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Antidepressants for smoking cessation

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 Library2011, Issue 8 Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
PLAIN LANGUAGE SUMMARY AUTHORS' CONCLUSIONS CHARACTERISTICS OF STUDIES 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 Analysis 1.6. Comparison 1 Bupropion. Abstinence at 6m or greater follow-up, Outcome 6 Bupropion for relapse Analysis 1.7. Comparison 1 Bupropion. Abstinence at 6m or greater follow-up, Outcome 7 Bupropion versus nicotine 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 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 Analysis 4.2. Comparison 4 Selective Serotonin Reuptake Inhibitors (SSRIs) versus placebo, Outcome 2 Paroxetine. Long Analysis 4.3. Comparison 4 Selective Serotonin Reuptake Inhibitors (SSRIs) versus placebo, Outcome 3 Sertraline. Long 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.
CONTRIBUTIONS OF AUTHORS Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Antidepressants for smoking cessation
John R Hughes1, Lindsay F Stead2, Tim Lancaster3 1Dept of Psychiatry, University of Vermont, Burlington, Vermont, USA. 2Department of Primary Care Health Sciences, University ofOxford, Oxford, UK. 3Department 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 ProspectStreet, Burlington, Vermont, 05401, USA. 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.
A B S T R A C T
There are at least three reasons to believe antidepressants might help in smoking cessation. Nicotine withdrawal may produce depressivesymptoms or precipitate a major depressive episode and antidepressants may relieve these. Nicotine may have antidepressant effectsthat maintain smoking, and antidepressants may substitute for this effect. Finally, some antidepressants may have a specific effect onneural pathways (e.g. inhibiting monoamine oxidase) or receptors, (e.g. blockade of nicotinic-cholinergic receptors) underlying nicotineaddiction.
The aim of this review is to assess the effect of antidepressant medications to aid long-term smoking cessation. The medications includebupropion; doxepin; fluoxetine; imipramine; moclobemide; nortriptyline; paroxetine; selegiline; sertraline, tryptophan, venlafaxineand St. John's wort.
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.
We considered randomized trials comparing antidepressant medications to placebo or an alternative pharmacotherapy for smokingcessation. We also included trials comparing different doses, using pharmacotherapy to prevent relapse or re-initiate smoking cessationor 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 ofrandomization, 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, expressedas a risk ratio (RR). We used the most rigorous definition of abstinence available in each trial, and biochemically validated rates ifavailable. Where appropriate, we performed meta-analysis using a fixed-effect model.
Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Main results
Thirteen new trials were identified since the 2006 update bringing the total number of included trials to 66. There were 49 trialsof bupropion and nine trials of nortriptyline. When used as the sole pharmacotherapy, bupropion (36 trials, N = 11,140, risk ratio[RR] 1.69; 95% confidence interval [CI] 1.53 to 1.85) and nortriptyline (six trials, N = 975, RR 2.03; 95% CI 1.48 to 2.78) bothsignificantly increased long term cessation. There is insufficient 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 anadditional long-term benefit. From the available data bupropion and nortriptyline appear to be equally effective and of similar efficacyto 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. Bupropionhas been associated with suicide risk, but whether this is causal is unclear. Nortriptyline has the potential for serious side-effects, butnone have been seen in the few small trials for smoking cessation. There was no evidence of a significant effect for selective serotoninreuptake inhibitors; fluoxetine 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 0.64to 1.82); sertraline 1 trial, N = 134, RR 0.71 (95% CI 0.30 to 1.64). Significant effects were not detected for the monoamine oxidaseinhibitors 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 to2.41) or the atypical antidepressant venlafaxine (N = 147, RR 1.22, 95% CI 0.64 to 2.32). No long term trials have been publishedfor St John's Wort.
The antidepressants bupropion and nortriptyline aid long-term smoking cessation but selective serotonin reuptake inhibitors (e.g.
fluoxetine) do not. Evidence suggests that the mode of action of bupropion and nortriptyline is independent of their antidepressanteffect and that they are of similar efficacy to nicotine replacement. Adverse events with both medications appear to be rarely serious orlead to stopping medication.
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 sideeffects of bupropion include insomnia, dry mouth and nausea and rarely (1:1000) seizures and perhaps psychiatric problems, but thelast 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 efficacy of bupropion and nortriptyline appears to besimilar to that for nicotine replacement and not restricted to people with a history of depression or depressive symptoms during smokingabstinence. Selective serotonin reuptake inhibitor antidepressants (for example, fluoxetine) have not been shown to help smokingcessation.
B A C K G R O U N D
ications for smoking cessation ; ).
Whilst nicotine replacement is the most widely used pharma- The following antidepressants have been investigated for their ef- cotherapy for smoking cessation, some people prefer a treatment fect on smoking behaviour in at least one study: that does not use nicotine. Others require alternative treatmentshaving failed to quit with nicotine replacement. Observations thata history of depression is found more frequently amongst smokers • the tricyclic antidepressants (TCAs) doxepin, imipramine than nonsmokers; that cessation may precipitate depression; that and nortriptyline nicotine may have antidepressant effects; and that antidepressantsinfluence the neurotransmitters and receptors involved in nicotine • the monoamine oxidase inhibitors (MAOI) moclobemide addiction provided a rationale for the study of antidepressant med- Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
• the selective serotonin reuptake inhibitors (SSRIs) Trials in which all participants received the same pharmacotherapy fluoxetine, paroxetine and sertraline regimen but different behavioural support were not included.
• the atypical antidepressants bupropion, tryptophan and Types of outcome measures
Efficacy was measured via a) abstinence from smoking or b) inci- • extracts of Hypericum perforatum L. (St. John's wort) dence of reducing cigarette consumption to 50% or less of base-line, both assessed at follow up at least six months from start of The focus of this review and meta-analysis is on trials that provide treatment. Safety was assessed by incidence of serious and other evidence for an effect on long-term smoking cessation. We describe adverse events, and drop-outs due to adverse events.
these in the Results section. For pharmacotherapies for which thereis still a lack of long-term data, we briefly describe results fromexcluded short-term trials in the Description of Studies section.
Search methods for identification of studies
We identified studies from the Tobacco Addiction Group's spe- O B J E C T I V E S
cialised register. All trials using pharmacotherapy other than nico-tine, clonidine or lobeline for smoking cessation were found, and To assess the evidence for the efficacy and safety in assisting long- those using medications generally classified as having an antide- term smoking cessation of medications with antidepressant prop- pressant effect were selected for inclusion in this review. The date erties, including: bupropion, doxepin, fluoxetine, imipramine, of the last search was June 2009. We checked the citation lists of moclobemide, nortriptyline, paroxetine, tryptophan, selegiline, these studies, recent reviews of non-nicotine pharmacotherapy and sertraline, venlafaxine and hypericum (St John's Wort).
abstracts from the meetings of the Society for Research on Nico- For each medication identified as having been used in a smoking tine and Tobacco. For each medication found from these sources cessation trial we tested the hypothesis that it was more effective we searched MEDLINE and EMBASE (via Ovid, 9th June 2009) than placebo, or an alternative treatment, in achieving long-term using the medication name and 'smoking' as a free text term. Sev- smoking cessation.
eral studies were located by contacting investigators in the area. Wealso checked all records of trials of bupropion held on the Glaxo-SmithKline Clinical Trials Register (http:ctr.glaxowellcome.co.uk)for unpublished studies.
Data collection and analysis
Criteria for considering studies for this review
LS and TL independently extracted data on the number of studyparticipants who had ceased to smoke at final follow up.
In each study we used the strictest available criteria to define cessa- Types of studies
tion, so we extracted figures for sustained abstinence in preference For efficacy, we examined randomized trials comparing antide- to point prevalence where both were presented. In studies that used pressant with placebo or with an alternative therapeutic control, biochemical validation of cessation, only those subjects meeting or comparing different dosages of an antidepressant that reported the criteria for biochemically confirmed abstinence were regarded six-month or longer follow ups. For safety, we examined data from as having stopped smoking. We treated subjects in either group randomized controlled trials and non-randomized post-marketing lost to follow up as continuing smokers. As far as possible we used surveillance data.
an Intention-to-Treat analysis. Where subjects appeared to havebeen randomized but were not included in the data presented bythe author we noted this in the study description (see 'Character- Types of participants
istics of Included Studies'). Assuming that people lost to follow up Current smokers, or recent quitters (for trials of relapse preven- 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). Some studies now use alternative methods to model Types of interventions
effects of missing data (; ). Where differen- Treatment with any medication with antidepressant properties to tial results using alternative models were reported we considered aid a smoking cessation attempt or to prevent relapse, or to reduce whether the results of the meta-analysis were sensitive to the use the number of cigarettes smoked and aid subsequent cessation.
of different denominators.
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), calcu- verse events. Because the safety of bupropion has been questioned lated as: (number of quitters in intervention group/ number ran- in some countries, we have supplemented trial data with data from domized to intervention group) / (number of quitters in control observational studies including national post-marketing surveil- group/ number randomized to control group). A risk ratio greater lance schemes where it was possible to estimate a denominator.
than 1.0 indicates a higher rate of quitting in the treatment group Nortriptyline is not currently licensed for smoking cessation, so than in the control group. For each type of medication where more this was not possible for this medication. We did not directly ex- than one eligible trial was identified, we performed meta-analysis amined safety data for bupropion or nortriptyline when used to using a Mantel-Haenszel fixed-effect method to estimate a pooled treat depression because these studies used higher doses and dif- risk ratio with 95% confidence intervals ). This is a ferent populations than those used for smoking cessation.
change from previous review versions that used odds ratios (OR),because ORs can be misleading ().
To investigate statistical heterogeneity we use the I² statistic, givenby the formula [(Q - df )/Q] x 100%, where Q is the chi squaredstatistic and df is its degrees of freedom (). This de- scribes the percentage of the variability in effect estimates that isdue to heterogeneity rather than sampling error (chance). We usedthreshold values of 50% and 70% as suggesting moderate and sub- Description of studies
stantial heterogeneity respectively. Although we give a summary statistic, the conclusions that can be drawn from it must be cau- tious. Where trials are small and few in number the confidence We identified thirteen additional trials for this update, giving a to- intervals will be wide. The derivation of the summary statistic im- tal of 66 included trials. The new trials were of bupropion ( plicitly 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 triptyline ) and selegiline, publication bias occurs in the field of smoking cessation research not previously covered by this review).
(), and this issue is discussed further in the Cochrane re- Five trials that were previously included based on unpublished re- view of nicotine replacement therapy (NRT) Thus, sults have now been published and the study identifiers are now we included unpublished studies or studies found only as abstracts based on year of publication (; where sufficient detail was available. We contacted authors for fur- The forty-nine trials of bupro- ther data if necessary.
pion included five We have added a subgroup meta-analysis by level of additional testing the medication for relapse preven- support using the same criteria applied in the Cochrane NRT re- tion and one of reduction (). Three of the bupro- view ); low intensity support was regarded as part of pion trials allowed a direct comparison with nicotine patch ther- the provision of routine care, so the duration of time spent with apy ; ; ), and three a direct the smoker (including assessment for the trial) had to be less than comparison with the nicotine receptor partial agonist varenicline 30 minutes at the initial consultation, with no more than two fur- ; ). Nine trials used nor- ther assessment and reinforcement visits. We distinguished in the triptyline including three which also used bupropion ( meta-analyses between trials testing an antidepressant as a single ), There were four trials of fluoxe- pharmacotherapy or as an adjunct to NRT for initial cessation. We also distinguished between cessation trials and those where the in- of selegiline (; ; tervention addressed relapse prevention or reduction in number of one of paroxetine one of sertraline cigarettes smoked. None of the trials located were specifically de- and one of venlafaxine ). These studies excluded signed to directly compare antidepressant pharmacotherapy with smokers with current depression but almost all included smokers with a past history of depression. Further details of the study de- Adverse events: Tables in the results section summarize the adverse signs are given in the table 'Characteristics of included studies'.
events reported in clinical trials for smoking cessation for med- We list 58 excluded studies. Most of these were short-term or ications which have shown evidence of efficacy (bupropion and laboratory-based studies. For medications where there is little or no nortriptyline). For other medications adverse effects are noted in evidence from long-term studies we briefly describe the results of the included studies the excluded short-term trials. The reasons for exclusion are given . The number of people who have received bupropion and nor- in the table 'Characteristics of excluded studies'. Papers reporting triptyline in smoking cessation trials is still relatively small, so there additional outcomes or subgroup analyses from included studies is limited power to estimate accurately the risk of uncommon ad- are listed as references under the study identifier. Six further studies 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 Thirty-six trials evaluated bupropion as a single pharmacotherapy sufficient data to assess for inclusion yet.
to assist initial cessation. Included in separate analyses are trialsthat tested bupropion as an adjunct to nicotine replacement ther-apy (; (part); ; and trials making direct comparisonsbetween bupropion and nicotine replacement therapy ( This antidepressant has both dopaminergic and adrenergic actions, ; ), bupropion and nortriptyline and appears to be an antagonist at the nicotinic acetylcholinergic ; and between bupro- receptor ). It may work by blocking nicotine effects, pion and varenicline , relieving withdrawal ) or reducing de- Trials testing the extended use of bupropion for relapse preven- pressed mood It has been licensed as a prescrip- tion aid to smoking cessation in many countries. The usual dose and its use for assisting in reducing the amount smoked for smoking cessation is 150mg once a day for three days increas- ) are pooled separately.
ing to 150 mg twice a day continued for 7 to 12 weeks. The quit The five studies that evaluated bupropion SR for relapse preven- attempt is generally initiated a week after starting pharmacother- tion each had slightly different designs (; ; ; ). These studies also con- Forty-nine studies with long-term follow up are included. Out- tribute to a separate Cochrane review on interventions for relapse comes for four studies are based on conference abstracts or phar- maceutical company data (; One study evaluated bupropion for reducing smoking in people not wanting to make a quit attempt but interested in reducing The majority of trials were conducted in North America but stud- ). During treatment, if participants decided they ies are also included from Europe ; wanted to try to quit, they were enrolled in a cessation programme during which they continued to use bupropion and were then Turkey ); Brazil ); New Zealand followed up for 19 weeks.
(Australia (and two multicontinent Two placebo-controlled trials studied the use of bupropion for studies ). Special populations re- smokeless tobacco cessation ). These tri- cruited include smokers with the following conditions; chronic als are excluded from the present review but are covered in the obstructive pulmonary disease ; ; Cochrane review of interventions for smokeless tobacco cessation ); schizophrenia ; ; ; ); post traumatic stress disorder Most of the bupropion trials excluded participants with current (alcoholism (and cardiovascular depression but not those with a history of depression. One study disease (- inpatients; as well as hospi- ) did include participants who may have been de- tal inpatients ). Other populations included adoles- pressed (i.e. several had a Center for Epidemiologic Studies De- cents ; ); smokers awaiting surgery pression (CES-D) score of over 16). Two studies explicitly ex- () hospital staff (); healthcare work- cluded participants with a history of major depression ers ); African-Americans (), and or any psychiatric disorder (). Amongst the Maori Two studies recruited smokers who had pre- studies recording the prevalence of a history of depression at base- viously failed to quit smoking using bupropion ; line the proportion ranged from 6% ) to 44% and one included smokers who had just failed to quit ), but was typically 20-30%.
using NRT ().
More than half the bupropion studies followed participants forat least 12 months from the start of treatment or the target quitday. Eighteen studies (37%) had only six months follow up ( Nine published studies of the tricyclic antidepressant nortriptyline are included. 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 ). The majority of studies reported an outcome of sustained ; one in the Netherlands abstinence. In 12 (24%) only point prevalence rates were given, and one in the UK Seven studies excluded or the definition of abstinence was unclear ( participants with current depression but most of these included people with a history of depression. All studies were placebo con- trolled and used doses of 75 to 100 mg/day or titrated doses to serum levels recommended for depression during the week prior Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
to the quit date. All studies used a definition of cessation based on a sustained period of abstinence. The three studies by Hall and Four trials with long-term follow up are included. Two studies colleagues, and reported outcomes after 12 months used fluoxetine as the only pharmacotherapy and had six months of follow up and the other five had six months of follow up. The follow up; a multicentre trial compared 30 mg daily, 60 mg daily design, length of treatment, level of common behavioural sup- or placebo for 10 weeks ), and a single-site study used port and use of nicotine replacement as common therapy varied 60 mg or placebo for 12 weeks ). Two trials provided as summarised below.
NRT to all participants and compared the addition of fluoxetine • used a 2x2 factorial design with nortriptyline and placebo over 12 months follow up; used 20 mg/ versus placebo for 12 weeks crossed with a 10-session cognitive day or placebo for three months as an adjunct to nicotine inhaler; behavioural mood management intervention versus a five session used 20 or 40 mg/day of placebo for 10 weeks as standard health education control. The behavioural arms are an adjunct to nicotine patch. Participants in all trials were not collapsed in this meta-analysis.
currently depressed but may have had a past history of depression.
• used a 3x2 factorial design with nortriptyline stratified by history of depression.
versus bupropion versus placebo for 12 weeks crossed with a five We excluded other short-term studies. One study tested 14 weeks session psychosocial behaviour therapy intervention versus of fluoxetine (40 mg/day) or dexfenfluramine (30 mg/day) ver- medical management involving only brief advice and sus placebo in normal weight women in a study investigating the counselling. The behavioural arms are collapsed.
effects of these medications in controlling post-cessation weight • Hall 2004 used a 2x2 factorial design with nortriptyline gain This study found an apparently lower ab- versus placebo crossed with extended treatment versus brief stinence rate with fluoxetine (20%) than with placebo (31%) at treatment. All participants received nicotine patch therapy for three months, but the difference was not statistically significant.
eight weeks and five sessions of group-based counselling. The and were also studies on fluoxetine 'brief ' treatment was 12 weeks of nortriptyline or placebo and in smokers attempting to quit, but considered outcomes other than weekly individual counselling. The extended treatment was 52 abstinence. Another pharmaceutical company-sponsored multi- weeks of nortriptyline or placebo and weekly and the monthly centre trial was completed but its results were never presented or individual counselling sessions. Since the brief nortriptyline published. One further trial is known to be underway ( regimen is similar to that of the other nortriptyline trials, we include the results of brief nortriptyline versus placebo andextended nortriptyline versus placebo separately in the meta-analysis ; ).
• tested nortriptyline versus placebo for 10 weeks with a behavioural intervention of two group sessions and One trial with six-month follow up assessed paroxetine (40 mg, 12 individual follow-up visits.
20 mg or placebo) for nine weeks as an adjunct to nicotine patch • tested nortriptyline versus placebo for 14 weeks as an adjunct to nicotine patch and brief behaviouralcounselling.
• tested nortriptyline versus placebo for six weeks with a behavioural intervention of six weekly groupcognitive therapy sessions.
One trial with six-month follow up assessed sertraline (200 mg/ • compared nortriptyline, bupropion or double day) for 11 weeks versus placebo in conjunction with six individ- placebo for 12 weeks with individual counselling and telephone ual counselling sessions. There were 134 participants, all current smokers with a past history of major depression • tested nortriptyline versus placebo for 60 One trial that combined sertraline with buspirone was excluded days with six individual counselling sessions.
because the specific effect of sertraline could not be evaluated • compared nortriptyline to placebo as an adjunct to participants' choice of NRT which could include acombination of products, and four weeks of behavioural support,mainly in a group setting.
One short-term study used a crossover design to investigate theeffect of the SSRIs citalopram or zimelidine on the smoking be- Selective Serotonin Reuptake Inhibitors (SSRIs)
haviour of heavy drinkers who were not attempting to stop smok- No new studies with SSRIs have been completed since the last ing. Their cigarette use did not change significantly between active update of the review.
medication and placebo periods ).
Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Monoamine oxidase inhibitors
term follow up (). Treatment was with 150 mg dox- The current review now includes selegiline in this category.
epin daily for three weeks prior to quit day and four weeks after-wards. Subjects forfeited a US$135 deposit if they failed to stopsmoking for seven days. Two months after cessation, 78% (7/9) of the doxepin group and 10% (1/10) of the placebo group re- Moclobemide is a reversible monoamine oxidase-A inhibitor. Since ported abstinence, a statistically significant difference (P < 0.02).
smoking acts as a monoamine oxidase-A inhibitor, substituting However one week post-cessation abstinence rates using stringent moclobemide for smoking might help with cessation. This has validated abstinence criteria failed to show a statistically significant been tested in one long-term placebo-controlled trial in France difference. Among withdrawal symptoms, there was a significant (Treatment with 400 mg/day began one week before group difference only for craving.
quit day and continued for two months, reducing to 200 mg/dayfor a further month. No behavioural counselling was provided.
Final follow up was at 12 months.
There are no long-term studies of this noradrenergic tricyclic an- tidepressant. One trial () compared imipramine (25 Selegiline is an irreversible, selective monoamine oxidase-B in- mg 3 times/day) with lobeline, dextroamphetamine, placebo and hibitor at low doses (10 mg/day) and has shown antidepressant a no-medication control. Some participants attended group sup- activity at higher doses, when it is non-selective ().
port sessions. After three months, success rates, which included In a short-term study it reduced smoking behaviour under labora- a reduction in smoking to less than 10% of baseline, were 56% tory conditions and reduced craving during two days of attempted (10/18) for imipramine, 40% (6/15) for placebo and 69% (27/ abstinence ). Two long-term trials have been 39) for the no-medications control. These differences were not published and one is included based on a conference abstract (All used 10mg/day oral treatment. Two hadtreatment durations of 9 weeks ; )and one continued therapy for 26 weeks (An unpublished study with preliminary short-term data is excluded(Three other phase II trials are known to be in Tryptophan may have antidepressant properties because it in- creases the level of serotonin. There have been no long-term stud- two of which are evaluating transdermal ies reported. Bowen and colleagues postulated that this serotonin- enhancing action in conjunction with a high carbohydrate (CHO)diet might relieve the negative affect of cigarette withdrawal. Orall-tryptophan (50mg/kg/day) and instructions to follow a high CHO, low-protein diet were compared with placebo pills and in- This selective monoamine oxidase-B inhibitor was evaluated in structions for a low-carbohydrate diet (). Participants an eight-week, dose finding, exploratory study (). The in both groups also received four two-hour weekly multi-compo- trial was halted early due to liver toxicity observed in trials of the nent group therapy sessions. Two weeks following the target ces- medications for other indications, and lazabemide is not being sation date 75% (12/16) of the tryptophan and high CHO diet developed further. Continuous four-week quit rates at the end of group were abstinent versus 47% (7/15) of the placebo and low treatment, including all drop-outs as treatment failures, were 17% CHO diet group. This difference was not statistically significant.
(18/108) for 200 mg/day, 11% (12/108) for 100 mg/day and 9%(10/114) for placebo.
This antidepressant inhibits re-uptake of serotonin and nore- No new studies of other antidepressants have been completed since pinephrine. One trial with 147 participants compared venlafaxine the last review.
at a dose of up to 225 mg/day with placebo. All participants alsoreceived nicotine patches and nine brief individual counselling ses-sions; follow up was for 12 months An unpub- lished short-term study ) reported no difference There are no long-term studies of this serotonergic tricyclic an- in abstinence rates at eight weeks, and frequent side effects in the tidepressant. It has been evaluated in a single small trial with short- treatment group.
Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Hypericum (St John's Wort)
of the third week after the target quit date (TQD) onward and Extracts of hypericum have antidepressant properties. No studies validated at intermediate and final follow ups.
are eligible to be included in the review. compared Additional details about the methodology of individual trials are two doses for smoking cessation in an open randomized study given in the table 'Characteristics of Included Studies'. Consistent with no placebo control. Quit rates were low and did not differ with Cochrane methods, we included some trials that have only between dose levels. No participants maintained abstinence for 12 been published as abstracts, which have limited information on months. One uncontrolled study is excluded A methodological issues (For some studies we have controlled study has been completed but not yet published obtained additional information from authors, or from the phar- maceutical company funding the study. Use of unpublished datain the meta-analysis is noted in the Included Studies table.
