Serotonin Reuptake Inhibitors (SSRIs) versus placebo Outcome: 2 Paroxetine. Long term abstinence

Study or subgroup n/N Killen 2000 35/150

Control n/N 16/74

Risk Ratio M-H,Fixed,95% CI

Weight

Risk Ratio M-H,Fixed,95% CI

100.0 %

1.08 [ 0.64, 1.82 ]

Total (95% CI)


Total events: 35 (), 16 (Control) Heterogeneity: not applicable

150

74

100.0 %

1.08 [ 0.64, 1.82 ]

Test for overall effect: Z = 0.29 (P = 0.77)

0.1 0.2

0.5

10

Favours control

Favours treatment

Analysis 4.3. Comparison 4 Selective Serotonin Reuptake Inhibitors (SSRIs) versus placebo, Outcome 3 Sertraline. Long term abstinence.
Review: Antidepressants for smoking cessation

Comparison: 4 Selective Serotonin Reuptake Inhibitors (SSRIs) versus placebo Outcome: 3 Sertraline. Long term abstinence

Study or subgroup n/N Covey 2002 8/68

Control n/N 11/66

Risk Ratio M-H,Fixed,95% CI

Weight

Risk Ratio M-H,Fixed,95% CI

100.0 %

0.71 [ 0.30, 1.64 ]

Total (95% CI)


Total events: 8 (), 11 (Control) Heterogeneity: not applicable

68

66

100.0 %

0.71 [ 0.30, 1.64 ]

Test for overall effect: Z = 0.81 (P = 0.42)

0.1 0.2

0.5

10

Favours control

Favours treatment

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

116

Analysis 5.1. Comparison 5 Monoamine oxidase inhibitors (MAOIs) versus placebo, Outcome 1 Long term abstinence.
Review: Antidepressants for smoking cessation Comparison: 5 Monoamine oxidase inhibitors (MAOIs) versus placebo Outcome: 1 Long term abstinence

Study or subgroup

Treatment n/N

Control n/N

Risk Ratio M-H,Fixed,95% CI

Weight

Risk Ratio M-H,Fixed,95% CI

1 Moclobemide versus placebo Berlin 1995 11/44 7/44 30.1 % 1.57 [ 0.67, 3.68 ]

Subtotal (95% CI)


Total events: 11 (Treatment), 7 (Control) Heterogeneity: not applicable Test for overall effect: Z = 1.04 (P = 0.30) 2 Selegiline versus placebo Biberman 2003 George 2003 Weinberger 2009

44

44

30.1 %

1.57 [ 0.67, 3.68 ]

14/56 4/20 6/51

6/53 1/20 9/50

26.5 % 4.3 % 39.1 %

2.21 [ 0.92, 5.32 ] 4.00 [ 0.49, 32.72 ] 0.65 [ 0.25, 1.70 ]

Subtotal (95% CI)

127

123

69.9 %

1.45 [ 0.81, 2.61 ]

Total events: 24 (Treatment), 16 (Control) Heterogeneity: Chi2 = 4.44, df = 2 (P = 0.11); I2 =55% Test for overall effect: Z = 1.24 (P = 0.22)

Total (95% CI)

171

167

100.0 %

1.49 [ 0.92, 2.41 ]

Total events: 35 (Treatment), 23 (Control) Heterogeneity: Chi2 = 4.48, df = 3 (P = 0.21); I2 =33% Test for overall effect: Z = 1.61 (P = 0.11) Test for subgroup differences: Chi2 = 0.02, df = 1 (P = 0.88), I2 =0.0%

0.1 0.2

0.5

10

Favours control

Favours treatment

Analysis 6.1. Comparison 6 Venlafaxine versus placebo, Outcome 1 Long term abstinence.
Review: Antidepressants for smoking cessation

Comparison: 6 Venlafaxine versus placebo Outcome: 1 Long term abstinence

Study or subgroup

Treatment n/N

Control n/N 14/76

Risk Ratio M-H,Fixed,95% CI

Risk Ratio M-H,Fixed,95% CI 1.22 [ 0.64, 2.32 ]

