Antidepressants for smoking cessation

Q: How much did the participants receive for completing the initial assessment visit?

In addition, all participants received USD 30 for completing the initial assessment visit, USD 20 for completing the initial medication management visit, and USD 20 for completing the final post-treatment follow-up visit.

Q: How many sessions of support were needed to be identified as low intensity?

To be identified as low intensity, support had to be regarded as part of the provision of routine care, i.e. time spent with smoker (including assessment for the trial) less than 30 minutes at the initial consultation, with no more than two further assessment and reinforcement visits.

Q: What did the authors suggest was a significant percentage of the participants able to guess correctly?

"A significant percentage of participants were able to guess correctly whether they were taking active bupropion or placebo" but as results did not favour intervention group, authors suggest this unblinding did not bias the results.

Q: What was the effect of removing studies judged to be at high risk of bias?

A sensitivity analysis removing studies judged to be at high risk of bias was only appropriate for the cessation outcome; removing the one study deemed to be at high risk of bias did not alter the clinical interpretation of the result.

Q: What did the authors judge to be the outcome for the bupropion combination therapy?

for the bupropion combination therapy with NRT or varenicline comparisons, the authors judged the evidence for these safety outcomes to be of very low- and low-certainty, respectively.

Q: What did the authors do to investigate the potential impact of studies that the authors judged to be at high?

To investigate the potential impact of studies that the authors judged to be at high risk of bias on results, the authors carried out sensitivity analyses, removing studies judged to be at high risk from analyses and observing the eFects on results (where this was possible).

Q: What is the evidence that bupropion is an eFective agent to aid smoking?

The authors found evidence that nortriptyline is also an eFective agent to aid smoking cessation when compared with placebo, based on a meta-analysis of six studies, including 975 participants.

Question

Q1. What are the contributions in this paper?

Q2. How much did the participants receive for completing the initial assessment visit?

Q3. How many sessions of support were needed to be identified as low intensity?

Q4. What did the authors suggest was a significant percentage of the participants able to guess correctly?

Q5. What was the effect of removing studies judged to be at high risk of bias?

Q6. What did the authors judge to be the outcome for the bupropion combination therapy?

Q7. What did the authors do to investigate the potential impact of studies that the authors judged to be at high?

Q8. What is the evidence that bupropion is an eFective agent to aid smoking?