Risk of bias in included studies
Effects of interventions
All of the trials used placebo controls except , and (Selected analyses are displayed as Figures in the text. Other anal- which compared two different doses of a pharmacotherapy.
yses are shown in the 'Data & Analyses' section online and full All the trials were described as randomized, but most failed to re- pdf versions of the review) port randomization and concealment methods in detail. Thirty-two studies (48%) reported a method of allocation judged ade-quate to ensure that treatment assignment was concealed at the time of enrollment. All but one of the other trials were categorised We distinguish between the subgroup of trials where bupropion unclear because the method of allocation was not described. One was tested as the only pharmacotherapy, and those trials where the bupropion trial described the use of a random num- effect of bupropion when added to NRT was assessed. One trial ber table but no mention of a blinded allocation list so was cate- contributed arms to both subgroups.
gorised as potentially inadequate. This was a small trial so its inclu-sion or exclusion did not change the results. Restricting inclusionin the largest meta-analysis (bupropion versus placebo) to studies Compared to placebo control, no other pharmacotherapy
assessed as using adequate allocation concealment no effect on the There were 36 trials in which bupropion was the sole pharma- cotherapy, with over 11,000 participants. The pooled risk ratio The definition of abstinence was not always explicit and biochem- [RR] was 1.69 (95% confidence interval [CI] 1.53 to 1.85) with ical validation of self-reported smoking status was not always used; little evidence of heterogeneity (I² = 11%), see figure 1, analysis however all but one of the bupropion studies ) and all 1.1. The estimated effect is smaller when expressed as a risk ratio, but one of the nortriptyline studies for which de- but has not really changed since the last version of the review, com- tails were available did use biochemical verification for most self- paring odds ratios (i.e. OR in 2006; 1.94, OR now; 1.86). The reported quitters at some assessment points. In a small number of control group quit rates ranged from 0% to 22%, with a weighted studies we were able to obtain a sustained outcome that was not average of 9%. Intervention group quit rates ranged from 4% to given in the published report. Most of the sustained abstinence 43% with a weighted average of 17%.
rates are based on self-reported slip-free abstinence from the start 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
analysis was based on the 36 trials contributing to analysis 1.1 but Although in this update there was no overall evidence of hetero- excludes two trials where the level of support could not be classi- geneity amongst the 36 trials of bupropion as the only pharma- cotherapy we continued to use subgroup analyses to explore po-tential moderators of treatment effect. Twenty two of these trialshad 12-month follow up and fourteen had six months. The esti- Effect of dose
mated RR for the 12-month follow-up group was 1.64 (95% CI In the first multi-dose study ), cessation rate was lin- 1.46 to 1.84, I² = 34%, analysis 1.1.1) which was not significantly early related to dose (100 mg versus 150 mg versus 300 mg) lower than that for trials with only six months (RR 1.81; 95% CI through the end of treatment, consistent with pharmacological ef- 1.51 to 2.16), I² = 0%, analysis 1.1.2). Much of the difference, and ficacy, although the difference between 300 mg and 150 mg doses the heterogeneity in the 12-month subgroup, could be attributed was not significant at long-term follow up. A larger study com- pared 150 mg and 300 mg daily doses, without a placebo group,and reported similar 12-month point prevalence quit rates for bothdoses ). A study in adolescents also included 150 mg Sensitivity to clinical setting
and 300 mg doses ), with higher quit rates in In a post hoc subgroup analysis we distinguished between trials the larger does group. Doses above 300 mg have not been tested.
that recruited community volunteers and trials that recruited pa- Pooling the three studies and comparing 300 mg versus 150 mg tients in healthcare settings or with specific diagnoses. Whilst the shows no evidence of a significant difference in abstinence (N = estimated effect was smaller amongst trials that recruited commu- 2,042, RR 1.08; 95% CI 0.93 to 1.26, analysis 1.4).
nity volunteers than those recruiting in health care settings theconfidence intervals overlapped and effects were significant in bothgroups (analysis 1.2).
Bupropion & nicotine replacement combined therapy
compared to NRT alone
There was substantial heterogeneity in the results of six studies Effect of level of behavioural support
adding bupropion to nicotine patch therapy Three trials compared bupropion and placebo in factorial designs varying the behavioural support. There was no evidence from any 64%). Using a random-effects model to pool the studies did not that the efficacy of bupropion differed between lower and higher show evidence of a significant effect of adding bupropion (N = levels of behavioural support (; or by 1,106, RR 1.23; 95% CI 0.67 to 2.26, analysis 1.5). Of the six tri- type of counselling approach used (). Two other als, four recruited people who were potentially hard to treat; ado- studies have compared different levels of behavioural support for lescents (smokers with schizophrenia ( people prescribed bupropion (; These and smokers in treatment for alcohol dependence did not include placebo arms so do not provide evidence about ). was a small study with no quitters at within-study interactions between behavioural interventions and all in the control group. The significant benefit seen in one trial pharmacotherapy. We also explored a between-study subgroup ) may be due in part to the unusually poor results analysis of the possible interaction with behavioural support using from nicotine patch alone in this study. The confidence intervals the classification into low and high intensity used in the Cochrane around the estimate do not exclude a benefit that would be clin- NRT review (Low intensity was less than 30 minutes ically useful. One relapse prevention study has at the initial consultation, with no more than two further assess- compared open label nicotine inhaler, bupropion or both com- ment and reinforcement visits. Only one of the included trials had bined as initial therapy for cessation. After 12 weeks there was a such low intensity support () and it was too small to second phase of randomization, so long term effects cannot be draw conclusions from. (in a primary care setting) and part of had limited behavioural support butin both cases there were more than three visits. We also examined,within the more intensive therapy trials, evidence of a different Bupropion for relapse prevention
effect of bupropion versus placebo in eight trials that provided Five trials have evaluated extended use of bupropion for prevent- group-based behavioural interventions compared to the majority ing relapse in people who have already stooped smoking. Pooling where individual therapy was provided. We found no evidence studies suggests the possibility of a small benefit but confidence of a difference between subgroups (analysis 1.3). (This subgroup 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.
1.39, analysis 1.6). The studies were heterogeneous with respect of this interaction was not tested ). One study has re- to the length of initial abstinence, the period of pharmacotherapy ported a larger treatment effect for four- to seven-week abstinence and the length of post treatment follow-up. The results are dis- in males (). This was a study re-treating smokers cussed in more detail in a Cochrane review of relapse prevention who had already failed to quit with bupropion. In the relapse prevention study, there were no significant gender effectsIn summary, gender does not appear to consis-tently influence the efficacy of bupropion.
Bupropion and depression
There was not sufficient detail in most studies about results in Whilst most reports have not indicated any difference in treatment smokers with and without depression to conduct a meta-analysis.
effects between older and younger smokers, subgroup analyses of In three within-trial analyses, smokers with a past history of de- two trials, (reported in ), and pression did not benefit more than those without such a history (reported in found evidence of an interaction, with a (subgroup analysis of & larger treatment effect for older smokers. One study in adolescents subgroup analyses of ). In the did not show evidence of an effect for bupropion over nicotine only analysis specifically within the subgroup of smokers with no history of depression, bupropion was effective ).
Bupropion may alleviate some subclinical symptoms of depression Bupropion as second treatment
during treatment (; ), One relapse prevention trial described above () also ran- but although this may facilitate smoking cessation, other mech- domized 194 smokers who had not quit successfully using nico- anisms are probably more important (). In one trial tine patch therapy to bupropion or placebo as a second line treat- (reported in there was an interaction ment. Only one person, in the bupropion group, quit and sus- between nicotine dependence and treatment on post-cessation de- tained abstinence at six months. This is consistent with the results pression symptoms. Most smokers showed a reduction in depres- of other studies, which find low overall success rates in smokers sion symptoms during the treatment phase, whether they received offered further pharmacotherapy soon after treatment failure (eg bupropion or placebo. The reduction was maintained during fol- ; ). In contrast, a subgroup analysis low up. However highly dependent smokers showed a greater re- of (reported in ) suggested that bupro- duction in depression scores whilst receiving bupropion, and an pion was equally effective in smokers with and without a past his- increase when treatment ended.
tory of failure with NRT. In this trial the gap between the previousfailed attempt and the second attempt at cessation would havebeen longer.
Gender/age differences with bupropion
Too few of the studies have published data on long-term quit ratesby gender for it to be possible to conduct a definitive subgroup Bupropion versus NRT
meta-analysis. A meta-analysis of mainly short-term outcomes and Three studies allowed a direct comparison between bupropion and including 12 trials with 4421 participants showed no evidence of a nicotine patch (). In the treatment-gender interaction In these trials women only one that was placebo-controlled, bupropion was significantly were less successful at quitting than men overall, but bupropion more effective than nicotine patch (however, nico- was equally beneficial in men and women. A subgroup analysis of tine patch itself was not efficacious in this particular study. The long-term data from one study (, reported in other two smaller studies were open label and had non-significant ) did report an interaction such that women appeared to ben- effects. Because there was slight indication of heterogeneity (I² = efit relatively more from medication. A more recent study reported 44%) and there was borderline significance using a fixed-effect a significant gender by smoking rate by treatment group interac- model we used a random-effects model to estimate the pooled ef- tion, such that bupropion seemed to benefit male heavy smok- fect, which did not show a significant difference (N = 657, RR ers and female light smokers but not others (This 1.26; 95% CI 0.73 to 2.18, analysis 1.7).
study also showed an interaction among treatment effect, genderand genotype (At the end of treatment, womenwith a variant CYP2B6 gene had significantly higher quit rates Bupropion versus varenicline
when treated with bupropion than on placebo. The bupropion In three studies there was a direct comparison between bupropion treatment effect was not significant for the other three gender/ and varenicline ; ). The genotype subgroups. A study in smokers with chronic obstructive pooled estimate showed a significantly lower rate of quitting with pulmonary disease (COPD) noted a larger treatment effect for bupropion than varenicline (N = 1622, RR 0.66; 95% CI 0.53 to women (ORs 2.7 versus 1.7), although the statistical significance 0.82, analysis 1.8), with no evidence of heterogeneity. The average 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% Pooling six trials using nortriptyline as the only pharmacotherapy for varenicline.
shows evidence of a significant benefit of nortriptyline over placebo(N = 975, RR 2.03; 95% CI 1.48 to 2.78, figure 2, analysis 2.1.1)without evidence of statistical heterogeneity (I² = 7%).
Bupropion for smoking reduction
One study offered bupropion to smokers not wishing to quit (). There were no significant differences in reduced Nortriptyline & nicotine replacement combined therapy
cigarettes/day, cotinine or cessation (analysis 1.9).
compared to NRT alone
Pooling three trials (one with a factorial design entered as twostudies) using nortriptyline as an adjunct to nicotine patch therapy does not show evidence of an additional benefit from nortriptyline(N = 1,219, RR 1.29; 95% CI 0.97 to 1.72, figure 2, analysis2.1.2) with much heterogeneity (I² = 34%).
Compared to placebo control, no other pharmacotherapy
Figure 2. Nortriptyline versus placebo, long term abstinence
In two within-study comparisons, the intensity of Subgroup and sensitivity analyses
adjunctive behaviour therapy did not influence the active versus There were too few trials of nortriptyline to examine effect of du- placebo effect (In the study by Hall and ration of follow up, past depression, or amount of behavioural colleagues of extended treatment (longer duration of both nor- therapy between subgroups of trials. In one within-study com- triptyline and behaviour therapy) versus brief treatment (similar to parison, a past history of depression did not appear to modulate other nortriptyline trials), the confidence intervals for nortripty- the efficacy of nortriptyline, but subgroup numbers were small 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 clinically useful effect (RR 1.22; 95% CI 0.64 to 2.32, analysis each treatment. The extended treatment increased absolute rates 6.1). Post hoc subgroup analyses suggested that there might be of abstinence and the relative effect for nortriptyline (RR 1.34 ver- greater evidence for an effect amongst lighter smokers.
sus 0.62) but this was not statistically significant. Dose-responsestudies with nortriptyline have not been reported.
We summarize adverse events (AEs) reported in trials of bupropion Bupropion versus nortriptyline
(analysis 1.10) and nortriptyline (analysis 2.2). In addition, for Three trials included a direct comparison between bupropion and bupropion we summarize data from national surveillance schemes nortriptyline (; ). In in the United Kingdom (UK), Australia and Canada (see each study the comparison favoured bupropion but none showed Although there are no new data, there have been some new significant differences. There was no evidence of heterogeneity.
warnings since the last review. Assessing AEs in smoking cessa- When pooled the difference remains non-significant, but does not tion medications is difficult because any AEs may be due, not to exclude a clinically useful difference in favour of bupropion (N = the medication, but to nicotine withdrawal (i.e., physical depen- 417, RR 1.30; 95% CI 0.93 to 1.82 analysis 3.1).
dence). In addition, given smokers are more likely to have severalmedical and psychiatric illnesses, some "new" AEs may be exacer- Selective Serotonin Reuptake Inhibitors (SSRIs)
bations of pre-existing illnesses ( Four trials of fluoxetine ; ; ;) and one each of paroxetine () and sertra- Adverse events reported for bupropion
line were included. The pooled RR for the fluoxe-tine trials was 0.92 (N = 1,486, 95% CI 0.68 to 1.24, analysis 4.1).
The most common side effects are insomnia, occurring in 30% to Pooling only and that used fluoxetine 40% of patients, dry mouth (10%) and nausea ( alone and not an adjunct to NRT did not alter the conclusion Typical drop-out rates due to adverse events that there was no evidence of a clinically important benefit (N = range from 7% to 12%, but in one study 31% of those on 300 1,236, RR 0.92; 95% CI 0.65 to 1.30). There was no evidence of mg and 26% on 150 mg discontinued medication benefit from paroxetine (, N = 224, RR 1.08; 95% CI Early trials of bupropion as a treatment for depression using the 0.64 to 1.82) or sertraline (N = 134, RR 0.71; 95% immediate release formulation and often doses greater than 300 mg/day suggested it increased the risk of seizures in those with aprior history of alcohol withdrawal, anorexia or head trauma. Thisled to the development of the slow release (SR) preparation now Monoamine oxidase inhibitors (MAOIs)
licensed for smoking cessation. Using this preparation in doses of One trial of moclobemide and three of selegiline 300 mg/day or less, and excluding those at risk of seizures, no (; ) were included.
seizures had been reported in any of the smoking cessation tri- The effect of moclobemide was significant at six-month follow als until the study in physicians and nurses in Europe ( up but was not at the final 12-month follow up (N = 88, RR In this study there were two seizures amongst 502 people 1.57 95% CI 0.67 to 3.68, analysis 5.1.1). The selegiline trials randomized to bupropion, one of whom had a familial history were all relatively small and had heterogeneous effects, with the (data from GlaxoSmithKline). Since then two seizures have been unpublished trial () reporting higher quit rates reported in a study in which 126 participants received bupro- in the placebo group. When pooled there was no evidence of a pion and one in a study with 329 treated significant effect (N = 250, RR 1.45; 95% CI 0.81 to 2.61, I² = Two seizures were also reported in an unpublished study 55%, analysis 5.1.2). Pooling all four trials of MAOIs also gave a with 100 participants prescribed bupropion (, per- non significant estimate (RR 1.49; 95% CI 0.92 to 2.41, analysis sonal communication). This gives a total of 7 seizures amongst 5.1). also reported significantly reduced ratings of around 8,000 people exposed in clinical trials, so despite the recent craving for cigarettes.
reports the overall seizure rate remains less than the rate of 1:1000 One trial of befloxatone showed no effect on cessation but data given in product safety data. The figure of 1:1000 derives from a are unpublished ).
large, open, uncontrolled observational safety surveillance studyconducted by the manufacturers ) which examined3100 adult patients using slow release bupropion for eight weeks for treatment of depression (not smoking cessation). Treatment One trial of venlafaxine failed to show a signif- was extended if necessary to a year, at a maximum dose of 150 mg icant increase in 12-month quit rates compared to nicotine patch twice daily. Patients with a history of eating disorder, or a personal and counselling alone, but confidence intervals do not exclude a or family history of epilepsy were excluded. Three participants (i.e.
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 19 suicidal ideation from 2001 to 2004 amongst approximately use of bupropion.
698,000 people exposed ). In all these populations Post-marketing surveillance data are available from some countries the risk based on reported events is in the order of 1:10,000.
in which bupropion is licensed only for smoking cessation. Their A review of the safety of bupropion was undertaken by the Eu- limitation is that the denominator is not definitely known, and ropean Agency for the Evaluation of Medicines for Human Use serious adverse events in medical practice are underreported by as ). Suicidal ideation had been observed in six out of a much as a factor of 10 (However, using number total of 4067 participants in clinical trials for smoking cessation, of prescriptions as the denominator, the rate of reported seizures a rate of 1: 677. The rate of suicidal ideation with bupropion was in the United Kingdom and Canada appears to be no higher (and stated to be low compared with the rates found in the general pop- possibly lower) than the rate of 1 in 1000 reported by Dunner et ulation but no data were presented. It was also stated that there al. In England an observational study provided data on a cohort was neither a pharmacological nor a clinical reason for suspecting of 11,753 patients who had been dispensed bupropion bupropion to be causally associated with depression or suicide.
). Eleven seizures were reported for a rate of 1 in 1000; four The committee concluded that the benefit/risk balance remained of these were associated with a past history of seizure. A second favourable, but made recommendations to strengthen warnings UK study (used a general practice database (The on hypersensitivity, and on depression, by advising clinicians to Health Improvement Network) and a self-controlled case series be aware of the possible emergence of significant depressive symp- method to estimate the relative incidence of death or seizure in toms in patients undergoing a smoking cessation attempt.
9329 individuals over a mean (SD) follow up of 1.9 (0.9) years.
A follow-up of 136 women exposed to bupropion prescribed for The self-controlled cases series method involves comparing each smoking cessation or depression during the first trimester of preg- individual during a 'high risk' period with him/herself outside nancy suggested that bupropion does not increase the rates of ma- this period. The definition of high risk period in this study was jor malformations, but there were significantly more spontaneous 28 days after a prescription for bupropion (a 63 day high risk abortions (). An assessment of potential in- period was also used to test for robustness of the analysis). The fant exposure to bupropion and active metabolites in breast milk reported death rates (case-series age adjusted estimate) were non- suggests that the exposure of an infant whose mother was taking a significantly lower during the high risk period (28 days: 0.5, 95% therapeutic dose would be small Bupropion is also an CI 0.12 to 2.05; 63 days: 0.47, 95% CI 0.18 to 1.19) while the inhibitor of CYP2D6 so care is needed when starting or stopping seizure rates were non-significantly higher during the same period bupropion use in patients taking other medication metabolized (28 days: 3.62, 95% CI 0.87 to 15.09; 63 days: 2.38, 95% CI 0.72 by this route ).
to 7.93). The seizures recorded in the first 28 days of treatment Although no patient is reported to have died while taking bupro- occurred on days 5 and 6 in one individual with no previous pion in trials for smoking cessation, some have died while taking history of epilepsy. Of note in this study was that 12 people had bupropion prescribed for smoking cessation in routine practice.
been prescribed bupropion despite previous diagnoses of seizure.
There has been no formal epidemiological analysis of these deaths, Allergic reactions have also been reported with bupropion. These but no national reporting scheme has concluded that bupropion include pruritus, hives, angioedema and dyspnoea. Symptoms of caused these deaths. Bupropion may cause adverse effects in over- this type requiring medical treatment have been reported at a rate dose. A review of bupropion-only non-therapeutic exposures re- of about 1 to 3 per thousand in clinical trials ), ported to the US Toxic Exposure Surveillance System for 1998- and this is approximately the level at which they are being reported 1999 identified 3755 exposures to Wellbutrin SR, 2184 to Well- in the national surveillance schemes. There have also been case butrin and 1409 to Zyban (These non-therapeutic reports of arthralgia, myalgia, and fever with rash and other symp- exposures included intentional overdose and unintentional inges- toms suggestive of delayed hypersensitivity. These symptoms may tion as well as reports of adverse reactions. Clinical effects related resemble serum sickness. From the national surveillance schemes to bupropion exposure developed in 31% of non-therapeutic ex- it is not possible to calculate the frequency of this outcome. Hy- posures, with vomiting the most common childhood symptom persensitivity reactions are listed as possible rare (occurring at rates and tachycardia the most common in teenagers and adults. Six less than 1 per 1000) adverse effects in the product data.
per cent of exposures (19% of symptomatic patients) developed In the UK, Australia and France, bupropion is licensed only for a seizure. Seizures were more common with Wellbutrin exposures smoking cessation. In the UK there were four reported suicides, (22% of symptomatic patients) compared to bupropion SR (16% 78 reports of suicidal ideation and five of suicide attempts/para- of symptomatic) and Zyban (13% of exposures). Moderate or se- suicide between the licensing of bupropion and May 2004 among vere outcomes were reported in 17% of Wellbutrin exposures, 12% an estimated 1,000,000 prescriptions (In Australia of Wellbutrin SR exposures and 9% of Zyban exposures. Seventy- there were 32 reports of suicide/self-injurious ideation from ap- eight per cent of the moderate and major effects resolved in less proximately 534,000 prescriptions up to 2004 (). In than 24 hours. Five deaths all involved suspected suicides and only France there were reports of 22 suicide/attempted suicides and one in five involved Zyban or Wellbutrin SR.
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 depres- the USPHS analysis. Also, it could be because the Cochrane anal- sion in adolescents suggested they may increase the risk for suicidal ysis was a collation of six within-study randomized comparisons ideation ). Based on this finding, the US FDA issued whereas the USPS was an across-study comparison of the results warnings for several clases of antidepressants including bupropion the combination arm in three trials to the results of the patch alone when used for depression in both children and adults ( arm in 32 studies.
). In 2009, the US FDA added new warnings about the risk Meta-analysis of the three bupropion trials that compared the rec- of serious neuropsychiatric symptoms in patients using bupropion ommended dose of 300 mg/day (150 mg twice daily) with a dose for smoking cessation ; ). The of only 150 mg failed to show a significant long-term benefit of the FDA stated "these symptoms include changes in behavior, hostil- higher dose. Whilst the power of the comparison is not sufficient ity, agitation, depressed mood, suicidal thoughts and behavior, and to establish equivalence, for people with troubling side effects such attempted suicide. The added warnings are based on the contin- as insomnia, a reduction in dose to 150mg in the morning would ued review of postmarketing adverse event reports for varenicline be an alternative to discontinuing pharmacotherapy altogether.
[a smoking cessation treatment, see ] and bupropionreceived by the FDA." There were 46 reports of suicidal ideation There is still insufficient evidence from head to head trials to pre- and 29 of suicidal behaviour for bupropion to November 27 2007 fer bupropion over NRT or vice versa. In indirect, across-study comparison the efficacy seems similar. The choice between thesetwo therapies will depend on patient preferences including a con-sideration of the risks of adverse events.
