Evidence-based Synthesis Program 

Comparative Effectiveness

of Smoking Cessation Treatments

for Patients With Depression:

A Systematic Review and

Meta-analysis of the Evidence

Department of Veterans Affairs

Health Services Research & Development Service

November 2010

Investigators: 

Principal Investigator: 

Jennifer M. Gierisch, PhD, MPH 

Coinvestigators:

Lori A. Bastian, MD, MHSc 

Patrick S. Calhoun, PhD 

Jennifer R. McDuffie, PhD

John W. Williams, Jr., MD, MHSc 

Medical Editor: 

Liz Wing, MA

Prepared for:

Department of Veterans Affairs

Veterans Health Administration

Health Services Research & Development Service

Washington, DC 20420

Prepared by:

Evidence-based Synthesis Program (ESP) Center

Durham VA Medical Center 

Durham, NC

John Williams, Jr., MD, MHSc, Director
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Comparative Effectiveness of Smoking Cessation Treatments 

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PREFACE

HSR&D’s Evidence-based Synthesis Program (ESP) was established to provide timely and 

accurate syntheses of targeted healthcare topics of particular importance to VA managers 

and policymakers, as they work to improve the health and healthcare of Veterans. The ESP 

disseminates these reports throughout VA. 

HSR&D provides funding for four ESP Centers and each Center has an active VA affiliation. The 

ESP Centers generate evidence syntheses on important clinical practice topics, and these reports 

help: 

• develop clinical policies informed by evidence, 

• the implementation of effective services to improve patient outcomes and 

to support VA clinical practice guidelines and performance measures, and 

• set the direction for future research to address gaps in clinical knowledge.

In 2009, an ESP Coordinating Center was created to expand the capacity of HSR&D Central 

Office and the four ESP sites by developing and maintaining program processes. In addition, 

the Center established a Steering Committee comprised of HSR&D field-based investigators, 

VA Patient Care Services, Office of Quality and Performance, and VISN Clinical Management 

Officers. The Steering Committee provides program oversight and guides strategic planning, 

coordinates dissemination activities, and develops collaborations with VA leadership to identify 

new ESP topics of importance to Veterans and the VA healthcare system. 

Comments on this evidence report are welcome and can be sent to Nicole Floyd, ESP

Coordinating Center Program Manager, at nicole.floyd@va.gov. 

Recommended citation: Gierisch JM, Bastian LA, Calhoun PS, McDuffie JR, Williams JW Jr. 

Comparative Effectiveness of Smoking Cessation Treatments for Patients With Depression: A 

Systematic Review and Meta-analysis of the Evidence. VA-ESP Project #09-010; 2010 

This report is based on research conducted by the Evidence-based Synthesis 

Program (ESP) Center located at the Durham VA Medical Center, Durham, NC, 

funded by the Department of Veterans Affairs, Veterans Health Administration, 

Office of Research and Development, Health Services Research and Development. 

The findings and conclusions in this document are those of the author(s) who are 

responsible for its contents; the findings and conclusions do not necessarily represent 

the views of the Department of Veterans Affairs or the United States government. 

Therefore, no statement in this article should be construed as an official position of 

the Department of Veterans Affairs. No investigators have any affiliations or financial 

involvement (e.g., employment, consultancies, honoraria, stock ownership or options, 

expert testimony, grants or patents received or pending, or royalties) that conflict with 

material presented in the report. 
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Comparative Effectiveness of Smoking Cessation Treatments 

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TABLE OF CONTENTS

Executive Summary............................................................................................................................................. 1

Background .......................................................................................................................................................1

Methods.............................................................................................................................................................2

Results...............................................................................................................................................................2

Key Question 1..................................................................................................................................................2

Key Question 2..................................................................................................................................................2

Key Question 3..................................................................................................................................................3

Key Question 4..................................................................................................................................................3

Key Question 5..................................................................................................................................................3

Future Research Recommendations .................................................................................................................3

Conclusions.......................................................................................................................................................4

Introduction .......................................................................................................................................................... 5

Methods................................................................................................................................................................... 6

Topic Development...........................................................................................................................................6

Search Strategy .................................................................................................................................................7

Study Selection .................................................................................................................................................7

Data Abstraction................................................................................................................................................8

Quality Assessment...........................................................................................................................................8

Data Synthesis...................................................................................................................................................9

Peer Review ....................................................................................................................................................10

Results ................................................................................................................................................................... 11

Literature Search and Study Characteristics................................................................................................... 11

Key Question 1................................................................................................................................................13

Key Question 2................................................................................................................................................21

Key Question 3................................................................................................................................................22

Key Question 4................................................................................................................................................22

Key Question 5................................................................................................................................................22

Discussion.............................................................................................................................................................. 25

Summary and Discussion................................................................................................................................25

Strengths and Limitations...............................................................................................................................26

Conclusions.....................................................................................................................................................27
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Future Research................................................................................................................................................ 29

References............................................................................................................................................................ 30

Appendix A: Search Strategy....................................................................................................................... 36

Appendix B: Reviewer Comments and Responses.................................................................................. 37

Appendix C: Evidence Table.......................................................................................................................... 46

List of Included Studies..................................................................................................................................70

Appendix D: Excluded Studies ..................................................................................................................... 71

List of Excluded Studies.................................................................................................................................74

Appendix E: Acronyms and Abbreviations............................................................................................... 79

Figures

Figure 1. Analytic Framework ........................................................................................................................7

Figure 2. Literature Flow Diagram ............................................................................................................... 11

Figure 3. Risk of Smoking Cessation at Least 6 Months After Start of Antidepressant Therapy

Plus Behavioral Counseling Compared With Placebo + Behavioral Counseling.........................16

Figure 4. Risk of Smoking Cessation at Least 6 Months After Start of Mood Management Treatment Plus 

Cotreatment Compared to Active Control.....................................................................................19

Tables

Table 1. Summary of Inclusion and Exclusion Criteria ................................................................................8

Table 2. Definitions for Strength of Evidence Rating .................................................................................10

Table 3. Summary of Study Characteristics................................................................................................12

Table 4. Smoking Cessation Studies of NRT Plus Brief Counseling Versus Placebo Plus Brief

Counseling .....................................................................................................................................14

Table 5. Smoking Cessation Studies of NRT Plus Behavioral Counseling Versus Active Control............15

Table 6. Smoking Cessation Studies of Antidepressant Therapy Plus Behavioral Counseling Versus

Placebo Plus Behavioral Counseling.............................................................................................15

Table 7. Smoking Cessation Studies of Antidepressant Therapy Plus Behavioral Counseling Plus NRT 

Versus Placebo Plus Behavioral Counseling Plus NRT ................................................................16

Table 8. Smoking Cessation Studies With a Mood Management Treatment Component..........................17

Table 9. Other Smoking Cessation Intervention Strategies Studies............................................................21

Table 10. Adverse Effects of Included Studies..............................................................................................23

Table 11. Summary of the Strength of Evidence for Key Questions 1 to 5..................................................28

Table 12. List of Excluded Studies................................................................................................................71 
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EVIDENCE REPORT