Cinciripini 2005

16/71

0.1 0.2

0.5

10

Favours control

Favours treatment

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

117

APPENDICES Appendix 1. Suspected adverse events from national reporting schemes

Country

No. of reports

No. of users

Rate of reports

Events reported Commonest: Urticaria/rashes/ pruritus (2357, 31% of total reports) Insomnia (994, 13%) Headache (779, 10%) Dizziness (747, 10%) Seizures: 184 (2.4% of reports, est rate 0.3/1000) Deaths: 60

Source/ date Medicines Control Agency 26 July 2002 http:// www.mca.gov.uk/ ourwork/ monitorsafequalmed/ safetymessages/ zyban26702.pdf

UK (safety notice 7,630 2002) 24 July 2002

540,000 patients 14/1000 (31 March 2002)

UK (MHRA rou- 8,452 (18,319 reactine data on sus- tions) to May 2004 pected adverse drug reactions). Includes reports summarised in UK safety notice 2002

Estimated approx- approx 8/1000 pre- By organ class: Medicine and imately 1,000,000 scriptions -General disorders: Healthcare products community pre4127 Regulatory Agency scriptions dispensed Includes insom- (MHRA) in UK 2000-April nia (1030), dizziness Adverse Drug Re2004, based on Eng(805), chest pain actions Information land (384) Service. Data prodata of 762,200 for -Skin & subcuta- vided April 2004. 2000-2003. Average neous tissue disor- Prescription data prescription was a 4 from DoH Prescripders: 3728 week course. Includes pruritus tion Cost Analysis (421), rashes (1094) (www.publications.doh.gov.uk/ , urticaria (1104), prescriptionstatistics/index.htm) angioedema (481) -Psychiatric disorders: 2417 Includes affective disorders (627), suicidal ideation/ suicide/parasuicide

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

118

(Continued)

(87) -Neurological disorders: 2338 Includes convulsions & epilepsy (212) -Gastrointestinal disturbances: 2176 Includes nausea / vomiting (775) -Deaths: 70, includes 4 suicides Canada (safety no- 1,127 tice 2001) 28 May 2001 1,245,000 Zy- 0.6/1000 ban, 699,000 Wellbutrin (April 30 2001) Full list not given Serious: 682 Seizures: 172 (Zyban 120, Wellbutrin 46 bupropion 6) (15% of reports, est rate 0.1/1000 for Zyban Deaths: 19 Serum sickness: 37 Canadian Adverse Reaction Monitoring Programme (CADRMP)GSK/ Health Canada Dear Doctor letter 3 July 2001 http://www.hcsc.gc.ca/hpfbdgpsa/tpd-dpt/ zybane.html Therapeutic Goods Administration (TGA) alert 31 August 2001 http:// www.health.gov.au/ tga/ docs/html/zyban.htm

Australia (safety 1,237 alert 2001) August 2001

Not given

not available

Full list not given skin reactions (499 reports), psychiatric disturbances (427) , nervous system (406, includes convulsions/twitching 74), gastrointestinal tract (258) , facial/angioedema (89), serum sickness (63) Deaths: 18

Australia (routine data)

1,672 (4,390 reac- Approx 534,000 approx 3/1,000 pretions) prescriptions 2000- scriptions March to March 2004 2004, mainly 30 pill/2 week

Deaths: 31 TGA data supplied Skin & subcuta- 31 March 2004 neous tissue: 930. Includes urticaria (366), pruritus (90) , rash (164), oedema (160) Nervous system: 792. Includes convulsions (105), Psy119