Adverse effects of nortriptyline
The adverse events reported included the well known tricyclic ef- In three trials, participants treated with bupropion were signif- fects of dry mouth, drowsiness, light-headedness and constipation icantly less likely to quit than those treated with varenicline, a observed in studies treating depression in which doses were often partial nicotinic agonist. Although this suggests varenicline should > 150 mg (In addition, nortriptyline can be lethal be preferred over bupropion as a first line therapy, further study is in overdoses. Based on experiences when used to treat depression, warranted for several reasons. First, the number of studies is small.
nortriptyline would be expected to have the potential for more Second, the three trials used very similar optimal samples, set- serious adverse events. In contrast, when used at 75 to 150 mg tings and procedures. Whether superiority for varenicline would doses in smokers, drop-out rates in the trials reporting this out- occur in a more real-world setting is unclear. Finally, given that come have ranged from 4% to 12%, with one exception ( both bupropion and varenicline block nicotine receptors and in- ). This rate is similar to that for bupropion and NRT. The crease dopamine, a biological explanation for superior efficacy for only serious adverse event in someone treated with nortriptyline varenicline has not been proposed. The evidence for efficacy of was collapse/palpitations thought possibly caused by treatment varenicline is covered by another Cochrane review (Since nortriptyline is not approved for smoking Further trials of extended therapy with bupropion for individuals cessation in any country, we are unaware of any post-marketing who have recently quit bring the number included to five, and the surveillance data.
pooled estimate only narrowly excludes 1 (RR 1.17; 95% CI 0.99to 1.39) but the clinical importance of any effect seems likely tobe small. Preventing relapse remains a major challenge.
Nortriptyline has also been shown to assist cessation; there is an D I S C U S S I O N
adequate evidence base although the number of trials and the Thirty-six trials now provide a large evidence base confirming the total number of participants is much smaller than for bupropion.
benefit from bupropion used as single pharmacotherapy for smok- As with bupropion there is no evidence that the combination of ing cessation. There is no statistical heterogeneity evident and the nortriptyline and NRT is more effective than NRT alone.
pooled estimate suggests that bupropion increased long term quit- There are no direct comparisons of nortriptyline with NRT or ting success by relative factor of 1.5 - 1.9. Treatment effects appear varenicline. Head to head comparison with bupropion in three to be comparable in a range of populations, settings and types of trials favour bupropion but do not show a significant difference.
behavioural support and in smokers with and without a past his- The pooled risk ratios of efficacy of nortriptyline and bupropion tory of depression. Clear evidence of an additional benefit from appear broadly similar. One argument for considering nortripty- adding bupropion to NRT was not demonstrated. The meta-anal- line as a first line therapy is its lower cost (). The ysis for the updated USPHS clinical practice guideline reported main argument against this is based on the potential for serious an odds ratio of 1.3 (95% CI 1.0 to 1.8) for a combination versus adverse effects ().
nicotine patch alone table 6.28). The difference inmeta-analytic outcomes may be because the current analysis in- Although not widely tested, the efficacy of bupropion and nor- cluded several studies of hard-to-treat populations not included in triptyline appear to be independent of a past history of depression Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(; ) and post-cessation depres- term trials have, somewhat surprisingly, failed to show that this sion , reporting an analysis of ). This class of antidepressants helps smoking cessation. Some studies have suggests that their efficacy is not due to a traditional antidepressant found SSRIs effective in post hoc-determined subgroups effect and that they benefit those with no history of depression.
but this requires verification. The most re- Although the pharmacological mechanism of action of bupropion cent trial (Spring 2007) found that although fluoxetine initially is still unclear, recent animal studies suggest that it may act as increased cessation amongst smokers with a history of depressive an antagonist at the nicotine receptor ; , disorder, by the end of the study it impaired cessation regardless How nortriptyline increases cessation is unclear.
of depressive history.
There is no clear evidence of long term efficacy for monoamine Although there is considerable research interest in genetic differ- oxidase inhibitors. Two early trials of selegiline suggested a possible ences that could help predict response to pharmacotherapy benefit whilst the most recent trial has not supported this.
), there is currently no genetic test that can be used for treat-ment matching in a clinical setting. There is preliminary evi-dence that smokers with normal dopamine receptor availability Mechanism of action of antidepressants
and function might respond better to bupropion (; Whether the efficacy of bupropion and nortriptyline is specific to ) whilst genotypes that are associated with impaired the unique pharmacology of these medications or whether it would dopaminergic systems could have relatively better outcomes with occur in all antidepressants has not been completely resolved. The NRT (). It is also possible that women with par- SSRI antidepressants appear not to be efficacious. This suggests ticular genotypes may respond differently to bupropion compared serotonin modulation is not important, leaving the dopaminergic with men having the same genotypes (The rate of or noradrenergic effects of nortriptyline and bupropion to account metabolism of nicotine has also been suggested as a moderator of for their efficacy. Although the efficacy of bupropion was initially treatment effect, with fast metabolisers benefiting from bupropion thought to be due to its dopaminergic actions, nortriptyline, which (, reported in ).
is also effective, has relatively weak dopaminergic activity. In addi- No seizures were reported in the first large studies of bupropion tion, bupropion has as much noradrenergic activity as dopamin- for smoking cessation but more recently four studies ( ergic activity. Another possibility, at least for bupropion, is that it acts as a nicotinic receptor blocker (). Whether the tal of 7 seizures. Since about 8,000 people have been exposed to same is true for nortriptyline is not clear (If no- bupropion in the cessation studies included in this review, the radrenergic effects are important in treatments for smoking, then averaged rate is still less than the 1:1000 estimated risk used in monoamine oxidase inhibitors and other tricyclic antidepressants product safety information, although the clustering of seizures in should be effective; however, only a few small trials of these are a few small studies is unexpected. Some suicides and deaths while taking bupropion have been reported. Currently, like many otherantidepressants and varenicline, bupropion has a warning aboutthe possibility of serious mood and behavioral changes. However, Comparison with prior reviews and meta-analyses
it remains unclear whether these outcomes were caused by bupro- The findings of this review are in agreement with the conclusions of pion effects.
other reviews and guidelines ; ; In studies in depressed patients nortriptyline sometimes caused sedation, constipation, urinary retention and cardiac problems, ). Many national smoking cessation and when taken as an overdose could be fatal. Based on the rate guidelines were last updated six years ago. The US guidelines were of significant adverse events when used to treat depression, nor- updated in 2008 ) and continue to recommend bupro- triptyline would be expected to have higher rate of drop-outs. This pion as a first line therapy and nortriptyline as a second-line ther- has not been the case in the relatively small number of subjects apy due to possible adverse events. Open uncontrolled trials and receiving nortriptyline in the existing studies (about 500), perhaps observational studies of bupropion have shown real-life quit rates because the dose of nortriptyline used (75 to 150 mg) is generally comparable to those found in clinical trials (; smaller than that used for depression and smokers are not acutely Studies of cost-effectiveness also support the ill. However, given this small sample size, the safety of these doses utility of bupropion ) and nortriptyline of nortriptyline for smoking cessation is still unclear.
The six long-term trials of selective serotonin reuptake inhibitors(SSRIs) (fluoxetine, paroxetine and sertraline) and other short- Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Implications for practice
Implications for research
The existing evidence supports a role for bupropion and nortripty- More research is needed with different antidepressants to deter- line in clinical practice. Nicotine replacement therapy has proven mine which antidepressants or classes of antidepressant are effec- efficacy in over 90 studies and has a very benign side- tive in smoking cessation. Determining this could provide insight effect profile. There is insufficient published evidence to conclude not only into the mechanism of action of antidepressant efficacy either bupropion or nortriptyline has superior efficacy to NRT or but also into the biological factors controlling nicotine depen- vice versa. The confidence intervals around the efficacy estimates dence and smoking. Antidepressants of the SSRI category are not for bupropion, nortriptyline and NRT overlap. Bupropion and effective, which suggests serotonin may not be an important fac- nortriptyline are equally effective in smokers with and without tor. However it is unclear whether dopaminergic, noradrenergic a history of depression and their efficacy does not appear to be or nicotinic-cholinergic monoaminergic activity or blockage of mediated by improving post-cessation depression. Although the nicotine receptors is most important for cessation efficacy. Given US Guideline ) suggests smokers with depres- some suggestive results with selegiline, further trials of this com- sion problems should use bupropion rather than NRT, whether pound and other monoamine oxidase inhibitors (MAOIs), which smokers with a previous history of depression or mild current de- have mostly adrenergic activity, could be helpful. Similarly, the pression would do better with antidepressants than NRT has not suggestive findings that genotype might moderate antidepressant been tested. Whether bupropion prevents depressive symptoms or treatment efficacy deserves follow-up. Also, it would be helpful relapse to depression better than NRT has also not been studied.
to know whether bupropion's efficacy is due to receptor block- Patient preferences, cost, availability and side-effect profile will all ade and whether nortriptyline also is a nicotine receptor blocker.
need to be taken into account in choosing among medications.
Research on the biological and behavioural mediators of the ef- Bupropion and nortriptyline may be helpful in those who fail ficacy of bupropion and nortriptyline is needed; e.g. how much on nicotine replacement therapy. Recent studies (; of their efficacy is due to craving or withdrawal relief, blocking ; ) comparing bupropion with vareni- nicotine reinforcement, or preventing lapses from becoming re- cline have shown higher quit rates with varenicline.
lapses. Knowledge of whether NRT or antidepressants have moreefficacy in decreasing depression post-cessation would help decide All smoking cessation medications can produce clinically signifi- whether smokers with a past history of depression should prefer cant adverse effects. When people are initially screened for poten- antidepressants over NRT.
tial adverse effects, however, fewer than 10% of those on antide-pressants for smoking cessation stop taking the medications due The use of antidepressants in combination with nicotine replace- to adverse effects. Although bupropion use has been associated ment therapy, in smokers who have failed with NRT, in smokers with deaths in lay public reports, currently there is insufficient ev- with baseline dysphoria, should be further investigated as initial idence to state that bupropion caused these deaths. There has also data suggest the combination may add efficacy. Given the concern been concern about antidepressants such as bupropion being as- by some about deaths and psychiatric disorders from antidepres- sociated with psychiatric disorders including suicidal ideation and sants used for smoking cessation, continued monitoring is indi- suicide attempts. Again, is not clear that there is a causal relation- ship. Smoking cessation may also precipitate depression (). Also, although nortriptyline is associated with more sideeffects when used for depression, in the doses used for smokingcessation 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 Our thanks to Drs Niaura, Borrelli, Spring, Fiore, Hurt, Mizes, America, Australia and Europe, but is not available in many other Ferry, Schuh, Cinciripini, Hays, Prochazka, Ahluwalia, Mayo, countries. Often, bupropion is available in these countries under Collins, Novotny, Brown, David & Evins for assistance with ad- the name Wellbutrin SR as a treatment for depression. Nortripty- ditional information or data on studies.
line is marketed as an antidepressant in many countries but isnot currently marketed as a smoking cessation aid in any country.
JR Hughes's contribution is supported by Research Scientist De- In almost all countries, bupropion and nortriptyline are available velopment Award DA-00490 from the National Institute on Drug only as prescription medications.
Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
R E F E R E N C E S
References to studies included in this review
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Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Cinciripini 2005 {published data only}
Pinto A, et al.Effect of bupropion on depression symptoms Cinciripini PM, Tsoh JY, Friedman K, Wetter D, in a smoking cessation clinical trial. Psychology of Addictive Cinciripini LG, Skaar KL. A placebo controlled evaluation of venlafaxine for smoking cessation: preliminary findings Lerman C, Roth D, Kaufmann V, Audrain J, Hawk L, [Abstract A18]. Society for Research on Nicotine and Liu AY, et al.Mediating mechanisms for the impact of Tobacco Annual Meeting; Mar 27-29 1998; New Orleans, bupropion in smoking cessation treatment. Drug and Louisiana. 1998.
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Uhl GR, Liu QR, Drgon T, Johnson C, Walther D, Rose Berrettini WH, Wileyto EP, Epstein L, Restine S, Hawk L, JE, et al.Molecular genetics of successful smoking cessation: Shields P, et al.Catechol-O-methyltransferase (COMT) gene convergent genome-wide association study results. Archives variants predict response to bupropion therapy for tobacco of General Psychiatry 2008;65(6):683–93.
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Wileyto EP, Patterson F, Niaura R, Epstein LH, Brown ∗ Collins B, Wileyto P, Patterson F, Rukstalis M, Audrain- RA, Audrain-McGovern J, et al.Recurrent event analysis of McGovern J, Kaufmann V, et al.Gender differences in lapse and recovery in a smoking cessation clinical trial using smoking cessation in a placebo-controlled trial of bupropion bupropion. Nicotine & Tobacco Research 2005;7:257–68.
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Covey LS, Glassman AH, Stetner F, Rivelli S. A trial of David SP, Strong DR, Munafo MR, Brown RA, Lloyd- sertraline for smokers with past major depression. Society Richardson EE, Wileyto PE, et al.Bupropion efficacy for for Research on Nicotine and Tobacco Meeting. Arlington, smoking cessation is influenced by the DRD2 Taq1A polymorphism: Analysis of pooled data from two clinical trials. Nicotine & Tobacco Research 2007;9(12):1251–7.
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Lee AM, Jepson C, Hoffmann E, Epstein L, Hawk LW,Lerman C, et al.CYP2B6 genotype alters abstinence rates in Covey 2007 {published data only}
a bupropion smoking cessation trial. Biological Psychiatry Covey LS, Botello-Harbaum M, Glassman AH, Masmela J, LoDuca C, Salzman V, et al.Smokers' response to Lerman C, Jepson C, Wileyto EP, Epstein LH, Rukstalis combination bupropion, nicotine patch, and counseling M, Patterson F, et al.Role of functional genetic variation treatment by race/ethnicity. Ethnicity & Disease 2008;18:
in the dopamine D2 receptor (DRD2) in response to bupropion and nicotine replacement therapy for tobacco ∗ Covey LS, Glassman AH, Jiang H, Fried J, Masmela J, dependence: results of two randomized clinical trials.
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Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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smoking cessation in schizophrenia. Journal of Clinical Clark MM, Hurt RD, Croghan IT, Patten CA, Novotny P, Sloan JA, et al.The prevalence of weight concerns in a Evins AE, Deckersbach T, Cather C, Freudenreich O, smoking abstinence clinical trial. Addictive Behaviors 2006; Culhane MA, Henderson DC, et al.Independent effects of tobacco abstinence and bupropion on cognitive function Croghan IT, Hurt RD, Croghan GA, Sloan JA. Comparing in schizophrenia. Journal of Clinical Psychiatry 2005;66:
nicotine inhaler, bupropion and nicotine inhaler plus bupropion in treating tobacco dependence [abstract].
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placebo-controlled trial of bupropion sustained-release for Sustained-release bupropion combined with transdermal Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
nicotine patch for smoking cessation in schizophrenia cigarette smoking using nortriptyline. Nicotine & Tobacco (SYM11C). Society for Research on Nicotine and Tobacco 13th Annual Meeting February 21-24, Austin, Texas. 2007.
∗ Hall SM, Reus VI, Munoz RF, Sees KL, Humfleet G,Hartz DT, et al.Nortriptyline and cognitive-behavioral Gonzales 2001 {published data only}
therapy in the treatment of cigarette smoking. Archives of ∗ Gonzales D, Nides M, Ferry LH, Segall N, Herrero L, Modell J, et al.Retreatment with bupropion SR: results Mooney ME, Reus VI, Gorecki J, Hall SM, Humfleet from 12-month follow-up (RP-83). Rapid Communication GL, Munoz RF, et al.Therapeutic drug monitoring of Poster Abstracts. Society for Research on Nicotine and nortriptyline in smoking cessation: a multistudy analysis.
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Gonzales DH, Nides MA, Ferry LH, Kustra RP, Jamerson Hall 2002 {published data only}
BD, Segall N, et al.Bupropion SR as an aid to smoking Hall SM, Gorecki JA, Reus VI, Humfleet GL, Munoz RF.
cessation in smokers treated previously with bupropion: A Belief about drug assignment and abstinence in treatment of randomized placebo-controlled study. Clinical Pharmacology cigarette smoking using nortriptyline. Nicotine & Tobacco Research 2007;9(4):467–71.
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R, Hartz DT. Nortriptyline versus bupropion and medical ∗ Gonzales D, Rennard SI, Nides M, Oncken C, Azoulay management versus psychological intervention in smoking S, Billing CB, et al.Varenicline, an alpha4beta2 nicotinic treatment (PA 5A). Society for Research on Nicotine acetylcholine receptor partial agonist, vs sustained-release and Tobacco 7th Annual Meeting March 23-23 Seattle, bupropion and placebo for smoking cessation: a randomized controlled trial. JAMA 2006;296:47–55.
∗ Hall SM, Humfleet GL, Reus VI, Munoz RF, Hartz Jackson KC, Nahoopii R, Said Q, Dirani R, Brixner DT, Maude-Griffin R. Psychological intervention and D. An employer-based cost-benefit analysis of a novel antidepressant treatment in smoking cessation. Archives of pharmacotherapy agent for smoking cessation. Journal of Occupational & Environmental Medicine 2007;49(4):
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Górecka D, Bednarek M, Nowinski A, Puscinska E, Goljan- Geremek A, Zielinski J. Effect of treatment for nicotine Mooney ME, Reus VI, Gorecki J, Hall SM, Humfleet dependence in patients with COPD [Wyniki leczenia GL, Munoz RF, et al.Therapeutic drug monitoring of uzaleznienia od nikotyny chorych na przewlekla obturacyjna nortriptyline in smoking cessation: a multistudy analysis.
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Haggsträm FM, Chatkin JM, Sussenbach-Vaz E, Cesari DH, Extended nortriptyline and psychological treatment for Fam CF, Fritscher CC. A controlled trial of nortriptyline, cigarette smoking. American Journal of Psychiatry 2004;161:
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Rennard S, Hatsukami D, Malcolm R E, Patel MK, Hall SM, Gorecki JA, Reus VI, Humfleet GL, Munoz RF.
Jamerson BD, Dozier G. Zyban (bupropion HCL SR) vs Belief about drug assignment and abstinence in treatment of placebo as an aid to smoking reduction among smokers 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 Andrew Johnston December 10 1996.
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Durcan MJ, Deener G, White J, Johnston JA, Gonzales Johnston JA, Fiedler-Kelly J, Glover ED, Sachs DP, Grasela D, Niaura R, et al.The effect of bupropion sustained- TH, DeVeaugh-Geiss J. Relationship between drug exposure release on cigarette craving after smoking cessation. Clinical and the efficacy and safety of bupropion sustained release for smoking cessation. Nicotine Tob Res 2001;3:131–40.
Durcan MJ, Johnston JA, White J, Gonzales D, Sachs DP,Rigotti N, Niaura R. Bupropion SR for relapse prevention: Hurt 2003 {published and unpublished data}
a "slips-allowed" analysis. American Journal of Health Hurt RD, Croghan GA, Sloan JA, Krook JE, Silberstein PT. Bupropion for relapse prevention after nicotine patch Gonzales D, Bjornson W, Durcan MJ, White JD, Johnston therapy [PA 5B abstract ]. Society for Research on Nicotine JA, Buist AS, et al.Effects of gender on relapse prevention and Tobacco 7th Annual Meeting, March 23-23 2001, in smokers treated with bupropion SR. American Journal of Seattle, Washington. 2001:32.
∗ Hurt RD, Krook JE, Croghan IT, Loprinzi CL, Sloan JA, ∗ Hays JT, Hurt RD, Rigotti NA, Niaura R, Gonzales Novotny PJ, et al.Nicotine patch therapy based on smoking D, Durcan MJ, et al.Sustained-release bupropion for rate followed by bupropion for prevention of relapse to pharmacologic relapse prevention after smoking cessation.
smoking. Journal of Clinical Oncology 2003;21:914–20.
A randomized, controlled trial. Annals of Internal Medicine Jorenby 1999 {published data only}
Durcan MJ, White J, Jorenby DE, Fiore MC, Rennard SI, Hurt RD, Wolter TD, Rigotti N, Hays JT, Niaura R, Leischow SJ, et al.Impact of prior nicotine replacement Durcan MJ, et al.Bupropion for pharmacologic relapse therapy on smoking cessation efficacy. American Journal of prevention to smoking - Predictors of outcome. Addictive Jamerson BD, Nides M, Jorenby DE, Donahue R, Garrett Rigotti N, Thorndike AN, Durcan MJ, White JD, Johnston P, Johnston JA, et al.Late-term smoking cessation despite AJ, Niaura R, et al.Attenuation of post-cessation weight gain initial failure: an evaluation of bupropion sustained release, in smokers taking bupropion: The effect of gender. Abstract nicotine patch, combination therapy, and placebo. Clinical Book. Society for Research on Nicotine and Tobacco 6th Annual Meeting; Feb 18-20 2000; Arlington VA. 2000.
∗ Jorenby DE, Leischow SJ, Nides MA, Rennard SI,Johnston JA, Hughes AR, et al.A controlled trial of Hertzberg 2001 {published data only}
sustained-release bupropion, a nicotine patch, or both for Hertzberg MA, Moore SD, Feldman ME, Beckham JC.
smoking cessation. New England Journal of Medicine 1999; A preliminary study of bupropion sustained-release for smoking cessation in patients with chronic posttraumatic Nielsen K, Fiore MC. Cost-benefit analysis of sustained- stress disorder. Journal of Clinical Psychopharmacology 2001; release bupropion, nicotine patch, or both for smoking cessation. Preventive Medicine 2000;30:209–216.
Holt 2005 {published data only}
Smith SS, Jorenby DE, Leischow SJ, Nides MA, Rennard Holt S, Timu-Parata C, Ryder-Lewis S, Weatherall M, SI, Johnston AJ, et al.Targeting smokers at increased risk Beasley R. Efficacy of bupropion in the indigenous Maori for relapse: treating women and those with a history of population in New Zealand. Thorax 2005;60:120–23.
depression. Nicotine & Tobacco Research 2003;5:99–109.
Hurt 1997 {published and unpublished data}
Jorenby 2006 {published data only}
Dale LC, Glover ED, Sachs DP, Schroeder DR, Offord ∗ Jorenby DE, Hays JT, Rigotti NA, Azoulay S, Watsky EJ, KP, Croghan IT, et al.Bupropion for smoking cessation: Williams KE, et al.Efficacy of varenicline, an alpha4beta2 predictors of successful outcome. Chest 2001;119:
nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation: a Glaxo Wellcome. Presentation for FDA approval of randomized controlled trial. JAMA 2006;296:56–63.
Bupropion sustained release for smoking cessation. Dr J.
West R, Baker CL, Cappelleri JC, Bushmakin AG. Effect Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
of varenicline and bupropion SR on craving, nicotine meeting, March 2005; Prague, Czech Republic. Rapid withdrawal symptoms, and rewarding effects of smoking Communications posters. 2005.
during a quit attempt. Psychopharmacology 2008;197(3):
Myles 2004 {published data only}
Myles PS, Leslie K, Angliss M, Mezzavia P, Lee L.
Killen 2000 {published data only}
Effectiveness of bupropion as an aid to stopping smoking Killen JD, Fortmann SP, Schatzberg A, Hayward C, Varady before elective surgery: a randomised controlled trial.
A. Onset of major depression during treatment for nicotine dependence. Addictive Behaviors 2003;28:461–70.
Niaura 2002 {published data only}
∗ Killen JD, Fortmann SP, Schatzberg AF, Hayward Borrelli B, Niaura R, Keuthen NJ, Goldstein MG, Depue C, Sussman L, Rothman M, et al.Nicotine patch and JD, Murphy C, et al.Development of major depressive paroxetine for smoking cessation. Journal of Consulting and disorder during smoking-cessation treatment. Journal of Killen 2004 {published data only}
Borrelli B, Papandonatos G, Spring B, Hitsman B, Niaura Killen JD, Robinson TN, Ammerman S, Hayward C, R. Experimenter-defined quit dates for smoking cessation: Rogers J, Samuels D. Major depression among adolescent adherence improves outcomes for women but not for men.
smokers undergoing treatment for nicotine dependence.