INTRODUCTION

Tobacco smoking is the single greatest preventable cause of disease in the United States.1,2 Half 

of all American smokers who fail to quit will die of a smoking-related illness.3 Cigarette use 

is higher among Americans with depression than in the general U.S. population.4

 Persons with 

depression are about twice as likely (45% versus 22%) to be current smokers than are individuals 

who are not depressed,5

 and smokers are more likely to have a history of depression.6,7 Moreover, 

veterans have higher rates of depression and smoking compared to the general population.8-12

Several hypotheses have been offered to explicate the association between smoking and 

depression, including mood-enhancing effects of nicotine13,14 and common genetic and 

environmental factors. Depression also appears to be an important factor in smoking 

cessation.15-20 Smokers who are depressed are more likely to relapse from a quit attempt, have 

higher nicotine dependence, suffer negative mood symptoms from withdrawal, and suffer greater 

smoking-related morbidity and mortality than the general population of smokers.17,18,21-24

Smokers with depression are highly motivated to quit smoking.7,25 One study found that 79% 

of smokers with depression intended to quit, with 24% ready to make a quit attempt in the 

next month.26 Despite the complex relationship between tobacco use and depression, smokers 

with depression should be offered cessation services.27,28 Several evidence-based smoking 

cessation intervention strategies exist for the general population of smokers.29-35 All forms of 

nicotine replacement therapy (NRT) (e.g., gum, transdermal patch, inhaler, lozenges) augment 

successful quit attempts, increasing quit rates by as much as 50 to 70%.35 Also, use of some 

antidepressants (i.e., bupropion, nortriptyline) can double the chances of smoking cessation, 

and this effect seems independent of the antidepressive effects of these medications.36 For 

behavioral interventions, there is a strong dose-response relationship between treatment intensity 

and smoking cessation rates.37 More intensive interventions, measured by total contact time, are 

associated with increased abstinence rates. For example, smoking cessation counseling improves 

quit attempts over self-help aids and other less intensive therapies.29,33,34,38 Combining behavioral 

interventions with pharmacotherapy increases quit attempts over each therapy delivered alone 

and is considered the gold standard of care for effective smoking cessation treatment.29,37,39

Gender, depression status (e.g., history positive, depression symptom severity), and content 

delivery timing (i.e., sequential, concurrent) may differentially impact the effectiveness 

of smoking cessation intervention efforts for smokers with depression. When trying to 

quit smoking, women who are depressed may experience more difficulty with withdrawal 

symptoms and, consequently, higher rates of smoking relapse to alleviate withdrawal symptoms 

compared to their male smoker counterparts.40 Level of depressive symptoms or depression 

type may influence patients’ ability to make and maintain quit attempts.17,18,22 Also, smokers 

with depression may benefit from smoking cessation programs that target both depression 

symptoms and tobacco use. However, it is not known if these two conditions should be treated 

concurrently or sequentially. For example, it is not known if treating depression first influences 

smoking cessation treatment effectiveness. Treating depression first may lead to greater 

treatment adherence and, consequently, better cessation rates. It is plausible but unstudied. 

Smokers with psychiatric comorbidities may benefit from combined behavioral counseling and 
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pharmacotherapy with longer therapeutic smoking cessation approaches (i.e., exceeding 8 to 

12 weeks) to reduce likelihood of dropout and depression relapse.27,41 However, no systematic 

reviews have synthesized the comparative effectiveness of smoking cessation strategies for 

persons with depressive symptoms. Many unanswered questions remain about how effective 

smoking cessation interventions are for adults with depression.

METHODS

Topic Development

This review was commissioned by the Department of Veterans Affairs’ Evidence-based Synthesis 

Program. The topic was selected after a formal topic nomination and prioritization process that 

included representatives from the Office of Mental Health Services, Health Services Research 

and Development, the Mental Health QUERI, and the Office of Mental Health and Primary 

Care Integration. The key research questions for this review were developed and refined after 

preliminary review of published peer-reviewed literature and consultation with VA and non-VA 

experts to select the patients and subgroups, interventions, outcomes, and settings addressed in 

this review. 

The final key questions were as follows: 

Key Question 1: For patients with a history of a depressive disorder or current significant 

depressive symptoms, what is the comparative effectiveness of different smoking cessation 

strategies on smoking abstinence rates?

Key Question 2: For patients with a history of a depressive disorder or current significant 

depressive symptoms, are there differential effects of smoking cessation strategies by depression 

status (i.e., history of MDD, current depressive symptoms, current MDD)?

Key Question 3: For patients with a history of a depressive disorder or current significant 

depressive symptoms, are there differential effects of smoking cessation strategies by gender? 

Key Question 4: For patients with a history of a depressive disorder or current significant 

depressive symptoms, does treatment effectiveness differ by whether smoking cessation/

depression treatments are delivered concurrently or sequentially? 

Key Question 5: What is the nature and frequency of adverse effects of smoking cessation 

treatments in patients with a history of a depressive disorder or current significant depressive 

symptoms?

We developed and followed a standard protocol for all steps of this review. Our approach was 

guided by the analytic framework shown in Figure 1.
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Figure 1. Analytic Framework

Search Strategy

We searched for English-language publications in MEDLINE (via PubMed), Embase, 

PsycINFO, and the Cochrane Library from database inception through March 10, 2010. We 

developed search strategies in consultation with a master librarian. The search terms and MeSH 

headings for the search strategies appear in Appendix A. We supplemented electronic searching 

by examining the bibliographies of included studies.

Study Selection

Using prespecified inclusion/exclusion criteria, two trained researchers reviewed the list of 

titles and selected articles for further review. Each article retrieved was reviewed with a brief 

screening form used to determine eligibility. To be included in our evidence report, a study 

had to (1) be a randomized controlled trial (RCT), (2) compare two or more smoking cessation 

interventions or compare intervention to control, and (3) report smoking cessation outcomes in 

adults with depression. Detailed eligibility criteria are described in Table 1. 

Adverse effects of

treatment

Adult 

smokers 

with 

depressive 

symptoms

Patient-level smoking 

cessation strategies alone

or in combination with

other strategies

• Depression status (KQ 2)

• Gender (KQ 3)

• Treatment sequencing (KQ 4)

Smoking abstinence

(KQs 1-5) (KQ 5)

(KQ 1)
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Table 1. Summary of Inclusion and Exclusion Criteria

Study 

characteristic Inclusion criteria Exclusion criteria

Study design RCTs or a secondary data analysis from 

RCTs of smoking cessation interventions 

Non-English language publication, crosssectional studies

Population Adults age 18 and over with a history of a 

depressive disorder or current significant 

depressive symptomsa

Pregnant women, adolescents, postpartum depression, depressive symptoms 

secondary to another primary condition 

(e.g., substance abuse, schizophrenia)

Interventions Any patient-level smoking cessation strategies (e.g., self-help, quit lines, physician or 

brief advice, behavioral counseling, pharmacologic therapies) alone or in combination 

with other strategies

Policy-level interventions (e.g., smoking 

bans), mass media campaigns

Comparators Active comparators or control (e.g., usual 

care or placebo)

None

Setting Outpatient (e.g., mental health clinics, 

primary care) or delivered through remote 

communication technologies (e.g., telephone, Web)

Hospital-based (inpatient) interventions 

Outcome KQs 1-4: Smoking abstinence reported at ≥ 

3 months postrandomization

KQ 5: Adverse effects including behavioral 

symptoms, increased anxiety, depressionb

Relapse preventionc 

a We define significant depressive symptoms as meeting a designated threshold on a validated assessment instrument (e.g., 

CES-D, BDI). 

b We considered depression as an adverse effect when participants moved from depressive symptoms to a depressive disorder, 

or when the intervention arm showed significantly more depressive symptoms compared to a decrease in symptoms in the 

comparator condition.

c Intervention strategies that reduce the likelihood of recent quitters returning to smoking.