Accepted Answer

The authors searched the Cochrane Tobacco Addiction Specialized Register, which includes reports of trials indexed in the Cochrane Central Register of Controlled Trials ( CENTRAL ), MEDLINE, Embase, and PsycINFO, clinicaltrials. The authors excluded trials with less than six months follow-up from eFicacy analyses. The authors included trials with any follow-up length in safety analyses. The authors extracted data and assessed risk of bias using standard Cochrane methods. The primary outcome measure was smoking cessation aIer at least six months follow-up, expressed as a risk ratio ( RR ) and 95 % confidence intervals ( CIs ). Where appropriate, the authors performed meta-analysis using a fixed-eFect model. Similarly, the authors presented incidence of safety and tolerance outcomes, including adverse events ( AEs ), serious adverse events ( SAEs ), psychiatric AEs, seizures, overdoses, suicide attempts, death by suicide, all-cause mortality, and trial dropout due to drug, as RRs ( 95 % CIs ). The authors included 115 studies ( 33 new to this update ) in this review ; most recruited adult participants from the community or from smoking cessation clinics. The authors judged 28 of the studies to be at high risk of bias ; however, restricting analyses only to studies at low or unclear Antidepressants for smoking cessation ( Review ) Copyright © 2020 The Cochrane Collaboration. This review looks at whether using antidepressants actually helps people to stop smoking ( for six months or longer ), and also looks at the safety of using these medicines. This review includes 115 studies looking at how helpful and safe diFerent antidepressants are when used to quit smoking. This means that the findings of those questions may change when more research is carried out. No of participants ( studies ) Certainty of the evidence ( GRADE ) Comments Study population Smoking cessation ( at least six months follow-up ) 11 per 100 18 per 100 ( 17 to 20 ) RR 1. 64 ( 1. 52 to 1. 77 ) 17,866 ( 46 RCTs ) ⊕⊕⊕⊕ High Study population Serious adverse events 2 per 100 3 per 100 ( 2 to 3 ) RR 1. 16 ( 0. 90 to 1. 48 ) 10,625 ( 21 RCTs ) ⊕⊕⊕⊝ Moderatea Study population Dropouts due to adverse events of the drug 7 per 100 9 per 100 ( 8 to 10 ) RR 1. 37 ( 1. 21 to 1. 56 ) 12,340 ( 25 RCTs ) ⊕⊕⊕⊕ High * The risk in the intervention group ( and its 95 % confidence interval ) is based on the assumed risk in the comparison group and the relative effect of the intervention ( and its 95 % CI ). No of participants ( studies ) Certainty of the evidence ( GRADE ) Comments Study population Smoking cessation ( at least six months follow-up ) 19 per 100 22 per 100 ( 17 to 28 ) RR 1. 19 ( 0. 94 to 1. 51 ) 3487 ( 12 RCTs ) ⊕⊕⊝⊝ Lowa, b Study population Serious adverse events 1 per 100 1 per 100 ( 0 to 6 ) RR 1. 53 ( 0. 25 to 8. 91 ) 607 ( 3 RCTs ) ⊕⊝⊝⊝ Removing this study reduced the point estimate to 1. 00. No of participants ( studies ) Certainty of the evidence ( GRADE ) Comments Study population Smoking cessation ( at least six months follow-up ) 21 per 100 26 per 100 ( 20 to 33 ) RR 1. 21 ( 0. 95 to 1. 55 ) 1057 ( 3 RCTs ) ⊕⊕⊕⊝ Moderatea Study population Serious adverse events 2 per 100 3 per 100 ( 1 to 6 ) RR 1. 36 ( 0. 65 to 2. 84 ) 1094 ( 5 RCTs ) ⊕⊕⊝⊝ Lowb Study population Dropouts due to adverse events of the drug 4 per 100 3 per 100 ( 2 to 6 ) RR 0. 80 ( 0. 45 to 1. 45 ) 1230 ( 4 RCTs ) ⊕⊕⊝⊝ Lowb * The risk in the intervention group ( and its 95 % confidence interval ) is based on the assumed risk in the comparison group and the relative effect of the intervention ( and its 95 % CI ). The following medications and substances, regarded as having antidepressant properties, have been investigated for their eFect on smoking cessation in at least one study. The recommended regimen is 10 to 28 days of titration before the quit attempt, followed by a 12-week dose of 75 mg to 100 mg daily ( Cahill 2013 ). How the intervention might work Multiple observations have provided a rationale for studying the eFects of antidepressant medications for smoking cessation: a history of depression is found more frequently amongst smokers than nonsmokers, nicotine may have antidepressant eFects, and antidepressants influence the neurotransmitters and receptors involved in nicotine addiction ( Benowitz 2000 ; Kotlyar 2001 ). The mechanisms of other antidepressants for smoking cessation remain unstudied. Why it is important to do this review Since the last update of this review was published in 2014 ( Hughes 2014 ), a substantial amount of new evidence has emerged to assess antidepressants as smoking cessation aids. M E T H O D S Criteria for considering studies for this review Types of studies The authors did not include pregnant women, as these smokers are covered in a separate Cochrane Review ( Coleman 2015 ). The authors included trials studying pharmacotherapies with antidepressant properties for smoking cessation. The following comparators were eligible for assessing safety, eFicacy and tolerability: placebo, no pharmacotherapy, alternative therapeutic control, or diFerent dosages/treatment regimes of the same antidepressant. For this outcome the authors only included studies that set out to report smoking cessation rates at least six months aIer baseline, in line with the standard methods of Cochrane Tobacco Addiction. Where cessation was assessed at multiple intervals, the authors report only the longest follow-up data. Additionally, where multiple definitions of abstinence are assessed, the authors report the strictest of these definitions ( e. g. continuous/prolonged abstinence over point prevalence abstinence ). The authors also report biochemical validation of abstinence over self-reported abstinence ( but it was not necessary for abstinence to have been biochemically validated for a study to be included ). The authors also recorded the following SAEs specifically, as these have previously been associated with the use of antidepressants for smoking cessation. For all safety and tolerability outcomes, the authors considered studies with follow-up of any length. The authors searched the Register for reports of studies evaluating bupropion, nortriptyline or any other pharmacotherapy classified as having an antidepressant eFect. For conference abstracts or trial registry entries where the record contained insuFicient evidence for us to determine the eligibility of the study, the authors attempted to contact study investigators to obtain any additional data needed to make a final decision. The authors recorded all screening decisions made and presented the flow of studies and references through the reviewing process using a PRISMA flow diagram ( Moher 2009 ). Two review authors ( of BH, JHB, JLB, NL, SH ) independently extracted the following study data and compared the findings. The authors assessed included