Borrelli B, Spring B, Niaura R, Hitsman B, Papandonatos ∗ Killen JD, Robinson TN, Ammerman S, Hayward C, G. Influences of gender and weight gain on short-term Rogers J, Stone C, et al.Randomized clinical trial of the relapse to smoking in a cessation trial. Journal of Consulting efficacy of bupropion combined with nicotine patch in the and Clinical Psychology 2001;69:511–15.
treatment of adolescent smokers. Journal of Consulting and Borrelli B, Spring B, Niaura R, Kristeller J, Ockene JK, Keuthen NJ. Weight suppression and weight rebound in ex-smokers treated with fluoxetine. Journal of Consulting and Killen 2006 {published data only}
Killen JD, Fortmann SP, Murphy GM Jr, Hayward C, Cook JW, Spring B, McChargue DE, Borrelli B, Hitsman Arredondo C, Cromp D, et al.Extended Treatment With B, Niaura R, et al.Influence of fluoxetine on positive and Bupropion SR for Cigarette Smoking Cessation. Journal of negative affect in a clinic-based smoking cessation trial.
Consulting and Clinical Psychology 2006;74(2):286–94.
McCarthy 2008 {published data only}
Doran N, Spring B, Borrelli B, McChargue D, Hitsman B, McCarthy DE. Mechanisms of tobacco cessation treatment: Niaura R, Hedeker D. Elevated positive mood: a mixed Self-report mediators of counseling and bupropion sustained blessing for abstinence. Psychology of Addictive Behaviors release treatment. Dissertation Abstracts International: Section B: The Sciences and Engineering 2007;67(9-B):5414.
Hitsman B, Spring B, Borrelli B, Niaura R, Papandonatos McCarthy DE, Piasecki TM, Lawrence DL, Jorenby GD. Influence of antidepressant pharmacotherapy on DE, Shiffman S, Baker TB. Psychological mediators behavioral treatment adherence and smoking cessation of bupropion sustained-release treatment for smoking outcome in a combined treatment involving fluoxetine.
Experimental & Clinical Psychopharmacology 2001;9:
∗ McCarthy DE, Piasecki TM, Lawrence DL, Jorenby DE, Shiffman S, Fiore MC, et al.A randomized controlled Mizes JS, Sloan DM, Segraves K, Spring B, Pingatore R, clinical trial of bupropion SR and individual smoking Kristeller J. Fluoxetine and weight-gain in smoking cessation cessation counseling. Nicotine & Tobacco Research 2008;10:
- examination of actual weight-gain and fear of weight-gain [abstract]. Psychopharmacology Bulletin 1996;32:491.
McCarthy DE. Piasecki TM, Lawrence DL, Fiore MC, Niaura R, Goldstein M, Spring B, Keuthen N, Kristeller Baker TB. Efficacy of bupropion SR and individual J, DePue J, et al.Fluoxetine for smoking cessation: A counseling among adults attempting to quit smoking multicenter randomized double blind dose reponse study.
(POS1-041). Society for Research on Nicotine and Tobacco Society for Behavioral Medicine Annual Meeting; April 18 10th Annual Meeting February 18-21, Phoenix, Arizona.
1997; San Francisco, CA.
∗ Niaura R, Spring B, Borrelli B, Hedeker D, Goldstein Muramoto 2007 {published data only}
MG, Keuthen N, et al.Multicenter trial of fluoxetine as an ∗ Muramoto ML, Leischow SJ, Sherrill D, Matthews E, adjunct to behavioral smoking cessation treatment. Journal Strayer LJ. Randomized, double-blind, placebo-controlled of Consulting and Clinical Psychology 2002;70:887–96.
trial of 2 dosages of sustained-release bupropion for Swan GE, Jack LM, Niaura R, Borrelli B, Spring B.
adolescent smoking cessation. Archives of Pediatrics & Subgroups of smokers with different success rates after treatment with fluoxetine for smoking cessation [abstract].
Taren D, Fankem S, Muramoto M. Weight loss in Nicotine & Tobacco Research 1999;1:281.
adolescents who quit smoking with bupropion [RP-071].
Nides 2006 {published data only}
Society for Research on Nicotine and Tobacco 11th annual ∗ Nides M, Oncken C, Gonzales D, Rennard S, Watsky 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, Saules 2004 {published and unpublished data}
a selective alpha4beta2 nicotinic receptor partial agonist: ∗ Saules KK, Schuh LM, Arfken CL, Reed K, Kilbey Results from a 7-week, randomized, placebo- and MM, Schuster CR. Double-blind placebo-controlled trial bupropion-controlled trial with 1-year follow-up. Archives of fluoxetine in smoking cessation treatment including of Internal Medicine 2006;166:1561–8.
nicotine patch and cognitive-behavioral group therapy.
Oncken C, Watsky E, Reeves K, Anziano R. Varenicline American Journal on Addictions 2004;14:438–46.
is efficacious and well tolerated in promoting smoking Schuh LM, Downey KK, Hopper JA, Tancer M, Schuster cessation: results from a 7-week, randomized, placebo- CR. Fluoxetine in smoking cessation treatment. College on and bupropion-controlled trial. Society for Research on Problems of Drug Dependence Annual Meeting, San Juan, Nicotine and Tobacco 11th Annual Meeting, 20-23 March Puerto Rico 2000.
2005, Prague, Czech Republic. 2005.
Schmitz 2007 {published data only}
Piper 2007 {published data only}
Schmitz JM, Stotts AL, Mooney ME, Delaune KA, Moeller Piper ME. Bupropion alone and in combination with GF. Bupropion and cognitive-behavioral therapy for nicotine gum: Efficacy, mediation and moderation.
smoking cessation in women.[erratum appears in Nicotine Dissertation Abstracts International: Section B: The Sciences Tob Res. 2007 Jul;9(7):785]. Nicotine & Tobacco Research ∗ Piper ME, Federman EB, McCarthy DE, Bolt DM, Selby 2003 {unpublished data only}
Smith SS, Fiore MC, et al.Efficacy of bupropion alone and GlaxoSmithKline Clinical Trials Register. Study No: in combination with nicotine gum. Nicotine & Tobacco ZYB40001. A randomized, double-blind, placebo- controlled, 12-week smoking cessation trial of Zyban (150 Piper ME, Federman EB, Smith SS, Fiore MC, Baker TB.
mg bid) in adult smokers previously treated with Zyban.
Efficacy of bupropion SR alone and combined with 4- mg gum (PA2-2). Society for Research on Nicotine and IV˙ZYB40001.pdf (accessed 23rd August 2006).
Tobacco 10th Annual Meeting February 18-21, Phoenix, Selby P, Ainslie M, Stepner N, Roberts J. Sustained-release Arizona. 2004:18.
bupropion (Zybanr) is effective in the re-treatment of Piper ME, Federmen EB, McCarthy DE, Bolt DM, Smith relapsed adult smokers. Am J Respir Crit Care Med 2003; SS, Fiore MC, et al.Using mediational models to explore the nature of tobacco motivation and tobacco treatment effects.
∗ Selby P, Brands B, Stepner N. Retreatment with ZYban Journal of Abnormal Psychology 2008;117:94–105.
SR: 52 week follow-up of a Canadian Multicentre trial Prochazka 1998 {published data only}
(POS3-63). Society for Research on Nicotine and Tobacco Prochazka AV, Weaver MJ, Keller RT, Fryer GE, Licari PA, 9th Annual Meeting, February 19-22, New Orleans. 2003.
Lofaso D. A randomized trial of nortriptyline for smoking Selby P, Brosky G, Baker R, Lertzman M, Dakin P, Roberts cessation. Archives of Internal Medicine 1998;158:2035–9.
J. Zyban is effective in the retreatment of relapsed adultsmokers (PO4 68). Society for Research on Nicotine Prochazka 2004 {published data only}
and Tobacco 7th Annual Meeting March 23-23 Seattle ∗ Prochazka AV, Kick S, Steinbrunn C, Miyoshi T, Fryer GE. A randomized trial of nortriptyline combined withtransdermal nicotine for smoking cessation. Archives of Simon 2004 {published data only}
Caplan BJ. The "bupropion for smoking cessation" trial Prochazka AV, Reyes R, Steinbrunn C, Miyoshi T.
from a family practice perspective. Archives of Internal Randomized trial of nortriptyline combined with transdermal nicotine for smoking cessation (PO3 26).
Simon JA, Duncan C, Carmody TP, Hudes ES. Bupropion Society for Research on Nicotine and Tobacco 7th Annual for smoking cessation: a randomized trial. Archives of Meeting, March 23-23 2001, Seattle, Washington. 2001: Simon JA, Duncan C, Carmody TP, Hudes ES. Bupropionplus nicotine replacement no better than replacement alone.
Rigotti 2006 {published data only}
Journal of Family Practice 2004;53:953–4.
Rigotti N, Thorndike A, Regan S, Pasternak R, ChangY, McKool K, et al.Safety and efficacy of bupropion for Simon 2009 {published data only}
smokers hospitalized with acute cardiovascular disease Simon JA, Duncan C, Huggins J, Solkowitz S, Carmody [abstract]. Nicotine & Tobacco Research 2005;7:682.
TP. Sustained-release bupropion for hospital-based smoking ∗ Rigotti NA, Thorndike AN, Regan S, McKool K, cessation: a randomized trial. Nicotine & Tobacco Research Pasternak RC, Chang Y, et al.Bupropion for smokers hospitalized with acute cardiovascular disease. American SMK20001 {unpublished data only}
Journal of Medicine 2006;119:1080–7.
GlaxoSmithKline Clinical Trials Register. Study No: SMK Thorndike AN, Regan S, McKool K, Pasternak RC, Swartz 20001. A Multi-Center, Double-Blind, Double-Dummy, S, Torres-Finnerty N, et al.Depressive symptoms and Placebo-Controlled, Randomized, Parallel Group, Dose smoking cessation after hospitalization for cardiovascular Response Evaluation of a New Chemical Entity (NCE) and disease. Archives of Internal Medicine 2008;168(2):186–91.
ZYBAN (bupropion hydrochloride) Sustained Release 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.
for smoking cessation in a health care setting: a randomized trial. Archives of Internal Medicine 2003;163:2337–44.
(accessed 4th August 2009).
Swan GE, Valdes AM, Ring HZ, Khroyan TV, Jack LM,Ton CC, et al.Dopamine receptor DRD2 genotype and Spring 2007 {published data only}
smoking cessation outcome following treatment with Carrington A, Doran N, Spring B. Fluoxetine moderates bupropion SR. Pharmacogenomics Journal 2005;5:21–9.
the association between trait-anxiety and smoking statusfollowing behavioral treatment for smoking cessation Tashkin 2001 {published data only}
(POS4-81). Society for Research on Nicotine and Tobacco Patel MK, Tashkin DP, Kanner RE, Bailey WC, Buist A, 9th Annual Meeting February 19-22 New Orleans, Anderson PJ, et al.A multicenter evaluation of the effects Louisiana. 2003.
of bupropion hydrochloride sustained release tablets ∗ Spring B, Doran N, Pagoto S, McChargue D, Cook (Bup SR) versus placebo in a population of smokers with JW, Bailey K, et al.Fluoxetine, smoking, and history of chronic obstructive pulmonary disease (PO130). 11th major depression: A randomized controlled trial. Journal of World Conference on Tobacco or Health; Aug 6-11 2000; Consulting & Clinical Psychology 2007;75:85–94.
Chicago, ILL. 2000; Vol. 1:118.
Spring B, Doran N, Pagoto S, McChargue DE, Cook JW, ∗ Tashkin D, Kanner R, Bailey W, Buist S, Anderson P, Bailey K, et al.Reduced abstinence for smokers previously Nides M, et al.Smoking cessation in patients with chronic treated with fluoxetine (PA1-1). Society for Research on obstructive pulmonary disease: a double-blind, placebo- Nicotine and Tobacco 10th Annual Meeting February 18- controlled, randomised trial. Lancet 2001;357:1571–75.
21, Phoenix, Arizona. 2004.
Tonnesen 2003 {published data only}
Swan 2003 {published data only}
Bolliger CT, Gilljam H, Lebargy F, van Spiegel PI, Edwards Catz S, Jack LM, Swan GE, McClure J. Adherence to J, Hider A, et al.Bupropion hydrochloride (Zyban) is bupropion SR in a smoking cessation effectiveness trial effective and well tolerated as an aid to smoking cessation (POS2-77). Society for Research on Nicotine and Tobacco - a multicountry study. Abstract and presentation at 11th 12th Annual Meeting February 15-18, Orlando, Florida.
Annual meeting of European Respiratory Society, Berlin, September 22-26 2001. European Respiratory Journal 2001; Jack LM, Swan GE, Thompson E, Curry SJ, McAfee T, 18 (Suppl 33):12s.
∗
Dacey S, Bergman K. Bupropion SR and smoking cessation Tonnesen P, Tonstad S, Hjalmarson A, Lebargy F, van in actual practice: methods for recruitment, screening, Spiegel PI, Hider A, et al.A multicentre, randomized, and exclusion for a field trial in a managed-care setting.
double-blind, placebo-controlled, 1-year study of bupropion SR for smoking cessation. Journal of Internal Medicine Javitz HS, Swan GE, Zbikowski SM, Curry SJ, McAfee TA, Decker DL, et al.Cost-effectiveness of different Tonstad S, Aaserud E, Hjalmarson A, Peiffer G, van der combinations of bupropion SR dose and behavioral Molen T, Hider, et al.Zyban is an effective and well tolerated treatment for smoking cessation: a societal perspective.
aid to smoking cessation in a general smoking population American Journal of Managed Care 2004;10:217–26.
- a multi-country study. Society for Research on Nicotine McAfee T, Zbikowski SM, Bush T, McClure J, Swan G, and Tobacco 3rd Europe Conference, September 19-22 Jack LM, Curry S. The effectiveness of bupropion SR and 2001, Paris, France 2001:46.
phone counseling for light and heavy smokers (PA2-1).
Tonstad 2003 {published data only}
Society for Research on Nicotine and Tobacco 10th Annual McRobbie H, Brath H, Astbury C, Hider A, Sweet R.
Meeting February 18-21, Phoenix, Arizona. 2004.
Bupropion hydrochloride sustained release (SR) is an Swan GE, Jack LM, Curry S, Chorost M, Javitz H, McAfee effective and well tolerated aid to smoking cessation in T, Dacey S. Bupropion SR and counseling for smoking smokers with cardiovascular disease 12 month follow-up cessation in actual practice: Predictors of outcome. Nicotine phase data (ZYB40014). Abstract and presentation at & Tobacco Research 2003;5:911–21.
European Respiratory Society meeting, 14-18 September Swan GE, Jack LM, Javitz HS, McAfee T, McClure JB.
2002, Stockholm, Sweden. 2002.
Predictors of 12-month outcome in smokers who received ∗ Tonstad S, Farsang C, Klaene G, Lewis K, Manolis A, bupropion sustained-release for smoking cessation. Central Perruchoud AP, Silagy C, van Spiegel PI, Astbury C, Hider Nervous System Drugs 2008;22(3):239–56.
A, Sweet R. Bupropion SR for smoking cessation in smokers Swan GE, Jack LM, Valdes AM, Ring HZ, Ton CC, Curry with cardiovascular disease: a multicentre, randomised SJ, et al.Joint effect of dopaminergic genes on likelihood of study. European Heart Journal 2003;24:946–55.
smoking following treatment with bupropion SR. Health van Spiegel PI, Lewis K, Seinost G, Astbury C, Hider A, Sweet R. Bupropion hydrochloride (Zyban) is an effective Swan GE, Javitz HS, Jack LM, Curry SJ, McAfee T.
and well tolerated aid to smoking cessation in smokers Heterogeneity in 12-month outcome among female and with cardiovascular disease - a multicountry study. Abstract male smokers. Addiction 2004;99:237–50.
and presentation at 11th Annual meeting of European ∗ Swan GE, McAfee T, Curry SJ, Jack LM, Javitz H, Dacey Respiratory Society, Berlin, September 22-26. European S, Bergman K. Effectiveness of bupropion sustained release Respiratory Journal 2001;18((Suppl 33)):13s.
Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Uyar 2007 {published data only}
Berlin 2005 {published data only}
Uyar M, Bayram N, Filiz A, Elbek O, Topçu A, Dikensoy Berlin I, Covey LS, Jiang HP, Hamer D. Lack of effect of O, et al.Comparison of nicotine patch and bupropion in D2 dopamine receptor TaqI A polymorphism on smoking treating tobacco dependence. European Respiratory Journal cessation. Nicotine & Tobacco Research 2005;7:725–8.
Bowen 1991 {published data only}
∗ Uyar M, Filiz A, Bayram N, Elbek O, Herken H, Topcu A, Bowen DJ, Spring B, Fox E. Tryptophan and high- et al.A randomized trial of smoking cessation. Medication carbohydrate diets as adjuncts to smoking cessation therapy.
versus motivation. Saudi Medical Journal 2007;28(6):
Journal of Behavioral Medicine 1991;14(2):97–110.
Brauer 2000 {unpublished data only}
Wagena 2005 {published data only}
Brauer LH, Paxton DA, Stock CT, Rose JE. Selegiline and Wagena EJ, Knipschild PG, Huibers MJ, Wouters EF, van transdermal nicotine for smoking cessation. Society for Schayck CP. Efficacy of bupropion and nortriptyline for Research on Nicotine and Tobacco Annual Conference; smoking cessation among people at risk for or with chronic 2000 Feb 18-20; Arlington VA (http://www.srnt.org/events/ obstructive pulmonary disease. Archives of Internal Medicine Breitling 2008 {published data only}
Weinberger 2009 {unpublished data only}
Breitling LP, Twardella D, Brenner H. High effectiveness of Weinberger AH, Reutenauer EL, O'Malley SS, Potenza short treatment with bupropion for smoking cessation in MN, George TP. A randomized placebo-controlled clinical general care. Thorax 2008;63:476–7.
trial of selegiline for smoking cessation: Preliminary results Carrão 2007 {published data only}
(POS5-29). Society for Research on Nicotine and Tobacco Carrao JL, Moreira LB, Fuchs FD. The efficacy of the 15th Annual Meeting April 27-30, 2009, Dublin, Ireland.
combination of sertraline with buspirone for smoking ∗ Weinberger AH, Reutenauer EL, Solorzano M, O'Malley cessation. A randomized clinical trial in nondepressed SS, Potenza MN, George TP. A randomized placebo smokers. European Archives of Psychiatry & Clinical controlled clinical trial of selegiline for smoking cessation (abstract 653). CPDD 71st Annual Meeting, June 20-252009, Reno Nevada.
Chan 2005 {published data only}
Chan B, Einarson A, Koren G. Effectiveness of bupropion Zellweger 2005 {published data only}
for smoking cessation during pregnancy. Journal of Addictive Puska P, Brath H, Astbury C, Hider AE. Zyban is an effective and well tolerated aid to smoking cessation in ahealthcare professionals population - a multi-country study.
Cornelius 1997 {published data only}
Society for Research on Nicotine and Tobacco 3rd European Cornelius JR, Salloum IM, Ehler JG, Jarrett PJ, Cornelius Conference, September 2001, Paris, France. 2001:45.
MD, Black A, et al.Double-blind fluoxetine in depressed Zellweger JP, Blaziene A, Astbury C, Hider A, Hogue S.
alcoholic smokers. Psychopharmacology Bulletin 1997;33:
Bupropion hydrochloride sustained release is an effective and well tolerated aid to smoking cessation in a healthcare Cornelius 1999 {published data only}
professionals population - a multicountry study. Abstract Cornelius JR, Perkins KA, Salloum IM, Thase ME, Moss and presentation at 11th Annual meeting of European HB. Fluoxetine versus placebo to decrease the smoking of Respiratory Society, Berlin, September 22-26 2001.
depressed alcoholic patients [letter]. Journal of Clinical European Respiratory Journal 2001;18 (Suppl 33):166s.
∗ Zellweger JP, Boelcskei PL, Carrozzi L, Sepper R, Sweet R, Dalack 1995 {published data only}
Hider AZ. Bupropion SR vs placebo for smoking cessation Dalack GW, Glassman AH, Rivelli S, Covey LS, Stetner in health care professionals. American Journal of Health F. Mood, major depression, and fluoxetine response in cigarette smokers. American Journal of Psychiatry 1995;152:
References to studies excluded from this review
Dale 2002 {published data only}
Barnes 2006 {published data only}
Dale LC, Ebbert JO, Schroeder DR, Croghan IT, Barnes J, Barber N, Wheatley D, Williamson EM. A pilot Rasmussen DF, Trautman JA, Cox LS, Hurt RD. Bupropion randomised, open, uncontrolled, clinical study of two for the treatment of nicotine dependence in spit tobacco dosages of St John's wort (Hypericum perforatum) herb users: a pilot study. Nicotine Tobacco Research 2002;4(3):
extract (LI-160) as an aid to motivational/behavioural support in smoking cessation. Planta Medica 2006;72(4):
Dale 2007 {published data only}
∗ Dale LC, Ebbert JO, Glover ED, Croghan IT, Schroeder Berlin 2002 {published data only}
DR, Severson HH, et al.Bupropion SR for the treatment of Berlin I, Aubin HJ, Pedarriosse AM, Rames A, Lancrenon smokeless tobacco use. Drug & Alcohol Dependence 2007; S, Lagrue G. Lazabemide, a selective, reversible monoamine oxidase B inhibitor, as an aid to smoking cessation.
Thomas JL, Ebbert JO, Patten CA, Dale LC, Bronars CA, Schroeder DR. Measuring nicotine dependence among Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
smokeless tobacco users. Addictive Behaviors 2006;31(9):
of smoking behavior with bupropion (PA9-4). Society for Research on Nicotine and Tobacco 14th Annual Meeting Edwards 1989 {published data only}
February 26-March 1, Portland, Oregon. 2008.
∗ Edwards NB, Murphy JK, Downs AD, Ackerman BJ, Hitsman 1999 {published data only}
Rosenthal TL. Doxepin as an adjunct to smoking cessation: ∗ Hitsman B, Pingitore R, Spring B, Mahableshwarkar a double-blind pilot study. American Journal of Psychiatry A, Mizes JS, Segraves KA, et al.Antidepressant pharmacotherapy helps some cigarette smokers more than Murphy JK, Edwards NB, Downs AD, Ackerman BJ, others. Journal of Consulting and Clinical Psychiatry 1999; Rosenthal TL. Effects of doxepin on withdrawal symptoms in smoking cessation. American Journal of Psychiatry 1990; Hitsman B, Spring B, Borrelli B, Niaura R, Papandonatos G. Adherence to medication versus behavioral therapy as Elsasser 2002 {published data only}
predictors of smoking cessation in combined treatment Elsasser GN, Guck TP, Destache CJ, Daher PM, Frey DR, involving fluoxetine [abstract]. Society for Research on Jones J, Larsen PM. Sustained release bupropion in the Nicotine and Tobacco Annual Conference; 2000 Feb 18- treatment of nicotine addiction among teenage smokers 20; Arlington VA 2000.
(RP-32). Rapid Communication Poster Abstracts. Society Houtsmuller 2002 {published data only}
for Research on Nicotine and Tobacco 8th Annual Meeting, Houtsmuller EJ, Stitzer ML. Selegiline effects on smoking February 20-23 Savannah, Georgia. 2002.
and abstinence [abstract]. CPDD Annual Meeting; 1998; Evins 2005b {published data only}
Scottsdale, AZ 1998.
Evins AE, Alpert JE, Pava J, Petersen TJ, Farabaugh ∗ Houtsmuller EJ, Thornton JA, Stitzer ML. Effects of AH, Fava M. A double blind placebo controlled trial of selegiline (l-deprenyl) during smoking and short-term bupropion added to nicotine patch and cognitive behavioral therapy in smokers with current or past unipolar depressive Jacobs 1971 {published data only}
disorder. Neuropsychopharmacology 2005;30 Suppl 1:S91.