Abbreviations: BDI = Beck Depression Inventory, CES-D = Center for Epidemiologic Studies-Depression Scale, RCT = 

randomized controlled trial

Data Abstraction

A trained researcher abstracted data from published reports into evidence tables; a second 

reviewer overread the evidence tables. We resolved disagreements by consensus among the 

first and second reviewer or by obtaining a third reviewer’s opinion when consensus could 

not be reached. We abstracted the following data from included studies: (1) Study design and 

setting, (2) eligibility criteria, (3) exclusion criteria, (4) sample size, (5) demographics, (6) 

duration of follow-up, (7) depression clinical category, (8) baseline smoking characteristics (e.g., 

cigarettes per day, tobacco dependence), (9) method used to assess depression, (10) intervention 

characteristics (e.g., mode, frequency, dose, core therapy components), (11) outcome measures, 

(12) results, and (13) adverse effects. 

Quality Assessment

We assessed risk of bias using the key quality criteria described in the Agency for Healthcare 

Research and Quality (AHRQ) Methods Guide for Effectiveness and Comparative Effectiveness 

Reviews (hereafter referred to as the General Methods Guide),

42 adapted for this specific topic. 

We abstracted data on adequacy of randomization and allocation concealment, comparability 
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of groups at baseline, blinding, completeness of follow-up and differential loss to follow-up, 

whether incomplete data were addressed appropriately, validity of outcome measures, and 

conflict of interest. Using these data elements, we assigned a summary quality score of Good, 

Fair, or Poor to individual RCTs.

Data Synthesis

We constructed evidence tables showing the study characteristics and results for all included 

studies, organized by key question and intervention, as appropriate. We critically analyzed 

studies to compare their characteristics, methods, and findings. We compiled a summary of 

findings for each key question. 

When study designs and outcomes reported were similar, we estimated pooled risk ratios with 

95% confidence intervals (CIs) by using a random effects model with the Mantel-Haenszel 

method. For these analyses, we classified each intervention element into the following categories: 

Antidepressants, nicotine replacement therapy (NRT), brief smoking cessation counseling, 

behavioral counseling for smoking cessation, or behavioral mood management treatment. We 

defined brief smoking cessation counseling as counseling that was similar in content to what may 

be given during a physician visit. We defined behavioral counseling for smoking cessation as 

multisession individual or group therapy that used behavioral strategies, such as those common 

in cognitive behavioral therapy (CBT), to influence tobacco use. Behavioral mood management 

treatment was defined as group or individual counseling intended to influence negative mood and 

improve depression symptomatology above and beyond standard smoking cessation counseling. 

Using these intervention categories, there were sufficient studies to perform meta-analyses for 

two comparisons: Mood management versus control and antidepressants versus control. Other 

comparisons were synthesized qualitatively. All studies that were analyzed quantitatively used 

behavioral counseling for smoking cessation in the intervention and control arms. For the mood 

management comparison, we subgrouped studies using NRT alone or in combination with 

antidepressants. 

The primary outcome was smoking abstinence without smoking relapse. Smoking abstinence 

was defined as smoking cessation collected as (1) point prevalence abstinence (e.g., in past 7 

days) or (2) extended abstinence (e.g., since quit date or last previous follow-up). We included 

only one effect size per study. Therefore, we assessed the most distal and rigorous (extended 

abstinence over point prevalence) outcomes reported and categorized as short-term (3 < 6 

months) or long-term (≥ 6 months) confirmed by self-report, biochemical validation, or both. 

Our outcome was informed by outcomes used in the Cochrane Collaborative reviews, which are 

based on the Russell Standard.43 The U.S. Department of Health and Human Services Tobacco 

Use and Dependence Guideline Panel recommended a minimum of a 6-month period to assess 

treatment differences in the longer term.37 Therefore, we used 6 months or longer outcomes for 

meta-analyses. Abstinence could be assessed by self-report or with biochemical verification. 

Two studies44,45 used a factorial design to compare pharmacological and behavioral interventions; 

these comparisons were treated as separate studies in the analyses. We evaluated heterogeneity 

visually and with the Cochran Q statistic46 using a threshold p-value of less than 0.1047 and the 

I2 statistic.48 We considered I2 statistic thresholds of 0% to 40%, 30% to 60%, 50% to 90%, and 

75% to 100% to represent between-study heterogeneity that might not be important, moderate, 
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substantial, or considerable, respectively.49 We planned a priori to conduct subgroup analyses by 

depression status (severity and specific diagnosis), gender, and treatment sequencing, but there 

were not sufficient studies to conduct these analyses. All analyses were performed using Review 

Manager 5.0 software (The Cochrane Collaboration, Oxford).

Grading the Evidence for Each Key Question 

We graded the strength of evidence for each key question using the principles from the 

GRADE Working Group.50 In brief, this approach assesses the strength of evidence for each 

critical outcome by considering risk of bias, consistency, directness, precision, and publication 

bias. Other domains relevant to observational designs were not pertinent to our review. After 

considering each domain, a summary rating of High, Moderate, Low, or Insufficient strength of 

evidence was assigned after discussion by two reviewers (Table 2).

Table 2. Definitions for Strength of Evidence Rating

Strength of evidence 

rating Definition

High quality Further research is very unlikely to change our confidence in the 

estimate of effect

Moderate quality Further research is likely to have an important impact on our 

confidence in the estimate of effect and may change the estimate

Low quality

Further research is very likely to have an important impact on our 

confidence in the estimate of effect and is likely to change the 

estimate

Insufficient Evidence on an outcome is absent or too weak, sparse or 

inconsistent to estimate an effect

Peer Review

Peer reviewer comments and our responses are presented in Appendix B.
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RESULTS

Literature Search and Study Characteristics

The combined literature search of PubMed, Embase, PsycINFO, and Cochrane databases, minus 

duplicates, contained 884 unique citations, of which we excluded 792 after reviewing titles and 

abstracts. We then conducted full-text reviews of 92 articles and pulled 6 additional papers in 

order to retrieve supplemental methodological or background information on studies included 

in the full-text review. Of these 98 papers, we excluded 75. Figure 2 summarizes the literature 

flow. The 23 included reports encompassed 16 unique trials with a total of 3,553 depressed and 

nondepressed participants. Table 3 summarizes study characteristics. In studies that included 

depressed and nondepressed participants, we report information for the depressed subgroup when 

available.