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

(Continued)

chiatric disorders: 992. Includes suicide/self-injurious ideation (32), depression (13) Gastointestinal disorders: 440. Includes nausea/ vomiting (221) France (analysis of pharmacovigilance database & GSK reports) 1682 of which 475 698,000 classied as serious, treated September 2001 to September 2004 patients approx 2.4/1,0000 Deaths: 21 (includ- Beyens 2008 people ing 3 suicides) Neuropsychiatric: 62, includes suicide attempts (21), suicidal ideation (19) , seizures: (75, incidence 0.01%). Skin & subcutaneous tissue: 148, includes angiodema (50), serum sickness like reaction (40), urticaria (27). 11 intentional overdose including 2 deaths

FEEDBACK Labelling of graphs

Summary In the graphs for bupropion the comparison is described under the outcome heading rather than the comparison heading Reply In this review the outcome is always abstinence from smoking at longest follow-up. In order to group comparisons for the same pharmacotherapy and to give an informative summary graph, the decision was taken to use the outcome level for the specic comparisons. Unfortunately it is not possible to alter the xed headings of Comparison and Outcome. Contributors Lindsay Stead, review author and Managing Editor

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

120

WHATS NEW
Last assessed as up-to-date: 29 July 2009.

Date 22 June 2011

Event Amended

Description Additional table converted to appendix to correct pdf format

HISTORY
Protocol rst published: Issue 3, 1997 Review rst published: Issue 3, 1997

Date 5 October 2009

Event Amended

Description Correction to excluded studies table, detail for Carro 2007 Updated with 13 new included trials including 3 of selegiline, not previously covered. No substantial change to effects, main conclusions not altered Converted to new review format.

30 July 2009

New search has been performed

17 June 2008 11 October 2006

Amended

New citation required but conclusions have not Seventeen new trials were added to the review for issue changed 1, 2007. There were no major changes to the reviewers conclusions. New citation required but conclusions have not New trials of bupropion, nortriptyline and uoxetine changed were added for issue 4, 2004, and additional information on adverse effects was included. There were no major changes to the reviewers conclusions. New citation required but conclusions have not New trials of bupropion and nortriptyline were added changed to the review in Issue 2 2003. There were no major changes to the reviewers conclusions New citation required but conclusions have not Four new studies on bupropion, and one each on norchanged triptyline and paroxetine were added to the review in Issue 1 2002. In press data from a trial of uoxetine are included which differ from unpublished data previously used. The reviewers conclusions about the efcacy of bupropion and nortriptyline were not changed substantively.

16 July 2004

8 January 2003

19 September 2001

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

121

(Continued)

28 August 2000

New citation required and conclusions have changed

Updates the earlier Cochrane review Anxiolytics and antidepressants for smoking cessation. Anxiolytics are evaluated in a separate review.

CONTRIBUTIONS OF AUTHORS
All authors contribute to the text of the review. LS and TL extracted study data.

DECLARATIONS OF INTEREST
JR Hughes has received consultancy fees from many pharmaceutical companies that provide tobacco related services or products or are developing new products, including Pzer (the maker of NRTs and varenicline) and GlaxoSmithKline (the makers of bupropion and NRTs).

SOURCES OF SUPPORT Internal sources


No sources of support supplied

External sources
National Institute on Drug Abuse (NIDA), USA. NHS Research and Development Programme, UK.

NOTES
This review was rst published as part of the review Anxiolytics and antidepressants for smoking cessation. From Issue 4 2000 the classes of drugs are reviewed separately.

INDEX TERMS Medical Subject Headings (MeSH)


Anti-Anxiety Agents [adverse effects; therapeutic use]; Antidepressive Agents [adverse effects; therapeutic use]; Randomized Controlled Trials as Topic; Smoking [ drug therapy]; Smoking Cessation [ methods]

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

122

MeSH check words


Humans

Antidepressants for smoking cessation (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

123

You might also like

pFad - Phonifier reborn

Pfad - The Proxy pFad of © 2024 Garber Painting. All rights reserved.

Note: This service is not intended for secure transactions such as banking, social media, email, or purchasing. Use at your own risk. We assume no liability whatsoever for broken pages.


Alternative Proxies:

Alternative Proxy

pFad Proxy

pFad v3 Proxy

pFad v4 Proxy