Jacobs MA, Spilken AZ, Norman MM, Wohlberg GW, Evins 2008 {published data only}
Knapp PH. Interaction of personality and treatment Evins AE, Culhane MA, Alpert JE, Pava J, Liese BS, conditions associated with success in a smoking control Farabaugh A, et al.A controlled trial of bupropion added to program. Psychosomatic Medicine 1971;33(6):545–56.
nicotine patch and behavioral therapy for smoking cessation Kalman 2004 {unpublished data only}
in adults with unipolar depressive disorders. Journal of Kalman D, Engler P, Monti P. Preliminary findings from a pilot treatment study of smokers in early alcohol recovery Fatemi 2005 {published data only}
(POS1-072). Society for Research on Nicotine and Tobacco Fatemi SH, Stary JM, Hatsukami DK, Murphy SE.
10th Annual Meeting February 18-21, Phoenix, Arizona.
A double-blind placebo-controlled cross over trial of bupropion in smoking reduction in schizophrenia.
Kotz 2009 {published data only}
Kotz D, Wesseling G, Huibers MJ, van Schayck OC.
Frederick 1997 {published data only}
Efficacy of confrontational counselling for smoking Frederick SL, Hall SM, Sees KL. The effect of venlafaxine cessation in smokers with previously undiagnosed mild to on smoking cessation in subjects with and without a history moderate airflow limitation: study protocol of a randomized of depression. NIDA Research Monograph 1997;174:208.
controlled trial. BMC Public Health 2007;7:332.
∗ Kotz D, Wesseling G, Huibers MJH, van Schayck OCP.
Gawin 1989 {published data only}
Efficacy of confronting smokers with airflow limitation for Gawin F, Compton M, Byck R. Buspirone reduces smoking smoking cessation. European Respiratory Journal 2009;33:
[letter]. Archives of General Psychiatry 1989;46(3):288–9.
Glover 2002 {published data only}
Lawvere 2006 {published data only}
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Characteristics of included studies [ordered by study ID]
BUPROPIONSetting: community-based health care centre, USARecruitment: community volunteers 600 African American smokers, > 10 CPD; 70% F, av. age 44, av. CPD 17, 27% hadpossible clinical depression (CES-D > 16) 1. Bupropion 300 mg/day for 7 weeks2. PlaceboBoth 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.
Risk of bias
Support for judgement
Random sequence generation (selection Low risk "Randomization codes were generated in blocks of 50 and sent to the pharmaceuticalcompany." Allocation concealment (selection bias) Blinded drugs provided to investigator; " .
[the pharmaceutical company]. packagedthe treatment and then shipped the blindeddrug to the investigator." Incomplete outcome data (attrition bias) Approximately 32% lost to follow-up in each group; included as smokers.
Aubin 2004
BUPROPIONSetting: 74 cessation outpatient clinics, FranceRecruitment: volunteersRandomization: computer-generated, blind 504 smokers, >= 10 CPD; 56% F, av age 41, av CPD NS, 16% history of MDD Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Aubin 2004
1. Bupropion 300 mg for 7 weeks2. PlaceboBoth arms: motivational support at clinic visits at baseline, w3, w7, w12 & 3 phone callsTQD, 2-3 days later, w5, w18 Abstinence at 26w (continuous from w4)Validation: CO < 10 ppm First included as Lebargy 2003 based on abstract.
Risk of bias
Support for judgement
Random sequence generation (selection Low risk "The computerized randomization sched- ule, prepared by the sponsor, was inacces-sible to the investigator who was providedwith a specific set of sequential treatmentnumbers." Allocation concealment (selection bias) "Subjects fulfilling the entry criteria wererandomized in a double-blind manner tostudy treatment in a 2:1 bupropion:placeboratio."; " Blinding was assured by matchingthe placebo to the bupropion tablets." Incomplete outcome data (attrition bias) 26% of the placebo and 27% of the bupro- pion groups lost; included as smokers.
Aveyard 2008
NORTRIPTYLINESetting: National Health Service stop smoking clinics, UKRecruitment: 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 capsulesAll participants received free NRT and had behavioural support, the majority attendinggroup 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 Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Aveyard 2008
Risk of bias
Support for judgement
Random sequence generation (selection Low risk "An independent statistician generated the randomisationschedule in Stata. We used block randomi-sation,with randomly ordered block sizes of two,four, and six,stratified by stop smoking adviser." Allocation concealment (selection bias) Study nurses recruited participants, and thestudy administrator (who had not met theparticipants) allocated participants in se-quence against the list for each adviser.
Only the administrator and the pharmacistknew the allocation.
Incomplete outcome data (attrition bias) 12% I, 17% C lost at 12m, included as smokers. Authors note that majority oflosses were already smoking.
Berlin 1995
MOCLOBEMIDESetting: clinic, FranceRecruitment: 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 month2. Placebo (P)No behavioural intervention or counselling Abstinence at 1 year (prolonged)Abstinence verified at all visits up to 6m by plasma cotinine <= 20 ng/ml. 1 year abstinencebased 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 inP.
Risk of bias
Support for judgement
Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Berlin 1995
Random sequence generation (selection Unclear risk Randomization method not described.
Allocation concealment (selection bias) Double-blind, but blinding at allocationnot explicit.
Incomplete outcome data (attrition bias) "Relapses and subjects lost from follow-up were considered treatment failures." SELEGILINESetting: 3 community-based clinic, IsraelRecruitment: 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 tapering2. Placebo & nicotine patchBoth arms: Behavioural support from trained family physician; weekly then fortnightlyvisits for 12w Abstinence at 52 w, continuous with validation at each visitValidation: negative for urine nicotine, cotinine, 3-hydroxycotinine (Niccheck) Included in 2009 update. No serious AEs, no significant differences in AEs, 2 selegilinediscontinuations.
Risk of bias
Support for judgement
Random sequence generation (selection Low risk "Four hundred dice-throwing generated a randomized sequence code; 199 containersprepacked with selegiline and 201 contain-ers prepacked with placebo were numberedaccordingly." Judged adequate.
Allocation concealment (selection bias) "The code was sealed, kept secretly and wasrevealed for the first time when the last par-ticipant finished the 12 months of follow-up. The first participant who joined thetrial after the initial visit run-in phase re-ceived the first bottle from the container setnumber 001, the secondparticipant from set number 002 and so on.
The trial coordinator arranged participant'sallocation." Judged adequate.
Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Incomplete outcome data (attrition bias) 19 lost to f-up, included as smokers in MA.
Blondal 1999
FLUOXETINESetting: cessation clinic, IcelandRecruitment: community volunteers 100 smokers (excl 5 early withdrawals), > 10 CPD; 62% F, av age 41, av CPD 28, 38%fluoxetine/56% placebo had history of depression 1. Nicotine inhaler and fluoxetine for 3m, option of continuing for 3m more. Fluoxetine10 mg/day initiated 16 days before TQD, increased to 20 mg/day on day 6.
2. Nicotine inhaler and placeboBoth arms: 5 x 1 hr group behaviour therapy. Advised to use 6-12 inhalers/day for upto 6m.
Abstinence at 1 year (sustained from quit day)Validation: CO < 10 ppm at all assessments (6w, 3,6, 12 m) Risk of bias
Support for judgement
Random sequence generation (selection Low risk Computer generated randomization; part of the randomization procedure was per-formed by the manufacturer at another lo-cation where the code was also kept until itwas broken in May 1997.
Allocation concealment (selection bias) ".pill boxes, with either fluoxetine or anidentical appearing placebo containing thesame ingredients except fluoxetine, were la-belled with numbers ranging from 100 to210.At the clinic a laboratory technicianthen dispensed the pill boxes immediatelyafter the baseline interview, usually 3± 4weeks before the quitting day, always deliv-ering the lowest numbered box." Incomplete outcome data (attrition bias) Results exclude 5 withdrawals; 3 from flu- oxetine group due to adverse effects - ner-vousness and anxiety, 1 from fluoxetine dueto pregnancy, 1 from placebo who had pur-chased fluoxetine.
Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Brown 2007
BUPROPIONSetting: 2 clinical sites (Butler Hospital, Miriam Hospital) Rhode Island, USARecruitment: community volunteers 524 smokers >= 10 CPD; 48% F, av. age 44, av. CPD 25, 17.6% with history of MDDsingle episode, 3.1% recurrent MDD 2 x 2 factorial design. Alternative psychosocial treatments were standard cessation therapyor plus CBT for depression. Both had 12 x 90 min groups twice weekly/ weekly/ monthlyfor 12w. TQD 5th session. Collapsed in this analysis1. Bupropion 300 mg/day for 12 weeks2. 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 combinethese participants with those reported in Collins 2004 Risk of bias
Support for judgement
Random sequence generation (selection Unclear risk "Participants were randomly assigned to one of two treatment sites, where they wereto receive one of two manualized grouptreatments . Participantswere then randomly assigned to receive oneof two medication conditions, bupropionor placebo, using the urn randomizationtechnique." Allocation concealment (selection bias) "Whereas we were able to balance the drugand placebo conditions on an individualbasis, behavioral treatments were random-ized by group and thus were more suscep-tible to fluctuations in recruitment and tothe availability at both sites of pairings ofa senior and a junior therapist trained inCBTD". Knowledge of behavioural assign-ment was probably not concealed but seemsunlikely to have lead to individual selectionbias.
Incomplete outcome data (attrition bias) 81% provided complete outcome data at all follow ups, not related to treatment condi-tion. All participants included in ITT anal-yses Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
VENLAFAXINESetting: clinic, USARecruitment: 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, including2w tapering.
2. PlaceboBoth 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/ulAdverse events/withdrawals: not reported First included as Cinciripini 1999 based on abstract.
Risk of bias
Support for judgement
Random sequence generation (selection Unclear risk Randomization method not described.
Stratification by depression history.
Allocation concealment (selection bias) Randomization by pharmacy, all study per-sonnel with direct patient contact blind.
Incomplete outcome data (attrition bias) Unclear how missing data was addressed Collins 2004
BUPROPIONSetting: 2 clinical research sites (Georgetown University Medical Center & State Uni-versity of New York), USARecruitment: 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 TQD2. PlaceboBoth arms: 7 sessions group behavioural counselling Abstinence at 6m (prolonged from w2, 7 consecutive days of smoking defined as relapse)Validation: saliva cotinine <= 15 ng/ml Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Collins 2004
Replaces Lerman 2002 which reported subset of data. Denominators supplied by 1stauthor, excludes 114 who withdrew before intervention. Some study details from Lerman2006. Some genotyping studies combine these participants with those reported in Brown2007.
Risk of bias
Support for judgement
Random sequence generation (selection Low risk "Randomization was determined by a com- puter-generated randomization scheme op-erated by a senior data manager; stratifica-tion was carried out by study site" (Lerman2006).
Allocation concealment (selection bias) Centrally generated & allocation concealedfrom counsellors & assessors.
Incomplete outcome data (attrition bias) 6% at 6 month follow-up; included as Covey 2002
SERTRALINESetting: clinic, USARecruitment: volunteers 134 smokers with a history of past MDD; 65% F, av age 44.5, 47% had history ofrecurrent MDD 1. Sertraline starting dose 50 mg/day, 200 mg/day by week 4 quit day. 9 day taper. Totalduration 10w + 9 day taper, including 1w placebo washout prior to randomization2. PlaceboBoth 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 Risk of bias
Support for judgement
Random sequence generation (selection Unclear risk Randomization method not described.
Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Covey 2002
Allocation concealment (selection bias) "Medications were provided in preparedbottles that were numbered according tothe randomization schedule and dispensedat each visit. All study staff at the clinic sitewere blinded to treatment assignment." Incomplete outcome data (attrition bias) "The subjects lost to follow-up after ran- dom assignment were considered treatmentfailures." Covey 2007
BUPROPIONSetting: Cessation clinic, USARecruitment: community volunteers quit after 8w bupropion & nicotine patch 289 abstainers (excludes 5 withdrawing consent before starting meds); 45% F, av. age43, av. cigs/day 21 All participants received 8 w open-label bupropion & nicotine patch (21mg with wean-ing) for 7w from TQD. Transition procedures preserved blinding for RP phase but al-lowed weaning from bupropion. Individual counselling including CBT techniques, 15min 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 16w2. Bupropion & placebo gum3. Nicotine gum & placebo pill (150 mg bupropion for first week)4. Double placebo (150 mg bupropion for first week) Abstinence (no relapse to 7 days of smoking) for 12m (10m after randomization, 6mafter EOT) (Primary outcome for study was time to relapse)Validation: CO ≤8ppm at each visit New for 2009 updateQuit rate after open-label treatment was 52% so the final quit rate of 30% for combi-nation therapy is equivalent to 16% of people starting treatment Risk of bias
Support for judgement
Random sequence generation (selection Low risk "A statistician who did not participate in the clinical phases of the study pro-vided computer-generated randomizationlists that were not accessible to the clini-cal staff ", stratified by gender & depressionhistory.
Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Covey 2007
Allocation concealment (selection bias) A research nurse who did not have directcontact with participants prepared individ-ual medication kits based on the random-ization schedule.
Incomplete outcome data (attrition bias) 5 randomized participants withdrew before double blind phase. Greater loss to followup in double placebo, losses included inITT analysis.
Croghan 2007
BUPROPIONSetting: clinics, USARecruitment: community volunteers for pharmacotherapy cessation & relapse preven-tion trial 405 abstainers after 3m pharmacotherapy, 74 from inhaler, 141 bupropion, 190 combi-nation. Participant characteristics not presented at start of RP phase In cessation phase participants had been randomized to bupropion (300mg), nicotineinhaler (up to 16 cartridges/day) or combination. Physician advice at entry, brief (<10min) 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 orplacebo for 9m.
Combined therapy abstainers randomized to 4 groups: combination, placebo & singletherapy, 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 respectiveplacebo arms.
Cessation rates at end of induction phase were 14% for inhaler, 26% for bupropion and34% for combination.
Risk of bias
Support for judgement
Random sequence generation (selection Low risk Randomization using a dynamic allocation procedure balancing stratification factors.
Allocation concealment (selection bias) Randomization procedure makes priorknowlege of allocation unlikely.
Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Croghan 2007
Incomplete outcome data (attrition bias) Losses to follow up post-medication were high and not enumerated by group, but allincluded in ITT analysis.
Da Costa 2002
NORTRIPTYLINESetting: cessation clinic, BrazilRecruitment: volunteers to a smokers' support group 144 smokers, >= 15 CPD; 'predominantly female' , age, CPD not described, 48% hada history of depression 1. Nortriptyline max 75 mg/day for 6w incl titration period, begun 1w before start ofbehaviour therapy2. PlaceboBoth arms: 6 weekly group cognitive behavioural therapy Abstinence 6m after end of treatment (prolonged)Validation: none Risk of bias
Support for judgement
Random sequence generation (selection Low risk "Each patient chose a blind number from a box .' Probably adequate.
Allocation concealment (selection bias) ". with each number corresponding toa "medication kit" that was externallyundistinguishable. Patients and profession-als participating in this study were blind-folded for this distribution." Potentially ad-equate but difference in numbers in eachgroup not accounted for.
Incomplete outcome data (attrition bias) Number lost in each group not clear.
Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
BUPROPIONSetting: 5 hospitals, DenmarkRecruitment: 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 weeks2. PlaceboBoth arms: motivational support around TQD, at w3 & 7, and at 12w follow up Abstinence at 6m (prolonged from w4)Validation: CO < 10 ppm Risk of bias
Support for judgement
Random sequence generation (selection Low risk Randomization was computer generated and blinded.
Allocation concealment (selection bias) Allocation was double-blinded and bupro-pion and placebo tablets were identical inform and number.
Incomplete outcome data (attrition bias) 32% of the bupropion group and 43% the placebo group discontinued treatment, in-cluded in analysis.
Evins 2001
BUPROPIONSetting: outpatient clinic, USARecruitment: volunteersRandomization: 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 w32. PlaceboBoth arms: 9x 1 hr weekly group CBT Abstinence at 6m, (prolonged)Validation: CO < 9 ppm or serum cotinine < 14 ng/mL Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Evins 2001
2 year follow up also reported (Evins et al 2004). 3 additional quitters, not used in meta-analysis since additional therapy used Risk of bias
Support for judgement
Random sequence generation (selection Unclear risk Randomization method not described.
Allocation concealment (selection bias) "Subjects were randomly assigned to 12weeks of double-blind bupropion SR, 150mg/day, or an identical appearing placebotablet added to their usual medication reg-imen." Incomplete outcome data (attrition bias) "Nineteen subjects were enrolled and 18 subjects completed the 6-month smokingcessation trial." Evins 2005
BUPROPIONSetting: clinic, USARecruitment: 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. PlaceboBoth arms: 12 session group CBT Abstinence at 6m (7 day PP)Validation: CO < 9 ppm There was a significant treatment effect at EOT.
Originally included as Evins 2003 based on abstracts Risk of bias
Support for judgement
Random sequence generation (selection Unclear risk Randomization method not stated.
Allocation concealment (selection bias) Allocation concealment not described.
Antidepressants for smoking cessation (Review)
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Evins 2005
Incomplete outcome data (attrition bias) Only people taking at least one dose of study medication included in analyses inpaper. 5 in each group lost to follow-up andincluded as smokers.
Evins 2007
BUPROPIONSetting: community mental health centre, USARecruitment: 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 mgnicotine gum2. 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 dataUsed in bup+NRT vs NRT comparison.
Risk of bias
Support for judgement
Random sequence generation (selection Unclear risk Randomization method not described.
Allocation concealment (selection bias) Allocation concealment not described.
Incomplete outcome data (attrition bias) 20% of the bupropion group and 18% of the placebo group were lost to follow-up atweek 12; included as smokers.
Ferry 1992
BUPROPIONSetting: clinic, USARandomization: no details Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Ferry 1992
1. Bupropion 300 mg/day for 3m2. PlaceboBoth arms: group smoking cessation and relapse prevention counselling Abstinence at 6m from end of treatment (sustained)Validation: saliva cotinine Abstract with no further details Risk of bias
Support for judgement
Random sequence generation (selection Unclear risk Randomization method not described.
Allocation concealment (selection bias) Allocation concealment not described.
Incomplete outcome data (attrition bias) No details given.
Ferry 1994
BUPROPIONSetting: Veterans Medical Centre, USA 1. Bupropion 100 mg x 3/day for 12w2. PlaceboBoth arms: group smoking cessation and relapse prevention counselling; TQD withinfirst 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.
Risk of bias
Support for judgement
Random sequence generation (selection Unclear risk Randomization method not described.
Allocation concealment (selection bias) Allocation concealment not described.
Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Ferry 1994
Incomplete outcome data (attrition bias) "The most conservative approach to anal- ysis would reclassify all of these individualsas smokers due to protocol violation." Fossati 2007
BUPROPIONSetting: primary care clinics, ItalyRecruitment: patients of 71 general practitioners 593 smokers, ≥ 10 CPD; 40% F, av. age 49, av. CPD 22 1. Bupropion 300 mg/day for 7 weeks2. PlaceboBoth arms: GP visits at enrollment & 4, 7, 26 & 52w, phone calls 1 day pre TQD, 3days post TQD, 10w post enrollment. Classified as low intensity Abstinence at 12m (continuous from week 4)Validation: CO ≤10ppm at each visit New for 2009 update Risk of bias
Support for judgement
Random sequence generation (selection Low risk Randomized; "GP assigned them a ran- domization code".
Allocation concealment (selection bias) Stated to be double-blind, but not explicitthat GPs blind to randomization code.
Incomplete outcome data (attrition bias) 15% Bupropion & 17% Placebo did not attend 12m f-up, included as smokers.
George 2002
BUPROPIONSetting: mental health clinic, USARecruitment: 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 w32. PlaceboBoth arms: 10x 60 min weekly group therapy Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
George 2002
Abstinence at 6m (7-day PP)Validation: CO < 10 ppm Risk of bias
Support for judgement
Random sequence generation (selection Unclear risk Randomization method not described.
Allocation concealment (selection bias) "Both subjects and research staff wereblinded to study medication assignment.
Study medications were prepared by re-search pharmacists at CMHC, using en-capsulation of SR bupropion tablets withblue 00 opaque capsules; placebo capsulescontained only a dextrose matrix." Incomplete outcome data (attrition bias) "Subjects who were lost during the trial or at 6-month follow-up were counted assmokers." George 2003
SELEGILINESetting: outpatient smoking research clinic, USARecruitment: 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 significant in the SEL comparedwith 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." Risk of bias
Support for judgement
Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
George 2003
Random sequence generation (selection Unclear risk Randomization method not described.
Allocation concealment (selection bias) Method not described. Subjects and raterswere blinded to medication assignment.
Incomplete outcome data (attrition bias) 29/40 not assessed at 6m. Greater loss to f- up in placebo, exact data not reported.
George 2008
BUPROPIONSetting: Mental Health CentreUSARecruitment: Outpatients 58 smokers with schizophrenia or schizoaffective disorder (excludes 1 receiving no studymedication); 40% F, av. age 40, av. CPD 23 1. Bupropion 300 mg/day for 9w, begun 7 days pre-TQD2. PlaceboBoth arms: Nicotine patch (21mg/24hrs) for 8w from TQD & group behaviour therapy10 weekly sessions Abstinence at 6m, PPValidation: CO <10 ppm New for 2009. Bupropion as adjunct to NRT Risk of bias
Support for judgement
Random sequence generation (selection Unclear risk Randomization method not described.
Allocation concealment (selection bias) "Double blind" but no additional detailsgiven.
Incomplete outcome data (attrition bias) 6/29 intervention & 10/29 control did not complete trial, included as smokers.
Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
BUPROPIONSetting: 16 clinical trial centres, USARecruitment: volunteers who had previously failed to quit using bupropion 450 smokers, >= 15 CPD, who had previously used bupropion for at least 2w withoutadverse effects; 55% F (Placebo), 48% F (Bup); av. age 45, av. CPD not specified, nodetails of depression history 1. Bupropion 300 mg/day for 12w, begun 7 days pre-TQD.
2. PlaceboBoth arms: brief individual counselling at visits w1-7, 9, 12, + telephone counselling at4 and 5m Abstinence at 12m, prolonged from w4Validation: CO <= 10 ppm at each visit 6m data published. 12m data presented in a poster used since 2003 update Risk of bias
Support for judgement
Random sequence generation (selection Low risk "Participants who satisfied the inclusion criteria were randomized to the treatmentphase and received either bupropion SR .
or matching placebo. Eligible participantswere assigned a protocol-specific treatmentnumber on the basis of a randomizationcode provided by GlaxoWellcome." Allocation concealment (selection bias) Although a double-blind study, allocationconcealment method not described Incomplete outcome data (attrition bias) ".all participants who stopped participat- ing in the study during the treatment phasewere considered to be smokers." BUPROPIONSetting: 19 clinical trial centres, USARecruitment: community volunteers 1025 smokers of >= 10 CPD (673 in relevant arms), recent MDD excluded, priorexposure to bupropion excluded; 46% F, av. age 42, av. CPD 21, no details of depressionhistory Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
1. Bupropion 300 mg/day for 12w, begun 7 days pre-TQD2. Varenicline 2mg/day3. PlaceboAll arms: Brief (<10 min) standardized individual counselling at 12 weekly visits duringdrug phase and 11 clinic/phone visits during follow up, problem solving and relapseprevention 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.
Risk of bias
Support for judgement
Random sequence generation (selection Low risk 'predefined . computer-generated ran- domization sequence', 1:1:1, using blocksize of 6, stratified by centre.
Allocation concealment (selection bias) Central allocation.
Incomplete outcome data (attrition bias) Loss to follow-up similar across conditions; 44% bupropion, 39.5% varenicline, 46%placebo, all included in analyses.