Figure 2. Literature Flow Diagram

6 articles from included 

studies retrieved for 

additional information

75 articles excluded at full-text review:

•	 Population not depressed = 37

•	 Main outcome not of interest = 14

•	 Not peer reviewed = 7

•	 Main outcome not reported at 

desired interval = 6

•	 Not RCT or secondary analysis of 

RCT = 6

•	 Analysis did not address key 

questions = 5

Articles retrieved 

for full-text review 

= 92

Search results 

= 884

Abstracted 23 

reports of 16 

unique trials

792 articles excluded 

at abstract screening
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moking Cessation Treatments 

Evidence-based Synthesis Program

haracteristics

Sample size Age Mean (SD) % Female % White FTND Mean (SD) Cigarettes per day Mean (SD) Depressed mood at baseline Mean (SD)

79 All MDD history positive 45.1 (9.3) 59.8 97.2 6.8 (1.9) NR BDI: 7.8 (6.31)05% MDD history positive 33.8b (8.2) 68.0b NR NR 30.3 (10.1) NR

34 All MDD history positive 44.5 (10.7) 63.4 87.3 6.1(2.4)b NR BDI: 8.0 (7.7) CES-D: 14.9 (10.8) HDRS: 4.8 (4.4)

84 5% depressed smokers 57.0 (9.9) 16.0 90.0 NR NR NR99 All MDD history positive 43.0 (11.0) 49.0 NR 5.8 (2.2) 25.0 (11) HDRS: 10.6 (6.3) 

49 1% MDD history positive 40.6 (9.2) 52.0 88.0 6.4 (1.9) 24.9 (10.9) BDI: 6.4 (5.9)c

01 2% MDD history positive 39.7 (NR) 52.0 92.0 NR 23.8 (9.8) BDI: 6.7 (5.4)

99 3% MDD history positive 41.9c (9.9) 42.0c 59.0c 5.5 (2.2)c 21.8 (10.4)c BDI: 12.1 (8.3)c

22 All with current depression 41.5 b (12.4) 69.6 68.3 3.8 (2.4) 15.8 (10.0) BDI: 20.6 (11.7)b15 9% MDD history positive 42.2 – 43.7d 54.6 96 FTQ: 7.1-7.3 (1.7) d 26.2(8.5) – 27.5(9.6)d BDI: 4.1(4.2) –4.7 (5.0) d69 4% met criteria for depression 40.4 (12.6) 41.6c (12.7) 51.0 61.0c 82.0 80.0c 5.6 (2.4)c 22 (10.4)c NR

08 2% met criteria for depression 38.5 (11.3)c 51.0c 78.6c Women: 5.6(2.3)c Men: 6.2 (2.3)c Women: 21.0(10.0)c men:26.6(11.7)c CES-D: Women: 24.8(7.0)c Men: 24.4 (6.9)c

8

All with mildly elevated depressive 

ymptoms

45.0 (12.2)b 48.5 (NR) 27.3 5.8 (1.8)b 18.8 (7.1)b BDI: 10.8 (5.2)b

36 8% MDE history positive 35.3 (NR) 38.2 0.0 NR 14.1 (8.2) CES-D: 21.3 (13.9)

50 0% MDD history positive 39.8 (NR) 54.5 73.2 5.9 (NR) NR BDI: 4.92 (NR)

0All with current depression 41.8 (12.1)b 100.0 98.0b NR 21.6 (11.1)b

HRSD:12.8 (6.0) CES-D:29.8 (9.3) 

criteria described in AHRQ’s General Methods Guide.

ups at baseline.

 Inventory, CES-D = Center for Epidemiologic Studies-Depression Scale, FTQ = Fagerstrom Tolerance Questionnaire, FTND = Fagerstrom Test for Nicotine 

sion Rating Scale, NR = not reported, MDD = major depressive disorder; MDE = major depressive episode 
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Most studies were of good quality according to quality criteria described in AHRQ’s General 

Methods Guide.

42 All studies were conducted in the U.S. with English-speaking participants 

except one, which was conducted with Spanish speakers living in the U.S.51 All reports, except 

one,52 reported smoking cessation outcomes for at least 6 months from the start of the trial. 

Most studies excluded participants with current MDD; however, 19 to 78% of participants in 

these studies had a history of MDD or exceeded a screening threshold for significant depressive 

symptoms. Of the studies that recruited smokers with depression, three recruited MDD historypositive participants,53-55 two recruited participants with current depression as measured by the 

CES-D56 or the PRIME-MD,57 and one recruited participants with mildly elevated depressive 

symptoms as assessed by the BDI-II.58 For the remainder of this report, we refer to depression 

as (1) significant depressive symptoms as measured by validated assessment instrument (e.g., 

CES-D, BDI) or (2) a history of MDD.

Key Question 1. For patients with a history of a depressive disorder 

or current significant depressive symptoms, what is the comparative 

effectiveness of different smoking cessation strategies on smoking 

abstinence rates?

Intervention Types

All but two interventions tested combination therapies consisting of some type of counseling 

and pharmacotherapy.51,53 Of the studies that included behavioral counseling, the most 

common therapy was CBT conducted in person via small group or individual therapy. Only 

one included study conducted behavioral counseling via telephone.59 Six studies included a 

behavioral mood management treatment.44,45,53,58-60 Mood management treatments ranged from 

smoking cessation–focused behavioral counseling augmented with one-time additional mood 

management counseling to intensive multisession group or individual CBT counseling. One 

study included mood management content delivered via mailed print materials.51 Of the studies 

that included antidepressant pharmacotherapies, four used bupropion,55,57,59,61 and three tested 

some other antidepressant (i.e., sertraline, fluoxetine, nortriptyline).45,54,62 Of studies that included 

antidepressants, two used NRT as a cotreatment,55,62 and two used NRT as a first-line therapy 

before offering bupropion.57,59 One study tested behavioral counseling plus a pill formulation 

of a long-acting opiate antagonist, naltrexone, as a smoking cessation aid.63 No studies using 

varenicline were identified that met our eligibility criteria. Below, we summarize the evidence 

for smoking cessation interventions for adults with depression. When able, we conducted metaanalysis to quantitatively summarize evidence of comparative effectiveness of interventions.

Comparative Effectiveness of Smoking Cessation Strategies 

NRT + Brief counseling versus placebo + brief counseling. Two studies of good quality 

compared the addition of nicotine gum to brief counseling compared to brief counseling plus 

placebo (Table 4).52,64 Kinnunen and colleagues (1996) compared the addition of 2 or 4 mg of 

nicotine gum to one-time brief counseling. Participants were advised to use the gum ad lib, with 

a target range of 9 to 15 pieces a day. In a subgroup analysis of participants with significant 

depressive symptoms as measured via the CES-D (n = 93), smokers with depression receiving 

either active gum dose were more likely to quit smoking than smokers with depression receiving 
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placebo gum (29.5% versus 12.5%; p-value NR) at 3 months post–quit date. In another trial, 

Kinnunen and colleagues (2008) reported the long-term effects of adding 2 or 4 mg of nicotine 

gum to 9 sessions of brief, 5- to 10-minute counseling sessions. Among participants with 

depression (n = 196), smokers receiving nicotine gum were more likely to remain abstinent at 12 

month post–quit date than were smokers receiving placebo gum (15.1% versus 5.7%; p = 0.01). 