studies for risks of selection bias ( method of random sequence generation and allocation concealment ), bias due to an absence of blinding ( taking into account both performance and detection bias in a single domain ), attrition bias ( levels and reporting of loss to follow-up ), and any other threats to study validity, using the Cochrane 'Risk of bias ' tool ( Higgins 2011 ). For each new study in this update, two review authors ( of JHB, JLB, NL, SH ) independently assessed each study for each domain, in accordance with 'Risk of bias ' guidance developed by Cochrane Tobacco Addiction to assess smoking cessation studies. Where there was any disagreement on the assessment, it was resolved through discussion with a third review author. The authors considered studies at high risk of performance and detection bias where there was no blinding of participants or personnel or where there was evidence of unblinding ; at unclear risk if insuFicient information was available with which to judge ; and at low risk if the study reported blinding of participants and personnel in detail and there was no evidence of unblinding. The authors considered studies to be at low risk of attrition bias where over half of the participants were followed up at the longest follow-up and where numbers followed up were similar across arms ( diFerence < 20 % ). The authors calculated cessation rates for all studies that reported cessation at least six months following baseline. For each study, the authors used the strictest available criteria to define cessation as described above. Where data were available, the authors expressed cessation as a risk ratio ( RR ) for each study. The authors calculated this as follows: ( quitters in treatment group/total randomized to treatment group ) / ( quitters in control group/total randomized to control group ), alongside 95 % confidence intervals ( CIs ). The authors calculated AE rates for all studies that reported adequate data, regardless of study length. The authors calculated this as follows: ( number of participants reporting ( S ) AEs in treatment group/total randomized to treatment group ) / ( number of participants reporting ( S ) AEs in control group/total randomized to control group ). In addition to overall AEs and overall SAEs, the authors calculated RRs ( 95 % CI ) for the following safety and tolerability outcomes, where data were available. This study was not pooled in any meta-analysis due to substantial heterogeneity of programme eFects across clusters. As far as possible, the authors used an intention-to-treat ( ITT ) analysis with people who dropped out or were lost to follow-up treated as continuing smokers. Where participants appeared to have been randomized, but were not included in the data presented by the authors ( and the authors were unable to obtain these ), they noted this in the study description ( see Characteristics of included studies ). The authors extracted numbers lost to follow-up from study reports and used these to assess the risk of attrition bias. Assessment of heterogeneity Before pooling studies, the authors considered both methodological and clinical variance between studies. Where pooling was deemed appropriate the authors investigated statistical heterogeneity using the I2 statistic ( Higgins 2003 ). Where a comparison included a suFicient number of studies ( ≥ 10 ), the authors generated funnel plots to analyse and report on potential publication bias as advised by the Cochrane Handbook for Systematic Reviews of Interventions ( Higgins 2019 ). The authors therefore generated funnel plots for the following comparisons. For each type of medication and comparison where more than one eligible trial was identified, the authors performed separate metaanalyses of cessation and safety outcomes using Mantel-Haenszel fixed-eFect methods. The authors pooled RRs and 95 % CIs from individual study estimates to estimate pooled RRs ( 95 % CIs ). The authors also carried out post hoc, exploratory analyses to inform their approach to safety and tolerance for the next update of this review. The authors combined the following comparisons when evaluating AEs, psychiatric AEs, SAEs, and dropouts due to adverse eFects. For comparisons where the authors had suFicient data, they separated participant data into the following subgroups to determine whether antidepressants had diFerential eFects on the relevant population or intervention groups. Where reported, the authors also extracted data from analyses evaluating a potential interaction between current depression or past history of depression and quit rates. The authors relied upon the definition of depression used by study authors, which included both formal diagnoses and scores on validated depression scales. The authors carried out the following sensitivity analyses. The authors did this in two stages: 1 ) they excluded studies that were funded by the pharmaceutical industry ; 2 ) they excluded studies that were funded by the pharmaceutical industry or where the study medication was provided by the pharmaceutical industry. The authors created 'Summary of findings ' tables using standard Cochrane methodology ( Higgins 2019 ), for the following comparisons, which they judged to be most clinically relevant. Following standard Cochrane methodology ( Higgins 2019 ), the authors used GRADEpro GDT soIware and the five GRADE considerations ( risk of bias, consistency of eFect, imprecision, indirectness, and publication bias ) to assess the certainty of the body of evidence for smoking cessation, SAEs, and dropout due to adverse events of the drug, and to draw conclusions about the certainty of the evidence within the text of the review ( Schünemann 2013 ). The authors chose these outcomes as they are important factors to consider regarding pharmaceutical eFicacy, safety and tolerability, and are therefore useful to both clinicians and patients when deciding whether to provide or use a smoking cessation pharmacotherapy. At this stage the authors identified 33 new, included studies ( reported across 85 records in total ) and three ongoing studies. The new trials studied: • bupropion: Anthenelli 2016 ; Benli 2017 ; Cinciripini 2018 ; CTRI/2013/07/003830 ; Ebbert 2014 ; Elsasser 2002 ; Fatemi 2013 ; Gilbert 2019 ; Gray 2011 ; Gray 2012 ; Johns 2017 ; KaramHage 2011 ; Moreno-Coutino 2015 ; NCT00132821 ; NCT00308763 ; NCT00495352 ; NCT00593099 ; NCT01406223 ; Perkins 2013 ; Rose 2014 ; Rose 2017 ; Sheng 2013 ; Singh 2010 ; Tidey 2011 ; Urdapilleta-Herrera 2013 ; Weiner 2012 ; White 2005 ; Zincir 2013 • EVT302: Berlin 2012 • fluoxetine: Minami 2014 ; NCT00578669 • lazabemide: Berlin 2002 • St John ’ s wort: Barnes 2006 Trials also studied specific populations of: • adolescents ( Gray 2011 ; Gray 2012 ; Killen 2004 ; Muramoto 2007 ) • African-Americans ( Ahluwalia 2002 ; Cox 2012 ) • healthcare workers ( Zellweger 2005 ) • hospital staF ( Dalsgarð 2004 ) • low-income and minority ( NCT00308763 ) • Maori ( Holt 2005 ) • males ( Rose 2017 ) • smokers awaiting surgery ( Myles 2004 ) • smokers who had previously failed to quit smoking using bupropion ( Gonzales 2001 ; Selby 2003 ) • smokers who had just failed to quit using nicotine replacement therapy ( NRT ) ( Hurt 2003 ; Rose 2013 ; Rose 2014 ). More than half the bupropion studies followed participants for at least 12 months from the start of treatment or the target quit day. The duration of follow-up was below six months for 12 of the included studies, was of unknown duration for six studies, and one study measured number of days abstinent rather than numbers abstinent at a particular time point ( Perkins 2013 ). In those studies which met or exceeded the six-month followup threshold, the majority reported an outcome of sustained ( prolonged ) abstinence. The authors included 10 studies of the tricyclic antidepressant, nortriptyline in this review. Aveyard 2008, Hall 1998, Hall 2002, Hall 2004, and Richmond 2013 reported outcomes at ≥ 12 months of follow-up and the other six studies had a maximum follow-up of six months. Conversely, the remaining studies provided a set amount of behavioural support to all participants, ranging from brief behavioural counselling to repeated group and individual sessions. Selective serotonin reuptake inhibitors ( SSRIs ) Fluoxetine Seven studies of fluoxetine have been included in this review, with two of these studies identified for inclusion in the current update ( Minami 2014 ; NCT00578669 ). Minami 2014 had a follow-up duration of fewer than six months, so the authors only evaluated adverse events data for this study. Selegiline Five long-term trials testing selegiline are included in this review, carried out in the USA ( George 2003 ; Kahn 2012 ; Killen 2010 ; Weinberger 2010 ), and Israel ( Biberman 2003 ). Three of the studies completed follow-up at six months ( George 2003 ; Kahn 2012 ; Killen 2010 ), and two continued follow-up to 12 months ( Biberman 2003 ; Weinberger 2010 ). Lazabemide Berlin 2002 is the only study of lazabemide included in this review. Due to its nature as a dose-finding, exploratory study, its follow-up period for smoking cessation was only eight weeks. Therefore, the authors only consider its safety data within this review. The study was conducted in both France and Belgium ; however, the method of participant recruitment is not reported. EVT302 Berlin 2012 is the only study of EVT302 included in this review. Its follow-up for smoking cessation is only eight weeks, therefore the authors only consider its safety data within this review. The study was conducted in Germany, with participants recruited through media advertisements. Venlafaxine Cinciripini 2005 is the only study of venflaxine included in this review. Sood 2012 is the only study of SAMe included in this review. For studies that were potentially relevant, but that the authors excluded, they have provided their reasons for exclusion in Characteristics of excluded studies. As part of this update to the review, the authors have excluded studies investigating the use of antidepressants for smoking relapse prevention and harm reduction, as these studies are included in other reviews ( Lindson-Hawley 2016 ; Livingstone-Banks 2019 ). The authors identified the following three ongoing studies as part of their search which are likely to be relevant for inclusion when complete. However, there is no clear evidence to suggest whether people taking bupropion experience more or fewer SAEs than those taking placebo ( moderate certainty ). Evidence suggests that bupropion may be as successful as NRT and nortriptyline in helping people to quit smoking, but that it is less eFective than varenicline. Due to the high-certainty evidence, further studies investigating the eFicacy of bupropion versus placebo are unlikely to change their interpretation of the eFect, providing no clear justification for pursuing bupropion for smoking cessation over front-line smoking cessation aids already available. However, the evidence does not suggest that bupropion is more likely to result in death, hospitalization, or life-threatening events, like seizures. The evidence does not suggest that taking bupropion at the same time as other stop-smoking medicines, like varenicline ( sometimes known as Champix or Chantix ) or nicotine replacement therapy makes people more likely to quit smoking. There is high-certainty evidence that bupropion helps people to quit smoking, meaning further research is very unlikely to change this conclusion. However, there is also high-certainty evidence to suggest that people using bupropion are more likely to stop taking the medicine because of unpleasant eFects than those taking a pill without medication ( a placebo ). Extrapolation based on current smoking trends, suggests that without widespread quitting, approximately 400 million tobacco-related deaths will occur between 2010 and 2050, mostly among current smokers ( Jha 2011 ). It has also been hypothesized that cessation may precipitate depression, however evidence suggests that this is unlikely to be the case, and that cessation may actually reduce the likelihood of depression ( Taylor 2014 ). Evidence suggests bupropion may aid smoking cessation by blocking nicotine eFects, relieving withdrawal ( Cryan 2003 ; West 2008 ), and reducing depressed mood ( Lerman 2002a ). This has the potential to change or strengthen their conclusions regarding the eFicacy of some of these antidepressants when compared with no treatment, whilst also strengthening the evidence regarding the safety of those antidepressant currently being used to help people quit smoking ( bupropion and nortriptyline ). Further evidence on safety outcomes may help to clarify the potential interaction between bupropion and seizures, as well as psychiatric adverse events. New evidence may also help us to directly compare the safety and eFicacy of antidepressants with other front-line smoking cessation medications, providing a further aid to decision making when helping people to quit tobacco smoking. To be identified as low intensity, support had to be regarded as part of the provision of routine care, i. e. time spent with smoker ( including assessment for the trial ) less than 30 minutes at the initial consultation, with no more than two further assessment and reinforcement visits. Further details of these newly included, as well as previously included studies, including dosing schedules, are recorded in the Characteristics of included studies tables. Treatment with 400 mg/day began one week before quit day and continued for two months, reducing to 200 mg/day for a further month. Further details of these ongoing studies are summarized in the Characteristics of ongoing studies table.