Grant 2007
BUPROPIONSetting: 2 substance use disorder clinics, USARecruitment: 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 tapering2. Placebo & nicotine patchBoth arms: 1 hour cessation group (& 4 weekly assessment visits) Abstinence at 6m, 7 day PPValidation: no biochemical val, collaterals contacted, inconsistent, adjusted rates notreported.
New for 2009 update Risk of bias
Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Grant 2007
Support for judgement
Random sequence generation (selection Unclear risk Randomization method not described.
Allocation concealment (selection bias) Double-blind, but not explicit who wasblinded.
Incomplete outcome data (attrition bias) Higher loss in bupropion (40%) than placebo (21%). ITT analysis.
BUPROPIONSetting: Smokers' clinic, PolandRecruitment: smokers with a diagnosis of COPD and failure to stop smoking with advicealone 70 smokers with COPD43% F, av age 56, av CPD 24 1. Bupropion 300 mg/day for 7w2. Nicotine patch (15mg) for 8wCommon components: support at clinic visits at baseline, 2w, EOT Abstinence at 1 year (sustained)Validation: CO < 10ppm Risk of bias
Support for judgement
Random sequence generation (selection Unclear risk Randomization method not described.
Allocation concealment (selection bias) Allocation concealment not described.
Incomplete outcome data (attrition bias) Not described.
Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
BUPROPION & NORTRIPTYLINESetting: Smoking cessation clinic, BrazilRecruitment: community volunteers.
156 smokers, FTND at least 4; 70% F placebo & nortrip, 59% Bup, av. age 44, av. CPDNS 1. Bupropion 300 mg/day for 60 days, placebo nortriptyline, TQD during week 22. Nortripytyline 75 mg/day for 60 days, placebo bupropion3. Double placeboAll arms: 6x 15-min individual CBT, weekly then bi-weekly.
Abstinence at 6m (continuous from TQD)Validation: CO <= 10 ppm at 3 & 6m Risk of bias
Support for judgement
Random sequence generation (selection Unclear risk Randomization method not described.
Allocation concealment (selection bias) Allocation concealment not described.
Incomplete outcome data (attrition bias) Numbers lost to follow-up not reported, all included as smokers.
Hall 1998
NORTRIPTYLINESetting: clinic, USARecruitment: community volunteers. Exclusion criteria included MDD within 3m ofbaseline 199 smokers of >= 10 CPD, 33% had history of MDD55% F, av age 40, av CPD 21-25 2 x 2 factorial design. Alternative psychological Rxs were 10 sessions of CBT or 5 sessionsof health education control. Collapsed in this analysis1. Nortriptyline titrated to therapeutic levels - usually 75-100 mg/day, 12w2. Placebo Abstinence at 1 year post-EOT, prolonged. PP rates also reported.
Validation: CO at weeks 12, 24, 39 and 64 There were no significant main or intervention effects for MDD category so these arepooled.
Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Hall 1998
Risk of bias
Support for judgement
Random sequence generation (selection Low risk Computer randomization, after stratifica- tion on history of MDD and number ofcigarettes smoked.
Allocation concealment (selection bias) Allocation generated at enrollment.
Incomplete outcome data (attrition bias) 30% did not complete treatment in placebo and 17% in active groups. Analyses withmissing =smoking given.
Hall 2002
BUPROPION & NORTRIPTYLINESetting: cessation research centre, USARecruitment: community volunteers 220 smokers, >= 10 CPD; 40-47% F, av. age 37-43, av. CPD 20-23, 33% had historyof 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 Psychoso-cial Intervention (PI, as MM plus 5x 90 min group sessions at 4,5,7,11w)Pharmacotherapy:1. Bupropion 300 mg/day, 12w2. Nortriptyline titrated to therapeutic levels, 12w3. Placebo Abstinence at 1 year (47w post quit date), prolonged. PP also reportedValidation: CO <= 10 ppm, urine cotinine <= 60 ng/mL No significant interaction between pharmacotherapy and behaviour therapy, so BT armscollapsed in main analysis. Bupropion & nortriptyline compared to placebo and head-to-head. Levels of support compared for bupropion only, PP rates used.
Risk of bias
Support for judgement
Random sequence generation (selection Unclear risk "Participants were stratified by number of cigarettes smoked, sex and history of de-pression vs no history, and randomly as-signed to 1 of the 6 experimental cells." Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Hall 2002
Allocation concealment (selection bias) "We encapsulated both drugs to maintainthe patency of the bupropion formulationand to provide a blinded drug. All partici-pants received capsules that were identicalin number and appearance" but blindingof allocation not explicit.
Incomplete outcome data (attrition bias) 19% lost to f-up at 52 w. No significant difference across conditions. Included assmokers in analyses.
Hall 2004 Brief
NORTRIPTYLINESetting: clinic, USARecruitment: community volunteers.
81 smokers of >= 10 CPD41% 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 lengthsubgroups entered as separate studies1. Nortriptyline titrated to 50-150 ng/ml ( 75-100 mg) for 12w, quit date week 52. PlaceboBoth 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 Risk of bias
Support for judgement
Random sequence generation (selection Unclear risk Randomization stratified on CPD, prior NRT use, MDD history; method not spec-ified.
Allocation concealment (selection bias) Allocation concealment not described.
Incomplete outcome data (attrition bias) 9% lost at week 52, included as smokers.
Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Hall 2004 Extended
NORTRIPTYLINESee 'Hall 2004 Brief ' 79 smokers of >= 10 CPD42% 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 final follow up.
BUPROPIONSetting: 12 clinical trial sites, USARecruitment: community volunteers 594 smoker of >= 20 CPD wanting to reduce amount smoked. Not quit for > 3m inprev 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 trial1. Bupropion 300 mg/day, 26w2. PlaceboBoth arms: written materials suggesting reduction techniques, monthly brief individualcounselling, telephone contact 2 days, 12 days, 5w after target reduction date. Participantsindicating a willingness to quit at any time were enrolled in a 7w cessation programmewith weekly visits followed by 19w of follow up Abstinence 6m after quit date (denominator 594; 214 entered cessation phaseValidation: urine cotinine Not used in main analysis38% of bupropion and 34% of placebo group entered cessation phase. Median time toattempting cessation shorter in bupropion group Risk of bias
Support for judgement
Random sequence generation (selection Low risk "Subjects were assigned randomly using a Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Allocation concealment (selection bias) Allocation concealment not described.
Incomplete outcome data (attrition bias) For cessation analyses, subjects who dropped out were considered to have re-sumed smoking [after withdrawal date].
Hays 2001
BUPROPIONSetting: 5 clinical trial centres, USARecruitment: 784 community volunteers 429 smokers of >= 15 CPD who quit after 7 weeks open label bupropion; 51% F, av age46, av CPD 26, 19% history of MDD 1. Bupropion 300 mg/day for 45 weeks2. PlaceboBoth arms: physician advice, S-H materials and brief individual counselling at follow-up visits.
Abstinence at 2 years (1 year after end of pharmacotherapy), prolongedValidation: CO <= 10 ppm Relapse prevention trial Risk of bias
Support for judgement
Random sequence generation (selection Low risk "Randomization to the placebo or bupro- pion groups was computer generated at acentral location;." Allocation concealment (selection bias) ".the investigators did not know thepatient assignments. All bupropion andplacebo pills were identical in shape, size,and color." Incomplete outcome data (attrition bias) "Participants who dropped out were con- sidered to have relapsed to smoking, but in-formation on other important factors, suchas weight gain, was not collected and there-fore could not be included in the analy-sis." Approximately 26% of the bupropiongroup and 27% of the placebo group didnot complete the study.
Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
BUPROPIONSetting: Veterans Affairs Medical Centre (VAMC), USARecruitment: 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. PlaceboBoth arms: individual counselling pre-quit, weeks 1,2,4,8,12.
Abstinence at 6m, prolonged, validated at weeks 2, 8, 12.
Validation: CO <= 10ppmPaper 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.
Risk of bias
Support for judgement
Random sequence generation (selection Unclear risk Randomization method not described.
Allocation concealment (selection bias) Allocation concealment not described.
Incomplete outcome data (attrition bias) 30% of the participants receiving bupro- pion SR did not complete the full 12-weektrial; 80% of the placebo group failed tocomplete the trial and were considered tohave resumed smoking.
Holt 2005
BUPROPIONSetting: Cessation clinic, New ZealandRecruitment: Maori community volunteers aged 16-70 134 smokers, >=10 CPD; 72% F, av age 42/38 1. Bupropion 300mg/day for 7w2. PlaceboBoth 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, undefined)Validation: CO at each visit Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Holt 2005
Risk of bias
Support for judgement
Random sequence generation (selection Low risk Randomization using a computer gener- Allocation concealment (selection bias) "Neither the study team nor the participantwas aware of which treatment had been al-located until the end of the 12 month studyperiod." Incomplete outcome data (attrition bias) 36% lost in bupropion group and 52% in placebo at 12 months. "Participants whowere lost to follow up were categorised assmokers . often this was confirmed byfamily members or friends." Hurt 1997
BUPROPIONSetting: multi-centre, USARecruitment: 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% alcoholismalone.
1. Bupropion 100 mg/day for 7 weeks2. Bupropion 150 mg/day3. Bupropion 300 mg/day4. PlaceboAll arms: physician advice, S-H materials, and brief individual counselling by studyassistant at each visit Abstinence at 12m (prolonged from day 22, data provided by Glaxo Wellcome) (con-tinuous 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 analysisThere was no evidence that history of major depression or alcoholism interacted withtreatment condition or was associated with poorer outcomes. Prolonged abstinence ratesat 12m as supplied by Glaxo Welcome: 300 mg 21; 150 mg 23; Placebo 15 Risk of bias
Support for judgement
Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Hurt 1997
Random sequence generation (selection Unclear risk Randomized, stratified by site, method not Allocation concealment (selection bias) Allocation concealment not described.
Incomplete outcome data (attrition bias) "Subjects who missed a follow-up visit were considered to be smoking. The rate ofcompletion of the study increased with thedose and was 57 percent, 65 percent, 64percent, and 71 percent for the placebo,100-mg, 150-mg, and 300-mg groups, re-spectively." Hurt 2003
BUPROPIONSetting: multi-centre 14 North Central Cancer Treatment Group sites, USARecruitment: community volunteers.
578 smokers recruited to first stage of study: >= 15 CPD; 57% F, av age 42, 21% historyof MDD176 smokers abstinent after 8w nicotine patch treatment randomized to relapse preven-tion intervention194 non-abstinent smokers randomized to bupropion as second line therapy (All participants first received nicotine patch for 8w, dose based on cig consumption)Relapse prevention arm:1. Bupropion for 26w2. PlaceboSecond line therapy arm:1. Bupropion for 8w2. 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.
Risk of bias
Support for judgement
Random sequence generation (selection Low risk Randomized using 'dynamic allocation'.
Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Hurt 2003
Allocation concealment (selection bias) Double-blind, but allocation concealmentnot described.
Incomplete outcome data (attrition bias) Patients lost to follow-up considered to be Jorenby 1999
BUPROPIONSetting: multi-centre clinical trial units, USARecruitment: community volunteers 893 smokers, > 15 CPD, no current major depressive episode, 15-20% had history ofMDD52% F, av age 43 av CPD 25 1. Nicotine patch (24 hr, 21 mg for 6w, tapered for 2w) and sustained release bupropion300 mg for 9w from 1w before quit day2. Bupropion 300 mg and placebo patch3. Nicotine patch and placebo tablets4. Placebo patch and placebo tabletsAll arms: Brief (< 15 min) individual counselling session at each weekly assessment. Onetelephone 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 abstinencesince quit day.
Risk of bias
Support for judgement
Random sequence generation (selection Low risk "The subjects were randomly assigned to one of four treatments with use of anunequal-cell design.[but] Randomizationwas not balanced within sites." Allocation concealment (selection bias) Allocation concealment method unclear.
Bupropion and placebo tablets lookedidentical.
Incomplete outcome data (attrition bias) "All subjects who discontinued treatment early or who were lost to follow-up wereclassified as smokers." Approximately 20%left the study and provided no additionalinformation. 15% stopped taking medica- Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Jorenby 1999
tion but participated in follow-up assess-ments.
Jorenby 2006
BUPROPIONSetting: multi-centre clinical trial units, USARecruitment: community volunteers 683 smokers (in relevant arms) >=10 CPD, no recent treatment for MDD, prior exposureto bupropion excluded; 41% F, av. age 42, av. CPD 22 1. Bupropion 300mg for 12 w +placebo varenicline2. Varenicline 2mg for 12 w +placebo bupropion3. Placebo bupropion + placebo vareniclineAll 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.
Risk of bias
Support for judgement
Random sequence generation (selection Low risk "Randomization was completed centrally by using a computer-generated list and sitesused an electronic system to assign partici-pants to treatment." Allocation concealment (selection bias) medication or placebo] for all participants(regardless of treatment assignment) wereidentical throughout the treatment phaseincluding a period of dose titration (week1) and treatment at the target dose (weeks2-12)." Incomplete outcome data (attrition bias) Over the period of treatment and follow-up 14% of those receiving varenicline were lostto follow-up; 14% randomized to bupro-pion lost to follow-up; 16% of the placebogroup were lost to follow-up. "Participantswhose smoking status was unknown orwhose carbon monoxide Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Jorenby 2006
level was higher than 10 ppm were classi-fied as smoking during both the treatmentphase and follow-up." Killen 2000
PAROXETINESetting: clinic, USARecruitment: 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 paroxetine3. Patch as 1 + placebo paroxetineAll 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 Risk of bias
Support for judgement
Random sequence generation (selection Unclear risk Randomization method not described.
Allocation concealment (selection bias) Double-blind but allocation concealmentnot explicitly described.
Incomplete outcome data (attrition bias) "Those failing to provide confirmation [of smoking status] were reclassified as smok-ers." Killen 2004
BUPROPIONSetting: continuation high schools, USARecruitment: adolescents at schools 211 adolescent smokers, >= 10 CPD, at least 1 failed quit attempt; 31% F, av. age 17,av. CPD 15 Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Killen 2004
1. Bupropion 150mg for 9w from 1w before TQD, Nicotine patch for 8w2. Placebo & nicotine patchBoth 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 Risk of bias
Support for judgement
Random sequence generation (selection Unclear risk Randomization method not described.
Allocation concealment (selection bias) Allocation concealment not described.
Incomplete outcome data (attrition bias) 38% bupropion & 35% placebo lost at 6 months, included in analysis.
Killen 2006
BUPROPIONSetting: clinics, USARecruitment: 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 openlabel combination pharmacotherapy of bupropion 300 mg for 11w, nicotine patch for10w. TQD day 7, 30 min individual relapse prevention skills training at 6 clinic visits.
1. Bupropion 150 mg for 14w2. 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 significant effects Risk of bias
Support for judgement
Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Killen 2006
Random sequence generation (selection Low risk Centrally generated pre-assigned random sequence stratified by gender, prior to openlabel phase.
Allocation concealment (selection bias) Centrally assigned.
Incomplete outcome data (attrition bias) 8% bupropion & 13% placebo lost at 12 months, included in analysis.
BUPROPIONSetting: Cessation clinic, USARecruitment: community volunteers 463 smokers; 50% F, av. age 36-41 across arms, av. CPD 22 Factorial trial1. Bupropion SR 300mg for 8 weeks2. PlaceboCounselling conditions:1. Counselling; 8 x10min session, 2 prequit, TQD, 5 over 4 wks2. Psychoeducation about medication, support & encouragement. Same no. of sessions,80mins less contact time Abstinence at 12m (7 day PP). Prolonged self-reported abstinence also assessedValidation: CO ≤10ppm New for 2009. Counselling conditions collapsed in main analysis, entered separately insubgroup analysis by intensity, condition 2 classified as low intensity Risk of bias
Support for judgement
Random sequence generation (selection Low risk Random number table.
Allocation concealment (selection bias) Staff who screened and enrolled partici-pants were unaware of the experimentalcondition to be assigned.
Incomplete outcome data (attrition bias) 171 (37%) failed to attend quit date visit or lost to follow up, similar across groups,included in ITT analysis.
Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
BUPROPIONSetting: research clinic, USARecruitment: adolescent community volunteers 312 adolescents (14 to 17) smoking ≥6 CPD; 46% F, median age 16, median CPD 11 1. Bupropion 300 mg for 7w2. Bupropion 150 mg3. PlaceboAll arms: Brief (10-20 min) individual counselling session pre quit and at each weeklyassessment.
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 2009300 mg arm contributes to main analysis. 2/105 quit in 150mg group Risk of bias
Support for judgement
Random sequence generation (selection Low risk "Active study medication and identical-ap- pearing placebo were prepackaged into 3sets of identical-appearing blister cards inaccordance with a computer-generated ran-domization list." Allocation concealment (selection bias) ". a research assistant assigned the sub-ject the next treatment number (and as-sociated blister cards) in sequence. Studysubjects and researchers remained blindto treatment group assignment throughoutthe study." Incomplete outcome data (attrition bias) Slightly higher lost to f-up/ declined further participation in placebo group (30%) thanactive arms (18%). ITT analysis.
Myles 2004
BUPROPIONSetting: preoperative clinic, AustraliaRecruitment: Smokers awaiting surgery 47 smokers expected to undergo surgery within 8-14w34% F, av age 45/40, 49% smoked 21-30 CPD Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Myles 2004
1. Bupropion 300 mg for 7w2. PlaceboBoth arms: Advice at baseline, 1 phone call 2-4 days after TQD. Low intensity Abstinence at 6m (28 day PP - classified as sustained)Validation CO <= 10 ppm New 2007More drop-outs in placebo group. Only 20 had surgery.
Risk of bias
Support for judgement
Random sequence generation (selection Low risk Patients were randomly allocated from a table of random numbers into one oftwo groups: active (bupropion) or placebo(identical appearance).
Allocation concealment (selection bias) Double-blind but not clear that randomnumber table concealed at allocation.
Incomplete outcome data (attrition bias) 17% lost to follow-up in the bupropion group; 9%b lost to follow-up in the placebogroup. "Patients lost to follow-up were as-sumed to still be smoking." Niaura 2002
FLUOXETINESetting: 16 clinical trial centres, USARecruitment: Community volunteers 989 non-depressed smokers, no history of bipolar or current psychiatric disorder61% F, av age 42 av CPD 28 1. Fluoxetine 30 mg for 10w, starting 2w before TQD2. Fluoxetine 60 mg for 10w, starting 2w before TQD3. PlaceboAll arms: 9 sessions (60-90 mins) individual CBT. Included coping skills, stimulus controltechniques and relapse prevention.
Abstinence at 32w from TQD, multiple PPValidation: 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).
Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Niaura 2002
Risk of bias
Support for judgement
Random sequence generation (selection Unclear risk Randomization method not described.
Allocation concealment (selection bias) Double-blind, but blinding of allocater notexplicit.
Incomplete outcome data (attrition bias) Missing data in treatment phase addressed, but unclear whether missing data in follow-up phase addressed.
Nides 2006
BUPROPIONSetting: 5 clinical sites, USARecruitment: Volunteers (phase II study) 638 smokers (255 in relevant arms, incl 2 bupropion & 4 placebo who did not startmedication). No major depression in past year51% F, av age 41, av CPD 20. 13-20% had used bupropion 1. Bupropion 300 mg for 7w2. Varenicline 2 mg for 7w (other dose regimens not used in reivew3. PlaceboAll 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 toreview.
Inclusion of 6 pretreatment drop-outs has minimal effect on OR.
Risk of bias
Support for judgement
Random sequence generation (selection Low risk ".a randomization list was computer gen- erated using a method of randomly per-muted blocks and a pseudorandom num-ber generator." Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Nides 2006
Allocation concealment (selection bias) "Investigators assigned medication to sub-jects in numerical order of acceptance intothe study." Incomplete outcome data (attrition bias) "Subjects who dropped out for any reason were considered to be smokers at all sub-sequent time points." 9.5% of vareniclinetartarate 0.3 mg, once daily; 7% of vareni-cline 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 groupwere lost to follow up.
Piper 2007
BUPROPIONSetting: USARecruitment: volunteersRandomization: method not stated 608 smokers of ≥ 10 CPD; 58% F, av. age 42, av CPD 22, no details of depressionhistory 1. Nicotine gum (4 mg) and bupropion (300 mg) (not used in this review)2. Placebo gum and bupropion3. Double placeboAll 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 Risk of bias
Support for judgement
Random sequence generation (selection Low risk "Randomization was conducted in double- blindfashion using blocked randomizationwithin each ofthe 10 [orientation session] cohorts." Allocation concealment (selection bias) Double blind at randomization.
Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Piper 2007
Incomplete outcome data (attrition bias) 32% of bupropion & 36% of placebo groups lost at 12 months. "Participantswho could not be reached at follow-up wereconsidered to be smoking for the purposesof follow-up analyses." NORTRIPTYLINESetting: VAMC & Army Medical Centre, USARecruitment: 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 indi-vidual 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.
Risk of bias
Support for judgement
Random sequence generation (selection Unclear risk Randomization method not described.
Allocation concealment (selection bias) "An unblinded research pharmacist recom-mended dosage reductions for those abovethetherapeutic range and dosage increases forthose who were subtherapeutic. To main-tain blinding, dose reductions and increaseson an equal number of randomly selectedplacebo-treated subjects were also recom-mended.our blinding was only partiallyeffective. Because of the high frequency ofdry mouth, the nurse and subjects were of-ten able to identify the active drug." Incomplete outcome data (attrition bias) 75% drop-out rate in placebo, 61% in drug group, majority classified as ineffec- Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
tive therapy.
NORTRIPTYLINESetting: clinic, USARecruitment: outpatient clinic & community volunteers 158 smokers, > 10 CPD, excluding current depression; 54% F, av. CPD 22, 6% historyof depression 1. Nortriptyline max 75 mg/day for 14w, from 2w before TQD tapered for 2w + nicotinepatch 8w from TQD2. 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 nortriptylinequitter in published paper Risk of bias
Support for judgement
Random sequence generation (selection Low risk "Subjects were stratified by history of pre- vious major depression and randomized bymeans of a computer-generated randomnumber list that was held by the ResearchPharmacy Service of the Denver VeteransAffairs Medical Center." Allocation concealment (selection bias) "Once a patient was enrolled, the ResearchPharmacy Service randomized the sub-ject according to the randomization list."Judged adequate.
Incomplete outcome data (attrition bias) "Subjects who dropped out were counted as smokers." Number of dropouts not given.
Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Rigotti 2006
BUPROPIONSetting: hospitals, USARecruitment: volunteers 248 smokers hospitalised with cardiovascular disease (excludes 3/3 dropped prior totreatment & 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 12w2. PlaceboBoth arms: Multicomponent CBT cessation & relapse prevention programme, motiva-tional interviewing approach, Begun in hospital, 30-45 mins, 5 X10 min post-dischargecontacts (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 Risk of bias
Support for judgement
Random sequence generation (selection Low risk "Using a computer program, the study statistician generated a sequence of ran-domly-permuted blocks of 4 within strataformed by study site and daily cigaretteconsumption (10 vs 10)." Allocation concealment (selection bias) "The study pharmacist used this sequence,concealed from enrollment staff, to assignparticipants to study arm. Subjects andstudy personnel, except the statistician andpharmacist, were blind to treatment assign-ment." Incomplete outcome data (attrition bias) "Subjects were considered smokers if they were lost to follow-up."; 23% lost to fol-low up in the bupropion group and 23%in the placebo group (Figure 1).
Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Saules 2004
FLUOXETINESetting: cessation clinic, USARecruitment: volunteers 150 smokers, 20% history of MDD; 55% F, av. age 40 1. Fluoxetine 40 mg for 14w, nicotine patch for 10w2. Fluoxetine 20 mg for 14w, nicotine patch for 10w3. Placebo & nicotine patchAll arms: TQD end of w4, CBT 6 sessions starting 2w before TQD, 11 clinic visits Abstinence at 12m (not defined)Validation: CO < 10 ppm Authors provided quit numbers by treatment group Risk of bias
Support for judgement
Random sequence generation (selection Unclear risk Randomzation method not described.