Table 4. Smoking Cessation Studies of NRT Plus Brief Counseling Versus Placebo Plus Brief 

Counseling 

Study, year Intervention Comparator Follow-up 

duration 

Kinnunen, 

1996

Nicotine gum + one-time brief 

individual behavioral counseling 

Placebo gum + one-time brief 

individual behavioral counseling 3 months

Kinnunen, 

2008

Nicotine gum + 9 brief in-person 

individual counseling sessions 

Placebo gum + 9 brief in-person 

individual counseling sessions 12 months

NRT + Behavioral counseling versus active control. Two studies compared the addition of 

NRT to behavioral counseling.44,57 In a two-by-two factorial design, Hall and colleagues (1996) 

compared nicotine gum to placebo gum with 10 sessions of group CBT smoking cessation 

counseling versus 10 sessions of health education (Table 5). Analyses were collapsed across 

treatment arms. Participants were given 2 mg nicotine gum or placebo gum starting at counseling 

session three and instructed to chew one piece per hour, 12 hours per day for the next 8 weeks. 

At Week 8, participants were given enough gum to taper treatment over the next 4 weeks. 

Smoking status was obtained and confirmed with biological assessments at Weeks 8, 12, 26, and 

52. For MDD history-positive participants (n = 88), 22% receiving nicotine gum were abstinent 

compared to 33% receiving placebo gum at 52 weeks (p-value NR). This study was of fair 

quality due to omission of several key quality indicators (i.e., follow-up rates, randomization and 

allocation procedures, baseline characteristics).

In a study of good quality, Hall and colleagues (2006) offered nicotine patches plus 6 weeks 

of individual staged-care CBT behavioral counseling and computerized motivational feedback 

(Table 5). All participants had a current diagnosis of depression based on the PRIME-MD. 

Counseling sessions lasted 30 minutes and took place over 8 weeks. Participants were offered 

21 mg patches for the first 6 weeks, 14 mg patches for the following 2 weeks, and then offered 

7 mg patches for an additional 2 weeks. If patients did not quit smoking with NRT or relapsed 

during treatment, patients could request bupropion. A brief contact and smoking cessation 

referral served as the control condition. Smoking status was confirmed at 3, 6, 12, and 18 months 

postrandomization by expired carbon monoxide at ≤ 10 ppm. Staged-care counseling condition 

plus NRT outperformed brief contact control over time (OR = 4.55, 95% CI 1.04 to 19.93) with 

abstinence rates of 14.11% and 9.43% at 12 months and 18.4% and 13.21% at 18 months for the 

intervention and control, respectively.
15

Comparative Effectiveness of Smoking Cessation Treatments 

for Patients With Depression Evidence-based Synthesis Program

Table 5. Smoking Cessation Studies of NRT Plus Behavioral Counseling Versus Active Control 

Study, year Intervention Comparator Follow-up 

duration 

Hall, 1996a

Nicotine gum + 10 sessions of 

group CBT smoking cessation 

counseling or 10 session health 

education 

Placebo gum 10 sessions of group 

CBT smoking cessation counseling 

or 10 sessions health education 

12 month

Hall, 2006

Transdermal nicotine patch 

(or bupropion if failed NRT) + 

staged motivational feedback 

+ 6 sessions of individual CBT 

smoking cessation counseling 

Brief contact + list of referrals to 

smoking cessation programs and 

stop smoking guide

18 months

a Factorial design and analysis collapsed across treatment arms.

Synthesis of Evidence on NRT 

Four studies addressed comparative effectiveness of adding single-form NRT (i.e., not 

combination NRT therapy) to other cotreatments versus an active control for adults with 

depression. Most trials reported smoking cessation outcomes of 12 months or greater from point 

of randomization. Of the four studies included in this review, only one intervened with adults 

with current depression;57 results of other studies are from subgroup analyses. Cotreatments were 

heterogeneous and ranged from intensive CBT counseling to brief one-time counseling. However, 

most studies were of good quality and reported a small, positive effect for the use of NRT.

Antidepressant therapy + cotreatment versus placebo + cotreatment. Five trials reported 

results of adding antidepressants to cotreatments compared to active control condition for 

smokers with depression. Three of these studies, all of good quality and involving 255 smokers 

with depression, provided 6-month or greater outcomes data and were included in a metaanalysis.45,54,61 These studies compared antidepressants plus behavioral counseling to behavioral 

counseling plus placebo (Table 6). Two studies compared antidepressant therapy plus a 

cotreatment of behavioral counseling and NRT. These studies reported outcomes less than 6 

months postrandomization and were not included in the meta-analysis.

Table 6. Smoking Cessation Studies of Antidepressant Therapy Plus Behavioral Counseling Versus 

Placebo Plus Behavioral Counseling

Study, year Intervention Comparator Follow-up 

duration 

Covey, 2002

Sertraline + 9 individual in-person 

smoking cessation behavioral 

counseling sessions augmented 

with supportive approach to manage negative affect associated with 

quitting smoking 

Placebo + 9 individual in-person 

smoking cessation behavioral 

counseling sessions augmented 

with supportive approach 

to manage negative affect 

associated with quitting smoking

34 weeks

Hall, 1998a

Nortriptyline + 10 session of group 

CBT smoking cessation counseling 

or 10 session health education 

Placebo + 10 session of 

group CBT smoking cessation 

counseling or 10 session health 

education 

64 weeks

Hayford, 1999 Bupropion + 11 brief in-person 

individual counseling sessions 

Placebo + 11 brief in-person 

individual counseling sessions 12 months

a Factorial design and analysis collapsed across treatment arms.
16

Comparative Effectiveness of Smoking Cessation Treatments 

for Patients With Depression Evidence-based Synthesis Program

Participants receiving antidepressants plus behavioral counseling were not more likely to be 

abstinent compared to participants receiving behavioral counseling plus placebo at 6-month 

postrandomization (RR = 1.31, 95% CI 0.73 to 2.34, Cochran Q = 0.55, p = 0.76, I2 = 0%) 

(Figure 3). 

Figure 3. Risk of Smoking Cessation at Least 6 Months After Start of Antidepressant Therapy Plus 

Behavioral Counseling Compared With Placebo + Behavioral Counseling 

Study or Subgroup

Hayford 1999

Hall 1998b

Covey 2002

Total (95% CI)

Total events

Heterogeneity: Tau2 = 0.00; Chi2 = 0.55, df = 2 (P = 0.76); I2 = 0%

Test for overall effect: Z = 0.90 (P = 0.37)

Events

4

7

11

22

Total

28

32

66

126

Events

2

7

8

17

Total

28

33

68

129

weight

13.0%

39.4%

47.5%

100.0%

M-H, Random, 95% CI

2.00 [0.40, 10.05]

1.03 [0.41, 2.61]

1.42 [0.61, 3.30]

1.31 [0.73, 2.34]

Antidepressant Placebo Risk Ratio Risk Ratio

M-H, Random, 95% CI

0.05 0.2 1 5 20

Favours control Favours antidepressant

In a study of good quality, Evins and colleagues (2008) tested the efficacy of adding 12 weeks of 

bupropion to a cotreatment consisting of 8 weeks of transdermal NRT and 13 sessions of group 

CBT smoking cessation counseling (Table 7).55 All participants had a lifetime history of unipolar 

depressive disorder (UDD). Results were in the expected direction, favoring antidepressant use 

in combination with behavioral counseling plus NRT over behavioral counseling plus NRT alone 

(36% versus 31%; p-value NR). However, participants randomized to receive bupropion were 

no more likely to achieve smoking abstinence at end of treatment in intention-to-treat (ITT) 

analysis with dropouts considered smokers. Moreover, smoking abstinence was associated with 

depressive symptoms, regardless of antidepressant use. 