Accepted Answer

In addition, all participants received USD 30 for completing the initial assessment visit, USD 20 for completing the initial medication management visit, and USD 20 for completing the final post-treatment follow-up visit.

Accepted Answer

To be identified as low intensity, support had to be regarded as part of the provision of routine care, i.e. time spent with smoker (including assessment for the trial) less than 30 minutes at the initial consultation, with no more than two further assessment and reinforcement visits.

Accepted Answer

"A significant percentage of participants were able to guess correctly whether they were taking active bupropion or placebo" but as results did not favour intervention group, authors suggest this unblinding did not bias the results.

Accepted Answer

A sensitivity analysis removing studies judged to be at high risk of bias was only appropriate for the cessation outcome; removing the one study deemed to be at high risk of bias did not alter the clinical interpretation of the result.

Accepted Answer

for the bupropion combination therapy with NRT or varenicline comparisons, the authors judged the evidence for these safety outcomes to be of very low- and low-certainty, respectively.

Accepted Answer

To investigate the potential impact of studies that the authors judged to be at high risk of bias on results, the authors carried out sensitivity analyses, removing studies judged to be at high risk from analyses and observing the eFects on results (where this was possible).

Accepted Answer

The authors found evidence that nortriptyline is also an eFective agent to aid smoking cessation when compared with placebo, based on a meta-analysis of six studies, including 975 participants.

Antidepressants for smoking cessation

Figures

Citations

2013 ESH/ESC Guidelines for the management of arterial hypertension: The Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC).

European Guidelines on Cardiovascular Disease Prevention in Clinical Practice (Version 2012)

2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC)

2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC).

Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association

References

Measuring inconsistency in meta-analyses

Bias in meta-analysis detected by a simple, graphical test

Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement

Statistical Aspects of the Analysis of Data From Retrospective Studies of Disease

Treating tobacco use and dependence-Clinical practice guideline

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