Allocation concealment (selection bias) Double-blind, but allocation concealmentnot explicit.
Incomplete outcome data (attrition bias) Subjects who dropped out of the study or lost to follow-up were considered to besmoking again.
Schmitz 2007
BUPROPIONSetting: Research clinic, USARecruitment: Community volunteers 154 women smokers >20 CPD; av. age 48, av. CPD 21 Factorial trial of bupropion and 2 group therapies1. Bupropion 300 mg/day for 7 weeks2. PlaceboBoth 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 Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Schmitz 2007
Risk of bias
Support for judgement
Random sequence generation (selection Low risk Urn procedure, balancing on a range of out- Allocation concealment (selection bias) Investigators and research staff blind to ran-domization codes? Incomplete outcome data (attrition bias) 14 'enrollment failures' who did not receive any treatment are excluded from analyses.
Other non-completers and losses to followup included in ITT analysis.
Selby 2003
BUPROPIONSetting: 15 clinical centres, CanadaRecruitment: community volunteers 284 smokers previously exposed to bupropion for at least 2w, not quit for more than 24hours in previous month 1. Bupropion 300mg for 12w2. PlaceboBehavioural support not described Abstinence at 12m (PP)Validation: CO <= 10 ppm at treatment visits Based on abstract Risk of bias
Support for judgement
Random sequence generation (selection Unclear risk Randomization method not described.
Allocation concealment (selection bias) No details given.
Incomplete outcome data (attrition bias) No details given.
Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Simon 2004
BUPROPIONSetting: VAMC outpatient units, USARecruitment: outpatientsRandomization: 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 2m2. Placebo bupropion, nicotine patch for 2mBoth 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 denominatorsOriginally based on abstract, now uses published data and sustained quitting outcome.
Risk of bias
Support for judgement
Random sequence generation (selection Low risk "We assigned participants to the 2 study arms by using a computer algorithm togenerate a random list of treatment assign-ments." Allocation concealment (selection bias) Double-blind, but allocation concealmentnot explicit.
Incomplete outcome data (attrition bias) "Of the 244 participants enrolled, 3 (1%) were lost to follow-up (all randomized tothe placebo arm).Participants lost to fol-low-up were considered smokers." Simon 2009
BUPROPIONSetting: VAMC hospital, USARecruitment: 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 7w2. PlaceboBoth arms: Individual cognitive behavioural 30-60 min during hospital stay + 5 phonecalls at w1, w3, w5, w8, w12, recycling encouraged.
Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Simon 2009
Abstinence at 6m, continuous at each assessmentValidation: saliva cotinine <15 ng/ml New for 2009. 1 death in bupropion, 1 in placebo excluded from analyses Risk of bias
Support for judgement
Random sequence generation (selection Low risk "computer algorithm to generate a random list of treatment assignments." Allocation concealment (selection bias) "All study personnel engaged in providinginterventions to participants were blindedto treatment assignment' but not explicitthat this included enrollment staff." Incomplete outcome data (attrition bias) 5 withdrawals, 1 lost to f-up, 1 death in placebo, 2 withdrawals, 1 lost, 1 death inbupropion. All except deaths included inMA BUPROPIONSetting: 6 clinical trial centres, USARecruitment: volunteers for phase II trial 286 smokers >=15 CPD, no prior use of bupropion48% F, av age 42, av CPD NS 1. Bupropion 300 mg for 7w & placebo novel therapy2. Double placeboNo information about behavioural support Abstinence at 12m (continuous)Validation: CO <= 10 ppm Identified from GSK trials website. Also included a novel cessation aid Risk of bias
Support for judgement
Random sequence generation (selection Unclear risk Randomization method not specified.
Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Allocation concealment (selection bias) Allocation concealment not described.
Incomplete outcome data (attrition bias) 34% lost in bupropion, 29% placebo, in- cluded as smokers.
Spring 2007
FLUOXETINESetting: clinic, USARecruitment: 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 weeks2. PlaceboBoth 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 sustainedabstinence Risk of bias
Support for judgement
Random sequence generation (selection Low risk "The study pharmacist stratified partici- pants by depression history and used com-puter- generated random numbers to as-sign them to drug or placebo." Allocation concealment (selection bias) "Research staff and participants wereblinded to medication status." Incomplete outcome data (attrition bias) Withdrawals/lost to follow-up 40% for flu- oxetine, 48% placebo. Authors report sim-ilar results from missing assumed smok-ing and GEE analyses. All participants in-cluded in MA.
Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Swan 2003
BUPROPIONSetting: HMO, USARecruitment: 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/dayFree & Clear proactive telephone counselling (4 brief calls), access to quitline and S-Hmaterials vsZyban Advantage Program (ZAP) tailored S-H materials, single telephone call afterTQD, access to Zyban support linePrescription was mailed. No face-to-face contact during enrolment or Rx Abstinence at 12m (7-day PP)Validation: none Based on published data from 2004No dose/behavioural treatment interaction at 12m so arms collapsed to compare 300 vs150Effects differed at 3 and 12m. Effect of higher dose disappeared and additional supportaided recycling.
Risk of bias
Support for judgement
Random sequence generation (selection Low risk "Open-label randomized trial.The com- puter code for the procedure calculatedprobabilities of group assignment that weredynamically modified based on the num-ber of members in each group so that fi-nal group sizes were equal. No restrictionssuch as stratification or blocking were usedas part of the randomization process." Allocation concealment (selection bias) Procedure built into study database.
Incomplete outcome data (attrition bias) Nonresponders treated as smoking.
Tashkin 2001
BUPROPION:Setting: multi-centre, USARecruitment: advertisements for volunteers Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Tashkin 2001
404 smokers with mild to moderate COPD. (Excludes 7 early drop-outs who did nottake any study medication); 45% F, av. age 53-54, av. CPD 28, 18% in Bupropion groupand 23% in Placebo had a history of depression.
1. Bupropion SR 300 mg/day for 12w from 1w before TQD2. PlaceboAll 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 reports6m data)Validation: CO =< 10 ppm at each visit 12m unpublished data used from 2003/2.
ITT population defined as those taking at least one dose of study medication.
Risk of bias
Support for judgement
Random sequence generation (selection Low risk "Randomised as per code provided by Glaxo Wellcome, using block sizes of fourstratified by centre. Within each blockof four, two participants were assignedplacebo and two bupropion SR. The ran-domisation codes were kept at the studysites during the trial and we instructed in-vestigators to break the code only for a med-ical emergency." Allocation concealment (selection bias) Double-blind study. Investigators did notknow how the subjects were randomised.
Incomplete outcome data (attrition bias) "All participants who withdrew from the study were taken to be smokers thereafter." BUPROPION:Setting: 28 clinical trial centres in 8 European countries, Australia, NZRecruitment: community volunteers 710 smokers >= 10 CPD; 51% F, av. age 42, median CPD 20, no details of depressionhistory Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
1. Bupropion SR 300 mg/day for 7w2. PlaceboBoth arms: brief motivational support at weekly clinic visits and telephone supportduring 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 defined as those taking at least one dose of study medication excludes 3randomized participants Risk of bias
Support for judgement
Random sequence generation (selection Low risk "GlaxoSmithKline created a randomiza- tion schedule in a 3 : 1 bupropion: placeboratio. Each centre received a list with treat-ment numbers and subjects were consecu-tively assigned a treatment number at thebaseline visit." Allocation concealment (selection bias) Double-blind; "GlaxoSmithKline suppliedbupropion SR 150 mg and placebo-to-match tablets for oral administration aswhite, film-coated tablets." Incomplete outcome data (attrition bias) 9% of bupropion SR and 12% placebo were lost to follow-up.
Tonstad 2003
BUPROPIONSetting: 28 clinical trial centres in 10 countries incl Europe, Australia, NZRecruitment: 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 TQD2. PlaceboBoth arms: brief motivational support at weekly clinic visits and telephone supportduring follow up. 9 clinic visits and 10 phone calls scheduled.
Abstinence at 12m (prolonged from w4)Validation: CO <= 10 ppm Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Tonstad 2003
First included 2003 as McRobbie 2003. ITT population = 626 defined as those takingat least one dose of study medication.
Risk of bias
Support for judgement
Random sequence generation (selection Unclear risk Randomization method not described.
Allocation concealment (selection bias) Double-blind but allocation concealmentmethod not described.
Incomplete outcome data (attrition bias) "Subjects with missing investigator assess- ments were assumed to be smokers at thatvisit." Uyar 2007
BUPROPIONSetting: cessation clinic, TurkeyRecruitment: cessation clinic patients 131 smokers; 81% M, av. age 36 1. Bupropion 300mg for 7 weeks2. Nicotine patch 21mg for 6 weeks incl tapering3. Advice and follow up onlyAll arms: Brief counselling on consequences of smoking with follow up for 24 weeks-more than low intensity Abstinence at 24w (not defined)Validation: CO < 10 ppm First included based on abstract. Contributes to bupropion vs control and bupropion vsnicotine patch Risk of bias
Support for judgement
Random sequence generation (selection Unclear risk 'Randomly allocated', method not de- scribed, unclear why fewer in control con-dition.
Allocation concealment (selection bias) Allocation concealment not described.
Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Uyar 2007
Incomplete outcome data (attrition bias) No mention of any losses to f-up.
Wagena 2005
BUPROPION & NORTRIPTYLINESetting: university medical centre, NetherlandsRecruitment: 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 12w2. Nortriptyline 75 mg/day for 12w3. Placebo bupropion or placebo nortriptylineAll arms: Individual counselling 10-20 mins at baseline, 1w & 3w post TQD (TQDtypically 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 Risk of bias
Support for judgement
Random sequence generation (selection Low risk Computer-generated by pharmacist, strat- ified by COPD severity, block size 33.
Allocation concealment (selection bias) Research staff blinded throughout study.
Incomplete outcome data (attrition bias) 10 (12%) bupropion, 13 (16%) nortripty- line, 12 (13%) lost or withdrawn. All in-cluded in ITT analysis.
SELEGILINESetting: clinics, USARecruitment: community volunteers 101 smokers (excludes 2 taking no medication), 50% F, av. age 47, av. CPD 22, 28%had history of MDD Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
1. Selegiline 10 mg/day for 9 weeks (5 mg/day in w1 & w9)2. PlaceboBoth arms; brief weekly counselling Abstinence at 6m (7-day PP)Validation: CO & cotinine New for 2009 based on conference abstract Risk of bias
Support for judgement
Random sequence generation (selection Unclear risk Randomization method not described.
Allocation concealment (selection bias) No information in abstract.
Incomplete outcome data (attrition bias) 27.5% selegiline, 42% placebo lost at 6 months. Including all participants is lessconservative.
BUPROPIONSetting: 26 clinical trial centres in 12 European countriesRecruitment: volunteers, healthcare professionals (qualified practising physician ornurse) 667 smokers (>= 10 CPD) (excludes 1 centre enrolling 20 people, and 3 people whotook 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 7w2. PlaceboBoth arms: Brief (10-15 min) motivational support at weekly clinic visits and telephonesupport 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 GlaxoSmithKlinedata. One centre excluded Risk of bias
Support for judgement
Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Random sequence generation (selection Unclear risk Randomization method not described.
Allocation concealment (selection bias) Double-blind but allocation concealmentmethod not described.
Incomplete outcome data (attrition bias) Participants with missing assessments or drop-outs considered to be smoking.
av: averageAE: adverse eventCBT: cognitive behavioural therapyCES-D: Center for Epidemiologic Studies Depression ScaleCO: carbon monoxide (in exhaled breath)COPD: chronic obstructive pulmonary diseaseCPD: cigarettes per dayCVD: cardiovascular diseaseEOT: end of treatmentf-up: follow upF: femaleFTND: Fagerstrom Test for Nicotine DependenceFTQ: Fagerstrom Tolerance QuestionnaireITT: intention to treatm: month/sMA: meta-analysisMDD: Major depressive disorderMI: myocardial infarctionNRT: nicotine replacement therapyNS: not statedP: PlaceboPP: Point Prevalence abstinenceRP: relapse preventionRx: TreatmentS-H: self-helpTQD: Target quit dateVAMC: Veterans Affairs Medical Centerw: 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.
Reason for exclusion St John's Wort - pilot study comparing two doses of St John's Wort, no quitters at 12 months.
Lazabemide (monoamine oxidase-B inhibitor) - short follow up Befloxatone (reversible monoamine oxidase-B inhibitor) - data not published, treatment reported to have hadno effect on abstinence rates.
Tryptophan - short follow upTryptophan 50 mg/kg/day, with high-carbohydrate low protein diet (7/1 ratio), vs placebo and low carbohydratehigh 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 financial 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 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.
Antidepressants for smoking cessation (Review)
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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 Niaura2002.
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 John's 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 notincluded 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 alcoholuse in non-depressed heavy drinkers.
Bupropion - trial of NRT as adjunct to bupropion Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Bupropion - placebo-controlled short-term study of effects on craving and withdrawal in patients not wantingto quit smoking permanently.
Trial of bupropion for methamphetamine dependence. Reduction in smoking was a secondary outcome. Only48/73 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. Adverseevent data from author used.
Bupropion +/- nicotine patch. Unable to confirm 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).
Characteristics of ongoing studies [ordered by study ID]
Brown 2007b
Trial name or title Sequential use of fluoxetine for smokers with elevated depressive symptoms Randomized, Double Blind (Subject, Investigator), Parallel Assignment, Efficacy Study Regular smokers with elevated depressive symptoms Fluoxetine 20mg , begun 8 weeks prior to and extended throughout brief (behavioral) standard smokingcessation treatment with transdermal nicotine patch vs placebo Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Brown 2007b
Biochemically validated abstinence at 1 year Contact information ClinicalTrials.gov identifier: NCT00578669 Trial name or title 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 Contact information Elbert Glover/ NIDA Record accessed 4th August 2009, last updated January 26 2009 Trial name or title Bupropion treatment for smokers in recovery Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, FactorialAssignment, Efficacy Study Bupropion or placebo for 8 weeks as adjunct to 7 weeks nicotine patch & counselling Smoking cessation at 24 weeks Contact information Record accessed 4th August 2009, last updated February 18 2009 Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Trial name or title 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 Contact information Joel Killen, Stanford University Record accessed 4th August 2009, last updated July 9 2008 Le Foll (NCT00390923)
Trial name or title 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 Contact information Bernard Le Foll, Centre for Addiction and Mental Health, Toronto Record accessed 4th August 2009, last updated November 4 2008 Trial name or title St. John's Wort for tobacco cessation Randomized, Double-Blind, Placebo Control, Parallel Assignment, Safety/Efficacy Study 12-week course of St John's Wort in two different oral doses of 300 mg or 600 mg three times a day comparedto placebo Abstinence at end of treatment (primary) and at 6 months (2ndry) Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Contact information 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.
Comparison 1. Bupropion. Abstinence at 6m or greater follow-up
Outcome or subgroup title
Effect size
Risk Ratio (M-H, Fixed, 95% CI) 1.69 [1.53, 1.85] Risk Ratio (M-H, Fixed, 95% CI) 1.64 [1.46, 1.84] Risk Ratio (M-H, Fixed, 95% CI) 1.81 [1.51, 2.16] Risk Ratio (M-H, Fixed, 95% CI) 1.69 [1.53, 1.85] Risk Ratio (M-H, Fixed, 95% CI) 1.66 [1.47, 1.87] Risk Ratio (M-H, Fixed, 95% CI) 1.86 [1.53, 2.25] Risk Ratio (M-H, Fixed, 95% CI) 1.32 [0.98, 1.78] Risk Ratio (M-H, Fixed, 95% CI) 2.25 [1.29, 3.90] Risk Ratio (M-H, Fixed, 95% CI) 1.70 [1.54, 1.88] Risk Ratio (M-H, Fixed, 95% CI) 1.62 [1.30, 2.03] Risk Ratio (M-H, Fixed, 95% CI) 1.72 [1.54, 1.91] Risk Ratio (M-H, Fixed, 95% CI) 2.88 [0.32, 25.68] Risk Ratio (M-H, Fixed, 95% CI) 1.08 [0.93, 1.26] Risk Ratio (M-H, Random, 95% CI) 1.23 [0.67, 2.26] Risk Ratio (M-H, Fixed, 95% CI) 1.17 [0.99, 1.39] Risk Ratio (M-H, Random, 95% CI) 1.26 [0.73, 2.18] Risk Ratio (M-H, Fixed, 95% CI) 0.66 [0.53, 0.82] Risk Ratio (M-H, Fixed, 95% CI) Totals not selected Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Comparison 2. Nortriptyline
Outcome or subgroup title
Effect size
Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) 2.03 [1.48, 2.78] Risk Ratio (M-H, Fixed, 95% CI) 1.29 [0.97, 1.72] Comparison 3. Bupropion versus nortriptyline
Outcome or subgroup title
Effect size
Risk Ratio (M-H, Fixed, 95% CI) 1.30 [0.93, 1.82] Comparison 4. Selective Serotonin Reuptake Inhibitors (SSRIs) versus placebo
Outcome or subgroup title
Effect size
Risk Ratio (M-H, Fixed, 95% CI) 0.92 [0.68, 1.24] Risk Ratio (M-H, Fixed, 95% CI) 0.92 [0.65, 1.30] Risk Ratio (M-H, Fixed, 95% CI) 0.92 [0.53, 1.61] Risk Ratio (M-H, Fixed, 95% CI) 1.08 [0.64, 1.82] Risk Ratio (M-H, Fixed, 95% CI) 0.71 [0.30, 1.64] Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Comparison 5. Monoamine oxidase inhibitors (MAOIs) versus placebo
Outcome or subgroup title
Effect size
Risk Ratio (M-H, Fixed, 95% CI) 1.49 [0.92, 2.41] Risk Ratio (M-H, Fixed, 95% CI) 1.57 [0.67, 3.68] Risk Ratio (M-H, Fixed, 95% CI) 1.45 [0.81, 2.61] Comparison 6. Venlafaxine versus placebo
Outcome or subgroup title
Effect size
Risk Ratio (M-H, Fixed, 95% CI) 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.
Antidepressants for smoking cessation 1 Bupropion. Abstinence at 6m or greater follow-up 1 Bupropion versus placebo/control. Subgroups by length of follow-up Study or subgroup 1 Twelve month follow-up 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 ] Favours treatment Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Study or subgroup 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)
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 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 ] Favours treatment Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Study or subgroup Subtotal (95% CI)
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)
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) 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.
Antidepressants for smoking cessation 1 Bupropion. Abstinence at 6m or greater follow-up 2 Bupropion versus placebo/control. Subgroups by clinical/recruitment setting Study or subgroup 1 Community volunteers 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 ] 1.53 [ 1.02, 2.31 ] Favours treatment Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Study or subgroup 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)
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 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)
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 2.58 [ 1.25, 5.32 ] 1.08 [ 0.77, 1.50 ] Subtotal (95% CI)
1.32 [ 0.98, 1.78 ]
Total events: 157 (Treatment), 44 (Control) Favours treatment Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Study or subgroup 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 3.96 [ 1.51, 10.38 ] 1.52 [ 0.76, 3.04 ] Subtotal (95% CI)
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)
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) Favours treatment Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 1.3. Comparison 1 Bupropion. Abstinence at 6m or greater follow-up, Outcome 3 Bupropion
versus placebo. Subgroups by level of behavioural support.
Antidepressants for smoking cessation 1 Bupropion. Abstinence at 6m or greater follow-up 3 Bupropion versus placebo. Subgroups by level of behavioural support Study or subgroup 1 Multisession group behavioural support 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)
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 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 ] Favours treatment Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Study or subgroup 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)
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 2.88 [ 0.32, 25.68 ] Subtotal (95% CI)
2.88 [ 0.32, 25.68 ]
Total events: 3 (Treatment), 1 (Control) Heterogeneity: not applicable Test for overall effect: Z = 0.95 (P = 0.34) Total (95% CI)
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) Favours treatment Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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.
Antidepressants for smoking cessation 1 Bupropion. Abstinence at 6m or greater follow-up 4 Bupropion dose response. 300 mg/day versus 150 mg/day Study or subgroup 300 mg/day bupropion 150 mg/day bupropion 0.90 [ 0.52, 1.55 ] 4.54 [ 1.01, 20.52 ] 1.07 [ 0.91, 1.25 ] Total (95% CI)
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) Favours 150mg dose Favours 300mg dose Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 1.5. Comparison 1 Bupropion. Abstinence at 6m or greater follow-up, Outcome 5 Bupropion and
NRT versus NRT alone.
Antidepressants for smoking cessation 1 Bupropion. Abstinence at 6m or greater follow-up 5 Bupropion and NRT versus NRT alone Study or subgroup M-H,Random,95% CI M-H,Random,95% CI 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)
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) Favours treatment Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 1.6. Comparison 1 Bupropion. Abstinence at 6m or greater follow-up, Outcome 6 Bupropion for
Antidepressants for smoking cessation 1 Bupropion. Abstinence at 6m or greater follow-up 6 Bupropion for relapse prevention Study or subgroup 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)
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) Favours treatment Analysis 1.7. Comparison 1 Bupropion. Abstinence at 6m or greater follow-up, Outcome 7 Bupropion
versus nicotine patch.
Antidepressants for smoking cessation 1 Bupropion. Abstinence at 6m or greater follow-up 7 Bupropion versus nicotine patch Study or subgroup M-H,Random,95% CI M-H,Random,95% CI 0.77 [ 0.28, 2.11 ] 1.88 [ 1.18, 2.98 ] 1.00 [ 0.52, 1.94 ] Total (95% CI)
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) Favours bupropion Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 1.8. Comparison 1 Bupropion. Abstinence at 6m or greater follow-up, Outcome 8 Bupropion
Antidepressants for smoking cessation 1 Bupropion. Abstinence at 6m or greater follow-up 8 Bupropion versus varenicline Study or subgroup 0.74 [ 0.54, 1.01 ] 0.64 [ 0.46, 0.88 ] 0.44 [ 0.20, 0.98 ] Total (95% CI)
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) Favours treatment Analysis 1.9. Comparison 1 Bupropion. Abstinence at 6m or greater follow-up, Outcome 9 Bupropion for
Antidepressants for smoking cessation 1 Bupropion. Abstinence at 6m or greater follow-up 9 Bupropion for harm reduction Study or subgroup 1 Reduction in cotinine >50% from baseline at 1y 0.43 [ 0.12, 1.58 ] 2 Cessation at 6m 1.27 [ 0.67, 2.40 ] Favours treatment Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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
Other adverse events
Withdrawal due to AE
No seizures occurred Insomnia (29.3 vs 20.7%) more No information No serious adverse events reported.
common with bupropion.
Dry mouth (28% vs 24%) No seizures occurred 61% on bupropion and 45% on 10% bupropion & 5% placebo 5 bupropion and 1 placebo serious placebo experienced at least one AE withdrew due to AEs AE during treatment, 2 bupropion Sleep disorder 33% bupropion vsduring f-up. 1 chest pain, tremor & 19% placebosweating & 1 depressive syndromeafter end of treatment consideredpossibly due to bupropion.