Saules and colleagues (2004) also tested the addition of an antidepressant to a cotreatment 

of NRT and behavioral counseling (Table 7).62 This study was of fair quality. Participants in 

the intervention arm received 10 weeks of transdermal NRT plus 14 weeks of either 20 or 40 

mg of fluoxetine in combination with 6 weeks of group CBT smoking cessation counseling. 

Again, results were in the expected direction and favored the addition of antidepressant therapy. 

However, among participants who were history positive for MDD (n = 30), Saules found no 

significant differences in abstinence rates when fluoxetine was added to NRT and intensive 

behavioral counseling.

Table 7. Smoking Cessation Studies of Antidepressant Therapy Plus Behavioral Counseling Plus 

NRT Versus Placebo Plus Behavioral Counseling Plus NRT

Study, year Intervention Comparator Follow-up 

duration 

Evins, 2008 Bupropion + 13 group CBT smoking 

cessation counseling + NRT patch 

Placebo + 13 group CBT smoking 

cessation counseling + NRT patch 13 weeks

Saules, 

2004

Fluoxetine + 6 group CBT smoking 

cessation counseling + NRT patch 

Placebo + 6 group CBT smoking 

cessation counseling + NRT patch 12 months
17

Comparative Effectiveness of Smoking Cessation Treatments 

for Patients With Depression Evidence-based Synthesis Program

Synthesis of Evidence on Antidepressants 

Five studies addressed comparative effectiveness of adding antidepressants to other cotreatments 

versus an active control (e.g., counseling + NRT + placebo) for adults with depression. For included 

studies, antidepressants were prescribed at therapeutic doses. Only two included studies recruited 

participants with histories of MDD;54,55 results of other studies are from subgroup analyses. All 

cotreatments included multisession counseling, and four studies were of good quality. However, 

there was heterogeneity in antidepressant type across included studies. Only one used bupropion, 

the only antidepressant with an FDA indication for smoking cessation. Overall, we did not find 

enough evidence to support adding antidepressants to other smoking cessation cotreatments in 

order to improve smoking cessation rates among persons with depression. 

Mood management treatment + cotreatment versus cotreatment/active control. Six trials reported 

results of adding mood management treatments to behavioral counseling (Table 8). Other 

cotreatments given to all participants include NRT,44,58-60 nortriptyline,45 or NRT plus bupropion 

or paroxetine.59 Five of these studies, involving 402 smokers with depression, provided sufficient 

data for meta-analysis.44,45,53,58,60

Table 8. Smoking Cessation Studies With a Mood Management Treatment Component

Study, year Intervention Comparator Follow-up 

duration 

Mood management treatment + behavioral counseling versus behavioral counseling

Brown, 2001 8 group sessions of depression and 

smoking cessation CBT 

8 group sessions of smoking 

cessation CBT 12 months

Mood management treatment + behavioral counseling + NRT versus behavioral counseling + NRT

Hall, 1994

5 group sessions of CBT mood 

management + 5 group sessions 

of smoking cessation counseling + 

nicotine gum

5 group sessions of smoking 

cessation counseling + nicotine 

gum

52 weeks

Hall, 1996a

5 group sessions of CBT mood 

management + 5 group sessions 

of smoking cessation counseling + 

nicotine gum

10 sessions of standard group 

smoking cessation health education 

+ nicotine gum

52 weeks

MacPherson, 

2010

8 group sessions of smoking cessation 

CBT that included behavioral activation 

therapy + NRT patch

8 group sessions of smoking 

cessation CBT + NRT patch 26 weeks

Mood management treatment + behavioral counseling + NRT/antidepressant versus control

Duffy, 2006

9 to 11 sessions of combined 

smoking, depression, alcohol abuse 

telephone CBT + bupropion + NRT (if 

failed bupropion monotherapy in the 

past) OR NRT + paroxetine (if failed 

bupropion in the past for depression)

One-time behavioral counseling 

and referral to appropriate services 

for substance use/abuse and/or 

depression

6 months

Hall, 1998a

5 group sessions of CBT mood 

management + 5 group sessions 

of smoking cessation counseling + 

nortriptyline or placebo

10 session health education + 

nortriptyline or placebo 64 weeks

a Factorial design and analysis collapsed across treatment arms.
18

Comparative Effectiveness of Smoking Cessation Treatments 

for Patients With Depression Evidence-based Synthesis Program

All studies included in the meta-analysis were in the expected direction, favoring the addition 

of mood management treatment to smoking cessation cotreatments (RR = 1.45, 95% CI 1.01 to 

2.07, Cochran Q = 2.16, p = 0.71, I2 = 0%). Subgroup analysis suggests smoking cessation may be 

more likely when mood management treatment was added to cotreatments that included NRT or 

antidepressants in addition to behavioral counseling (RR = 1.66, 95% CI 0.95 to 2.90, Cochran Q 

= 1.8, p = 0.62, I2 = 0%) (Figure 4). However, confidence intervals overlap, and this contrast was 

not statistically significant.
19

moking Cessation Treatments 

Evidence-based Synthesis Program

sation at Least 6 Months After Start of Mood Management Treatment Plus Cotreatment Compared to Active Control
20

Comparative Effectiveness of Smoking Cessation Treatments 

for Patients With Depression Evidence-based Synthesis Program

In a study of good quality, Duffy and colleagues (2006) tested a combined smoking, depression, and 

alcohol abuse CBT counseling protocol for head-and-neck cancer survivors.59 Smokers who were 

depressed were offered NRT and bupropion or paroxetine. Content was delivered by telephone over 

the course of 9 to 11 counseling sessions. One-time behavioral counseling and referral to appropriate 

follow-up services served as the comparator condition. Among participants who were smokers and 

depressed at baseline (n = 64), 51% were nonsmokers at 6 months from end of treatment compared 

to 17% in the control arm (p-value NR). Smoking status was verified by self-report only. 

Synthesis of Evidence on Mood Management Treatment 

Six trials addressed comparative effectiveness of adding mood management treatments to other 

smoking cessation cotreatments versus an active control for adults with depression. All trials 

reported smoking cessation outcomes at 6 months or greater from point of randomization. Four 

of these trials were of good quality. Of the five trials included in the meta-analysis, only two 

studies recruited participants with either a history of MDD53 or elevated depressive symptoms.58

Results of other studies are from subgroup analyses. Overall, results indicate a small, positive 

effect for the addition of mood management treatment to smoking cessation cotreatments.