Not reported in paper 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,prevention) constipation, insomnia, stomach-ache, depressedmood) was low (mean = 0.43, SD =0.91), and did notvary by treatment group (P = 0.69)' No seizures occurred Insomnia (28% vs 18%), dizziness 12% bupropion & 8% placebo No serious adverse event during (8% vs 1%) and skin problems (15% withdrew due to adverse event.
treatment phase. 3 events during fol- vs 7%) significantly more commonlow-up not considered to be drug with bupropion. Major depressionrelated including 1 death in bupro- more common in placebo (1% vspion group, No seizures occurred No information (only 19 partici- No informationpants) Not reported in abstract Not reported in abstract Not reported in abstract No seizures occurred (data from No information from abstract No information from abstract No seizures occurred (data from No information from abstract 3% bupropion & 3% placebo with- drew due to adverse experience (datafrom FDA submission) 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
No seizures occurred Dry mouth (6.3% vs 2.1%), Insom- 14% bupropion & 7% placebo 8 serious adverse events in bupro- nia (17.3% vs 6.2%), and constipa- withdrew due to AEspion group, of which 1 thought tion (11.0% vs 3.6%) significantlyto be medication related (suspected more common on bupropioncholangitis) No seizures occurred Dry mouth (62.5% vs 25.0%) , 2 bupropion & 5 placebo withdrewheadache (56.3% vs 37.5%), in- during treatment, no reasons givensomnia (43.8% vs 27.8%), mem-ory problems (50.0% vs 31.3%),blurred vision (50.0% vs 25.0%, ir-regular heartbeat (37.5% vs 12.5%),nausea/vomiting (43.8% vs 18.8%)diarrhoea (50.0% vs 25.0%), anx-iety/agitation (50.0% vs 25.0%),tremor (31.3% vs 12.5%) No seizures occurred. Three serious There were significant (p <.05) No information on AE related with-adverse events (SAEs) involved psy- group differences on concentration, drawalschotic decompensation, 2 placebo, jitteriness, lightheadedness, muscle1 bupropion. All deemed unrelated stiffness, and frequent nocturnalto study medications No seizures occurred. One serious No significant differences between 30 people discontinued medicationadverse event (rash with pruritus and bupropion & placebo. 72% on due to adverse event, 11 (5%)edema) in the bupropion group was bupropion reported adverse event vs placebo, 19 (8%) bupropion. Forassessed as being due to study med- 58% placebo. Most common ad- patients on bupropion most com-ication verse events insomnia (24% vs 11%) mon events were anxiety (4), dry, viral infections (13% vs 19%) dry mouth (3) and rash (3)mouth (13% vs 9%), headache (8%vs 13%), 1 seizure after 20 days of bupropion. Dry mouth (8.8% vs 5.5%, NS), 9.0% placebo, 15.2% bupropionNo other serious events assessed as nausea (12.5% vs 8.4%, NS), in- discontinued medicationdue to medication somnia (21.9% vs 12.8%) No seizures occurred Insomnia (37% vs 7%) 10 (33%) discontinued bupropionvs 3 (11%) placebo No seizures or other serious adverse Insomnia (50.9% vs 17.6%), dry No reportevents occurred mouth (50.9% vs 31.4%), diarrhoea(11.0% vs 3.9%) No seizures occurred No significant differences between No reportbupropion & placebo No seizures occurred. 8 serious AEs No details 60 people discontinued medication in bupropion, 3 placebo. One case of due to adverse events, 22 (7%) 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
chest pain thought to be treatment placebo, 38 (13%) bupropion.
No seizures occurred. No serious ad- No significant differences between 41 people discontinued medicationverse 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 in-somnia (10% vs 7%) and headache(24% vs 17%) also rhinitis, in-fluenza URI and accidental injury.
No seizures occurred. One patient No details One bupropion (ataxia, headache receiving bupropion suffered ataxia, headache and jitteriness.
No seizures or serious adverse events Insomnia 26% vs 9% Three discontinued bupropion dueto a rash.
No seizures occurred. One of three Bupropion 300mg was associated 37 people discontinued medica-serious adverse events could have with significantly more insomnia tion due to adverse events; 6 (5%)been associated with bupropion; ex- (34.6% vs 20.9%) and dry mouth placebo; 9 (6%) 100mg; 7 (5%)treme irritability restlessness, anger, (12.8% vs 4.6%) than placebo.
150mg; 13 (8%) 300mg. Tremor, anxiety and craving in a man who headaches, rash and urticaria were stopped smoking.
the most common reasons for stop-ping treatment.
No seizures occurred No significant differences.
Anxiety (16% vs 9%) and nervous-ness (13% vs 6%) more commonin bupropion group. Insomnia lesscommon (10% vs 17%).
No seizures occurred. Three seri- Bupropion was associated with more 79 people discontinued medica-ous adverse events were attributed insomnia (42.4% vs 19.5%) and tion due to adverse events; 6to bupropion, all consisted of rash dry mouth (10.7% vs 4.4%) than (3.8%) placebo; 16 (6.6%) patch; 29and pruritus, one with shortness of placebo.
(11.9%) bupropion and 28 (11.4%) breath and chest tightness. All had combined treatment group. 20% full resolution of symptoms dropped out of study, and 35% werelost to follow-up at 12 months.
No seizures occurred Bupropion was associated with more 16 (4.7%) bupropion vs 13 (3.8%) 1 serious adverse event attributed to insomnia (21.2% vs 12.4%), sleep placebo discontinued study due tobupropion; angioedema.
disorder (6.8% vs 2.6%), constipa- AEs. 12.6% vs 7.3% discontinuedtion (6.5% vs 1.5%), dry mouth medication.
(7.6% vs 3.2%).
No seizures occurred.
22 (21%) reported severe AEs in None reported No adverse effects judged to be se- bupropion & patch group vs 25vere by study physician (23%) in placebo & patch.
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
24 (23%) vs 35 (32%) reportedmoderate AEs 1 seizure during open-label phase During open-label phase 53% re- 30 (8%) discontinued medication 2 other serious adverse events during ported insomnia, 47% dry mouth, during open-label phase. 1 bupro-open label phase (oedema, depres- 44% vivid dreams, 23% nausea, pion and 2 placebo discontinuedsion) and 2 during extended treat- 22% headache, 17% racing heart during extended treatment phase.
ment (diagnosis of hyperthyroidism rate, 12% skin rash and 7% irregularin bupropion group, onset of im- heart rate.
mune thrombocytopenia purpura inplacebo group).
No seizures occurred. 1 hospitalisa- Headache and cough were common- Eight subjects discontinued medica-tion (150 mg/d group) for deliber- est reported AEs. No others signifi- tionate ingestion of Datura innoxia for cantly different.
early because of the following ad- recreational purposes. 1 hospitalisa- verse events: feeling tion (150 mg/d group) for inten- depressed, irritable, or angry; sleep tional overdose of study medication, disturbance; headache; other drugs & alcohol.
urticaria; anxiety; heart palpitations;suicide attempt;anticholinergic crisis related torecreational drug use; andpregnancy.
Two seizures, 2 other serious AEs 90% of bupropion and 88% on 16% bupropion & 10% placebo dis-in bupropion (persistent intermit- placebo experienced at least one AE.
continued medication tent bloody diarrhoea, syncope) all Insomnia 45% bupropion vs 22%considered to be possibly related to placebo, constipation 14% bupro-bupropion pion vs 4% placebo, dry mouth 12%bupropion vs 6% placebo.
No report of seizures 4.7% of adverse avents was insom- Not reportednia, not reported by condition No report of seizures. Two deaths in Not reported Withdrawals not reported placebo group.
Non cardiac serious adverse events;37% bupropion vs 31% placebo, nsRate of new cardiovascular eventsdid not differ significantly at 3months or 1 year. After 30 daysoff drug more bupropion group sus-tained a cardiovascular event, bor-derline significance after adjustmentfor cardiac risk factors.
No report of seizures or other serious Frequency of insomnia and abnor- Withdrawals not reportedAE mal dreams similar in both groups.
Dry mouth 22% bupropion vs 8% 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
placebo, gastrointestinal upset 9%bupropion vs 1% placebo No seizures occurred. 1 death in 11 (26%) bupropion vs 4 (9%) ineach group, causes not given (hospi- the placebo reported any AEs. Hy-tal population) peractivity and insomnia reportedsolely in bupropion group No seizures or deaths occurred. 7 pa- Overall rate of reporting of adverse 7% vs 1% withdrew due to AEstients (bupropion 4, placebo 3) ex- events 90% vs 83%. Sleep disordersperienced 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 inserious AEs reported difficulty sleeping (48% vs 41%) 150 mg group and 31% in 300 mg, difficulty concentrating (35% groupvs 28%), gastrointestinal problems(27% vs 20%) and shakiness/tremor(24% vs 17%) than lower dose.
No seizures occurred.
Bupropion associated with more in- 27 people discontinued medica- 6 patients (placebo 5, bupropion 1) somnia (24% vs 12%). Rates for tion, bupropion 14 (7%), placeboexperienced a serious adverse event. headache (6% vs 6%) and dry 13 (6.5%). Commonest reasons inOne event (transient ischaemic at- mouth (6% vs 5%) similar in 2 bupropion group were anxiety (5),tack) in placebo group thought to be groups.
related to study treatment.
No seizures occurred Bupropion associated with more in- 8% on bupropion and 6% on 7 patients (bupropion 6, placebo somnia (24% vs 15%), dry mouth placebo withdrew due to adverse1) experienced serious AEs within (13% vs 5%) headache (13% vs events.
a week of ending treatment. A rea- 10%) sleep disorder (10% vs 7%),sonable possibility that SAEs in 3 constipation (6% vs 1%) and dizzi-bupropion patients related to study ness (7% vs 4%)medication (fainting due to insom-nia, urticaria/angioedema (2). In ad-dition one bupropion patient deliv-ered twin girls 4 weeks after treat-ment termination, one still born.
No seizures occurred.
Bupropion associated with more in- 5% on bupropion and 6% on Five serious adverse events during somnia (24% vs 12%), dry mouth placebo withdrew due to adversetreatment, all on bupropion. Only 1 (18% vs 10%), nausea (13% vs 6%) events.
(lupus disseminatus) considered re- , dizziness (8% vs 5%). 11% in eachlated to medication. None led to group reported headache.
medication discontinuation. Three No evidence of any effect on vitalSAEs within a week of treatment, signs in CVD patients.
none related to bupropion use.
36 patients (Bupropion 24, placebo14) reported cardiovascular adverse 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
events.
4 deaths (2, 2) during follow-upphase, none related to study medi-cation.
No seizures occurred 56% on bupropion reported dry 4 (8%) discontinued bupropion duemouth, 44% headache, 40% insom- to adverse effectsnia. Sleep disturbance rates signifi-cantly higher than control (38% vs9.6%).
No seizures occurred No significant differences between 15% on bupropion and 9% on One death in placebo group, previ- bupropion & placebo. Insomnia placebo discontinued medicationously hospitalised with dermatolog- 34% vs 24%, Dry mouth 28% vsical reactions 20%, diarrhoea or constipation 34%vs 26% Two seizures occurred in bupropion Bupropion associated with more in- 9% on bupropion and 5% ongroup. One patient had a possible somnia (39% vs 22%). Similar rates placebo withdrew due to adversefamilial predisposition and the other of dry mouth (12% vs 10%), agita- events, most commonly due to ner-was sleep deprived. 1 patient on tion (10% vs 11%), nausea (10% vs vous system events in both groups.
placebo suffered a transient ischemic 7%).
attack and 1 a pulmonary sequestra-tion Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 2.1. Comparison 2 Nortriptyline, Outcome 1 Long term abstinence (6-12m).
Antidepressants for smoking cessation 1 Long term abstinence (6-12m) Study or subgroup 1 Nortriptyline versus placebo. No other pharmacotherapy 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)
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 1.26 [ 0.84, 1.87 ] 0.62 [ 0.25, 1.53 ] Hall 2004 Extended 1.34 [ 0.75, 2.38 ] 2.25 [ 1.04, 4.87 ] Subtotal (95% CI)
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) 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
Other adverse events
Withdrawal due to AE
2 admissions to hospital (1 inter- Dry mouth (80% vs 'more than No reportvention, 1 control) with collapse or half, OR 6.67, 5.12 to 8.69), Con-palpitations judged possibly caused stipation (OR 2.06, 1.66 to 2.56)by treatment and Sweating (OR 1.37, 1.11 to1.68) significantly more common 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
No significant differences between No reportgroups.
Dry mouth 44% vs 24%, constipa-tion 29% vs 12%, irritation 18%vs 24%, anxiety 18% vs 28%.
Dry mouth (67.3% vs 31.4%) and No reportdrowsiness (19.2% vs 11.8%) sig-nificantly more common with nor-triptylineConstipation (15.4% vs 9.8%) NS Dry mouth (78% vs 33%), light- 4 (4%) dropouts due to side ef-headedness (49% vs 22%), shaky fects in drug and 1 (1%) in placebohands (23% vs 11%) and blurry vi- group. Total dropout rates 30% insion (16% vs 6%) were significantly drug and 17% in placebo groupsmore common.
Dry mouth (72% vs 33%) and con- No reportstipation ( 32% vs 14%) signif-icantly more common with nor-triptyline (Includes data for all Hall 2004 par- 4 (10%) in active brief treatment,ticipants) 10 (25%) in active extended treat- Dry mouth (85% vs 40%), light- ment, 9 (11%) in placebo stoppedheadedness (44% vs 22%), shaky medication due to adverse effectshands (30% vs 14%) constipation (active vs placebo p=0.18, Fisher's(38% vs 15%), blurry vision (23% exact test)vs 7%), difficulty urinating (13%vs 2%), all p<0.01. Sexual difficul-ties (19% vs 2% p <0.02) Hall 2004 Extended During weeks 12-52, skin redness See Hall 2004 Brief(2.5% vs 0%, p=0.03, Fisher's ex-act test). Sexual difficulties (8.9%vs 1.2% p=0.03, Fisher's exact test) Dry mouth (64% vs 23%), dysgeu- 10 (9%) treatment withdrawal duesia (20% vs 8%), GI upset (41% to adverse events in nortriptylinevs 24%), drowsiness (24% vs 8%) group, vs 3 (3%) in placebo group.
significantly more common Dry mouth (38% vs 8%) & se- 10 (13%) discontinued nortripty-dation (20% vs 3%) significantly line including 1 subject with a nor-more common.
mal baseline ECG who developedasymptomatic prolongation of QTinterval, vs 1 placebo 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
One death in placebo group, pre- Dry mouth (61% vs 20%), di- 24% discontinued nortriptyline vsviously hospitalised with dermato- arrhoea or constipation (48% vs 9% placebological reactions 26%) and fatigue (20% vs 9%) sig-nificantly more common in nor-triptyline group Analysis 3.1. Comparison 3 Bupropion versus nortriptyline, Outcome 1 Long term abstinence.
Antidepressants for smoking cessation 3 Bupropion versus nortriptyline 1 Long term abstinence Study or subgroup 1.35 [ 0.80, 2.26 ] 1.71 [ 0.72, 4.11 ] 1.12 [ 0.67, 1.86 ] Total (95% CI)
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) Favours nortiptyline Favours bupropion Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 4.1. Comparison 4 Selective Serotonin Reuptake Inhibitors (SSRIs) versus placebo, Outcome 1
Fluoxetine. Long term abstinence.
Antidepressants for smoking cessation 4 Selective Serotonin Reuptake Inhibitors (SSRIs) versus placebo 1 Fluoxetine. Long term abstinence Study or subgroup 1 Fluoxetine versus placebo 0.98 [ 0.66, 1.47 ] 0.73 [ 0.35, 1.52 ] Subtotal (95% CI)
0.92 [ 0.65, 1.30 ]
Total events: 75 (), 48 (Control) 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 0.90 [ 0.43, 1.90 ] 0.94 [ 0.41, 2.18 ] Subtotal (95% CI)
0.92 [ 0.53, 1.61 ]
Total events: 24 (), 19 (Control) 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)
0.92 [ 0.68, 1.24 ]
Total events: 99 (), 67 (Control) Heterogeneity: Chi2 = 0.51, df = 3 (P = 0.92); I2 =0.0% Test for overall effect: Z = 0.56 (P = 0.58) Favours treatment Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 4.2. Comparison 4 Selective Serotonin Reuptake Inhibitors (SSRIs) versus placebo, Outcome 2
Paroxetine. Long term abstinence.
Antidepressants for smoking cessation 4 Selective Serotonin Reuptake Inhibitors (SSRIs) versus placebo 2 Paroxetine. Long term abstinence Study or subgroup 1.08 [ 0.64, 1.82 ] Total (95% CI)
1.08 [ 0.64, 1.82 ]
Total events: 35 (), 16 (Control) Heterogeneity: not applicable Test for overall effect: Z = 0.29 (P = 0.77) Favours treatment Analysis 4.3. Comparison 4 Selective Serotonin Reuptake Inhibitors (SSRIs) versus placebo, Outcome 3
Sertraline. Long term abstinence.
Antidepressants for smoking cessation 4 Selective Serotonin Reuptake Inhibitors (SSRIs) versus placebo 3 Sertraline. Long term abstinence Study or subgroup 0.71 [ 0.30, 1.64 ] Total (95% CI)
0.71 [ 0.30, 1.64 ]
Total events: 8 (), 11 (Control) Heterogeneity: not applicable Test for overall effect: Z = 0.81 (P = 0.42) Favours treatment Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 5.1. Comparison 5 Monoamine oxidase inhibitors (MAOIs) versus placebo, Outcome 1 Long term
Antidepressants for smoking cessation 5 Monoamine oxidase inhibitors (MAOIs) versus placebo 1 Long term abstinence Study or subgroup 1 Moclobemide versus placebo 1.57 [ 0.67, 3.68 ] Subtotal (95% CI)
1.57 [ 0.67, 3.68 ]
Total events: 11 (Treatment), 7 (Control) Heterogeneity: not applicable Test for overall effect: Z = 1.04 (P = 0.30) 2 Selegiline versus placebo 2.21 [ 0.92, 5.32 ] 4.00 [ 0.49, 32.72 ] 0.65 [ 0.25, 1.70 ] Subtotal (95% CI)
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)
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) Favours treatment Analysis 6.1. Comparison 6 Venlafaxine versus placebo, Outcome 1 Long term abstinence.
Antidepressants for smoking cessation 6 Venlafaxine versus placebo 1 Long term abstinence Study or subgroup 1.22 [ 0.64, 2.32 ] Favours treatment Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
A P P E N D I C E S
Appendix 1. Suspected adverse events from national reporting schemes
No. of reports
No. of users
Rate of reports
Source/ date
UK (safety notice 7,630 Medicines Control 26 July 2002 http:// (2357, 31% of total www.mca.gov.uk/reports) (994, monitorsafe- (779, safetymessages/ 10%)Seizures: 184 (2.4%of reports, est rate0.3/1000)Deaths: 60 UK (MHRA rou- 8,452 (18,319 reac- Estimated approx- approx 8/1000 pre- By organ class: tine data on sus- tions) to May 2004 imately 1,000,000 scriptions -General disorders: Healthcare products pected adverse drug Regulatory Agency reactions). Includes scriptions dispensed reports summarised nia (1030), dizziness Adverse Drug Re- in UK safety notice 2004, based on Eng- (805), chest pain actions Information Service. Data pro- data of 762,200 for -Skin & subcuta- vided April 2004.
2000-2003. Average neous tissue disor- Prescription prescription was a 4 from DoH Prescrip- week course.
pruritus tion Cost Analysis (421), rashes (1094) (www.publications.doh.gov.uk/, urticaria (1104), prescriptionstatis-angioedema (481) disorders (627), sui-cidal ideation/ sui-cide/parasuicide(87)-Neurological disor-ders: 2338Includes vulsions & epilepsy(212) Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
-Gastrointestinaldisturbances: 2176Includes nausea /vomiting (775)-Deaths: includes 4 suicides Canada (safety no- 1,127 Full list not given ban, 699,000 Well- Seizures: 172 (Zy- itoring Programme ban 120, Wellbutrin (CADRMP)GSK/46 bupropion 6) Health (15% of reports, est 'Dear Doctor' letterrate 0.1/1000 for 3 July 2001Zyban Serum sickness: 37 Full list not given skin reactions (499 tic Goods Adminis-reports), psychiatric tration (TGA) alertdisturbances (427) 31 August 2001, nervous system http://(406, includes con- www.health.gov.au/vulsions/twitch- tga/ docs/html/zy- ing 74), gastroin- ban.htmtestinal tract (258), facial/angioedema(89), serum sickness(63)Deaths: 18 1,672 (4,390 reac- Approx 534,000 approx 3/1,000 pre- Deaths: 31 TGA data supplied prescriptions 2000- scriptions Skin & subcuta- 31 March 2004 neous tissue: 930.
(366), pruritus (90), rash (164), oedema(160)Nervous 792. Includes con-vulsions (105), Psy-chiatric ders: 992. Includessuicide/self-inju-rious ideation (32),depression (13)Gastointestinal dis- Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
cludes nausea/ vom-iting (221) 1682 of which 475 698,000 patients approx 2.4/1,0000 Deaths: 21 (includ- (analysis of pharma- classified as serious, treated covigilance database September 2001 to 62, includes suicideattempts (21), sui-cidal ideation (19), seizures: (75, inci-dence 0.01%).
Skin & subcuta-neous tissue: 148,includes angiodema(50), serum sicknesslike reaction (40),urticaria (27).
11 intentional over-dose including 2deaths F E E D B A C K
Labelling of graphs
In the graphs for bupropion the comparison is described under the outcome heading rather than the comparison heading In this review the outcome is always abstinence from smoking at longest follow-up. In order to group comparisons for the samepharmacotherapy and to give an informative summary graph, the decision was taken to use the outcome level for the specific comparisons.
Unfortunately it is not possible to alter the fixed headings of 'Comparison' and 'Outcome'.
Lindsay Stead, review author and Managing Editor Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
W H A T ' S N E W
Last assessed as up-to-date: 29 July 2009.
Additional table converted to appendix to correct pdf format Protocol first published: Issue 3, 1997 Review first published: Issue 3, 1997 Correction to excluded studies table, detail for Carrão2007 New search has been performed Updated with 13 new included trials including 3 of se-legiline, not previously covered. No substantial changeto effects, main conclusions not altered Converted to new review format.
New citation required but conclusions have not Seventeen new trials were added to the review for issuechanged 1, 2007. There were no major changes to the reviewers'conclusions.
New citation required but conclusions have not New trials of bupropion, nortriptyline and fluoxetinechanged were added for issue 4, 2004, and additional informa-tion on adverse effects was included. There were nomajor changes to the reviewers' conclusions.
New citation required but conclusions have not New trials of bupropion and nortriptyline were addedchanged to the review in Issue 2 2003. There were no majorchanges to the reviewers' conclusions 19 September 2001 New citation required but conclusions have not Four new studies on bupropion, and one each on nor-changed triptyline and paroxetine were added to the review inIssue 1 2002. In press data from a trial of fluoxetine areincluded which differ from unpublished data previ-ously used. The reviewers' conclusions about the effi-cacy of bupropion and nortriptyline were not changedsubstantively.
Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
New citation required and conclusions have changed Updates the earlier Cochrane review 'Anxiolytics andantidepressants for smoking cessation'. Anxiolytics areevaluated in a separate review.
All authors contribute to the text of the review. LS and TL extracted study data.
JR Hughes has received consultancy fees from many pharmaceutical companies that provide tobacco related services or products or aredeveloping new products, including Pfizer (the maker of NRTs and varenicline) and GlaxoSmithKline (the makers of bupropion andNRTs).
• No sources of support supplied • National Institute on Drug Abuse (NIDA), USA.
• NHS Research and Development Programme, UK.
This review was first published as part of the review 'Anxiolytics and antidepressants for smoking cessation'. From Issue 4 2000 theclasses of drugs are reviewed separately.
I N D E X T E R M S
Medical Subject Headings (MeSH)
Anti-Anxiety Agents [adverse effects; ∗therapeutic use]; Antidepressive Agents [adverse effects; ∗therapeutic use]; Randomized Con-trolled 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.
MeSH check words
Antidepressants for smoking cessation (Review)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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