Other intervention strategies. Three additional trials tested other types of interventions. These are 

summarized below and in Table 9.

In a study of fair quality, Covey and colleagues (1999) tested behavioral counseling plus a 

long-acting opiate antagonist, naltrexone, as a smoking cessation aid.63 Participants received six 

individual brief behavioral counseling sessions. Participants in the control arm received the same 

counseling plus placebo. Smoking status was verified by blood cotinine level of < 15 ng/ml. Of 

the 36 participants with a history of MDD, results favored use of naltrexone in combination with 

counseling over counseling plus placebo (28.6% versus 9.1%; p-value NR). 

Munoz and colleagues (1997) tested the efficacy of a self-administered mood management 

intervention plus smoking cessation guide compared to a smoking cessation guide alone 

delivered through the mail for Spanish-speaking smokers.51 To be eligible for the trial, 

participants needed to indicate that they were either “completely” or “very” sure they wanted to 

quit smoking in the next 3 months. The smoking cessation guide was a 36-page booklet from the 

National Cancer Institute and contained tips on how to quit smoking. The mood management 

treatment consisted of relaxation exercises, self-monitoring booklet, and pleasant activity 

guide. An audio cassette explained how to use the materials. Among participants with a history 

of MDE, the addition of mailed mood management content improved cessation rates over the 

mailed smoking cessation guide (38.5% versus 7.4%; p = 0.01) at 6 months postrandomization. 

For smokers with current MDE, no significant differences were found (17.9% versus 8.0%; p = 

0.15). This study was of fair quality.

In another fair study, Vickers and colleagues (2009) conducted a small randomized pilot to test 

the feasibility of behavioral counseling to promote exercise as a smoking cessation intervention 

for depressed female smokers.56 Women were randomized to receive brief smoking cessation 

counseling plus 6 weeks of transdermal NRT, plus either 10 weeks of CBT to encourage exercise 

or a health education contact control condition. The intervention was feasible but did not 

significantly improve smoking cessation rates compared to the health education control (17% 

versus 23%; p = 0.75). 
21

Comparative Effectiveness of Smoking Cessation Treatments 

for Patients With Depression Evidence-based Synthesis Program

Table 9. Other Smoking Cessation Intervention Strategies Studies

Study, year Intervention Comparison Follow-up 

duration

Covey, 1999 Naltrexone + 6 individual in-person 

behavioral counseling sessions 

Placebo + 6 individual in-person 

behavioral counseling sessions 6 months

Munoz, 1997 Mailed smoking cessation guide + 

mood management guide 

Mailed smoking cessation guide 

+ mood management guide at 3 

months delayed

6 months

Vickers, 2009

10 in-person individual exercise 

counseling sessions that include brief 

smoking cessation counseling + NRT 

10 in-person individual health education sessions that include brief smoking cessation counseling + NRT

24 weeks

Synthesis of Evidence on Other Intervention Strategies

We identified three other types of smoking cessation strategies, each with only one RCT. 

Covey and colleagues (1999) and Munoz both reported positive results for participants with 

depression. However, studies were of fair quality (e.g., no ITT analysis, lack of detail on study 

measures, randomization and allocation concealment procedures not well described) and with 

select populations (e.g., Spanish speakers), which limits confidence in the estimates of effects 

and applicability of results to other populations. Results of Vickers and colleagues (2009) 

demonstrated no effect for using exercise counseling as a smoking cessation intervention strategy 

for smokers with depression. 

Key Question 2. For patients with a history of a depressive disorder 

or current significant depressive symptoms, are there differential effects of smoking cessation strategies by depression status (i.e., history of MDD, current depressive symptoms, current MDD)?

Only two studies provided sufficient information to report differential effectiveness of smoking 

cessation intervention strategies by depression status. For both reports, study researchers conducted 

subgroup analysis only; no treatment by depression interaction effects were directly tested.

Evins and colleagues (2008) recruited 199 smokers who had a lifetime diagnosis of UDD. 

Participants were randomized to 12 weeks of bupropion versus placebo. Both groups received a 

cotreatment consisting of 8 weeks of transdermal NRT and 13 sessions of group CBT smoking 

cessation counseling.55 Among participants who were history positive for unipolar depression 

(n = 109), 39% in the bupropion arm and 32% in the control arm were abstinent at the end of 

trial (p-value NS). Among participants with current depression (n = 90), bupropion did not 

significantly improve smoking cessation rates compared to cotreatment control condition (33% 

versus 31%; p-value NS). 

Munoz and colleagues (1997) tested the efficacy of a mailed self-administered mood 

management intervention plus smoking cessation guide compared to only a smoking cessation 

guide for Spanish-speaking smokers.51 The addition of mailed mood management content 

improved cessation rates over the mailed smoking cessation guide (38.5% versus 7.4%; p = 0.01) 

at 6 months postrandomization for participants with a history of MDE. Smokers with current 

MDE did not experience significant differences (17.9% versus 8.0%; p = 0.15).
22

Comparative Effectiveness of Smoking Cessation Treatments 

for Patients With Depression Evidence-based Synthesis Program

Key Question 3. For patients with a history of a depressive disorder 

or current significant depressive symptoms, are there differential effects of smoking cessation strategies by gender?

Only one included study reported a significant treatment by gender interaction among study 

participants with a history of or current depression.63 Covey and colleagues (1999) found a 

significant treatment by gender by depression interaction. Women with past histories of MDD (n

= 26) experienced higher quit rates when randomized to receive naltrexone in combination with 

six sessions of individual behavioral counseling compared to women with depression receiving 

placebo control at 6 months (22.2% versus 0%; p = 0.04). Men with past histories of MDD (n = 

10) did not experience significantly higher quit rates with naltrexone at 6 months. 

Key Question 4: For patients with a history of a depressive disorder 

or current significant depressive symptoms, does treatment effectiveness differ by whether smoking cessation/depression treatments are 

delivered concurrently or sequentially?

No studies directly compared smoking cessation and depression treatments delivered 

concurrently versus sequentially.

Key Question 5: What is the nature and frequency of adverse effects of smoking cessation treatments in patients with a history of a 

depressive disorder or current significant depressive symptoms?

Table 10 details reported adverse effects of the 16 included trials. Overall, 11 studies did not 

provide information on the nature and frequency of adverse effects of treatments. Of the five 

studies that reported adverse effects, three provided some level of detail about the magnitude and 

significance of adverse effects; other studies reported too few cases to conduct statistical tests. 

These three studies all evaluated the addition of antidepressants with other smoking cessation 

treatments. In two of the three studies, selected adverse effects were more common in patients 

randomized to antidepressants. 

Table 10 also summarizes change in depressive symptoms from baseline to follow-up when 

comparing intervention and control arms among participants classified as depressed at baseline. 

Seven trials did not report changes in depressive symptoms from baseline to follow-up per arm for 

participants classified as depressed at study entry. Six studies reported no significant differences. 

Of three studies that reported significant differences, only Vickers and colleagues (2009) reported 

more favorable changes in depressive symptoms associated with the control arm compared to the 

intervention arm. Kinnunen and colleagues (1996) and MacPherson and colleagues (2010) reported 

more favorable changes in depressive symptoms associated with the intervention arms. 
23

Comparative Effectiveness of Smoking Cessation Treatments 

for Patients With Depression Evidence-based Synthesis Program

Table 10. Adverse Effects of Included Studies

Study, year Intervention

Adverse effects reporteda

(% reported in intervention 

versus control)

Change in 

depressive 

symptomsb

Brown, 2001 8 group sessions of depression 

and smoking cessation CBT NR

No difference between 

intervention and control 

arms 

Covey, 1999

Naltrexone + 6 individual inperson behavioral counseling 

sessions

Panic attack, malaise, sleeplessness, concentration difficulty, nausea and vomiting, disoriented and 

shaky, spaciness, dizzy, abdominal 

pain, lightheadedness, shortness of 

breath

NR

Covey, 2002

Sertraline + 9 individual inperson smoking cessation 

behavioral counseling sessions 

augmented with supportive 

approach to manage negative 

affect associated with quitting 

smoking

NR

No difference between 

intervention and control 

arms

Duffy, 2006

9 to 11 sessions of combined 

smoking, depression, alcohol 

abuse telephone CBT + 

bupropion + NRT (if failed 

bupropion monotherapy in the 

past) OR NRT + paroxetine (if 

failed bupropion in the past for 

depression)

NR

No difference between 

intervention and control 

arms

Evins, 2008

Bupropion + 13 group sessions 

of CBT smoking cessation 

counseling + NRT patch

NR

No difference between 

intervention and control 

arms

Hall, 1994

5 group sessions of CBT mood 

management + 5 group sessions 

of smoking cessation counseling 

+ nicotine gum

NR NR

Hall, 1996

5 group sessions of CBT mood 

management + 5 group sessions 

of smoking cessation counseling 

+ nicotine gum

NR

No difference between 

intervention and control 

arms

Hall, 1998

5 group sessions of CBT mood 

management + 5 group sessions 

of smoking cessation counseling 

+ nortriptyline

Dry mouth (78% vs

33%)c

, lightheadedness (49% vs 

22%)c

, shaky hands (23% vs 11%)c, 

blurry vision (16% vs 6%)c

NR

Hall, 2006

Transdermal nicotine patch 

(or bupropion if failed NRT) + 

staged motivational feedback 

+ 6 sessions of individual CBT 

smoking cessation counseling

NR

No difference between 

intervention and control 

arms

Hayford, 

1999

Bupropion + 11 brief in-person 

individual counseling sessions

Headache (29% vs 31-33%) , 

insomnia (21% vs 30-35%)c

, rhinitis 

(17% vs 10 to 12%), dry mouth (5% 

vs 13%)c

, increased anxiety (11% vs 

5-7%)

NR

Kinnunen, 

1996

Nicotine gum + one-time brief 

individual behavioral counseling NR

Decrease in NRT gum 

arm and no change in 

placebo arm
24

Comparative Effectiveness of Smoking Cessation Treatments 

for Patients With Depression Evidence-based Synthesis Program

Study, year Intervention

Adverse effects reporteda

(% reported in intervention 

versus control)

Change in 

depressive 

symptomsb

Kinnunen, 

2008

Nicotine gum + 9 brief in-person 

individual counseling sessions

Heart palpitations, nausea, vomiting, 

dizziness, breathing difficulties, 

tongue blisters, damage to dental 

work, sore jawd

NR

MacPherson, 

2010

8 group sessions of smoking 

cessation CBT that included 

behavioral activation therapy + 

NRT patch

NR

Greater decrease 

in intervention arm 

compared to control 

arm 

Munoz, 1997 Mailed smoking cessation guide 

+ mood management guide NR NR

Saules, 2004

Fluoxetine + 6 group sessions 

of CBT smoking cessation 

counseling + NRT patch

Adverse effects not more common 

in intervention arms but did not list 

types

NR

Vickers, 2009

10 in-person individual exercise 

counseling sessions that 

include brief smoking cessation 

counseling + NRT

NR

Decrease in health 

education arm and 

increase in exercise 

counseling arm a Adverse effects reported for all subjects in trial. 

b For participants within depressed subgroup, statistically significant change in depressive symptoms from baseline 

to follow-up.

c Statistically significant and greater proportion affected in intervention arm compared to proportion affected in 

control arm. 

d Less than 2% of low-nicotine dependent and 6% of high-nicotine dependent participants in the intervention arms 

experienced most common NRT gum adverse effects (i.e., heart palpitations, nausea, vomiting, dizziness). 

Abbreviations: CBT = cognitive behavioral therapy, NR = not reported, NRT = nicotine replacement therapy
25

Comparative Effectiveness of Smoking Cessation Treatments 

for Patients With Depression Evidence-based Synthesis Program

DISCUSSION

Summary and Discussion

There is a synergistic and potentially bidirectional relationship between depression and 

smoking.6,14,19,65,66 Smokers with depression are significantly less likely to quit smoking, and 

depressed individuals are more likely to be smokers.5-7 Consequently, there is a need to identify 

effective smoking cessation interventions for this disproportionately affected population. We 

conducted a systematic review of smoking cessation intervention strategies for persons with 

depression. We also sought to examine differential effects of smoking cessation treatment 

by depression status, gender, and treatment sequencing and to characterize adverse effects of 

smoking cessation treatments in patients with depression. We found insufficient evidence to 

examine moderator effects and to characterize adverse effects. However, findings suggest several 

promising smoking cessation strategies for persons with depression. We summarize and discuss 

our findings here. 

We identified three types of intervention strategies: cotreatments augmented with behavioral 

mood management treatment (six trials), cotreatments augmented with antidepressant therapy 

(five trials), and cotreatments augmented with NRT (four trials). Cotreatments generally 

consisted of some type of smoking cessation counseling (e.g., brief, behavioral), with or 

without NRT. We also identified three additional trials that used behavioral counseling to 

promote exercise plus NRT,67 mailed self-help materials,51 or long-acting opiate antagonists 

plus behavioral counseling63 as smoking cessation interventions. Overall, we found insufficient 

evidence to support exercise behavioral counseling, mailed self-help materials, or naltrexone as 

smoking cessation strategies for smokers with depression. Although both naltrexone and mailed 

self-help materials showed positive effects in single trials, further study is required to assess the 

efficacy of these strategies. Also, it is possible that we may have missed studies with unpublished 

but relevant data. 

We did not identify any studies using varenicline that met our eligibility criteria. Varenicline 

stimulates dopamine release, which reduces nicotine cravings and withdrawal symptoms, and 

blocks nicotine receptors, which may reduce the pleasurable effects of continued nicotine usage. 

Pooled results of two RCTs showed significantly higher abstinence rates at the end of 12 weeks 

of varenicline treatment compared to both placebo and bupropion.68,69 However, given the latest 

concerns about mental health instability within the veteran population,70 varenicline should be 

reserved for special cases and will require close observation.

Smokers with depression are more likely to have increased levels of negative mood both 

precessation and postcessation.15,71-73 Also, negative mood is associated with greater relapse 

rates.74,75 Mood management therapy may serve to moderate negative mood associated with 

making and maintaining a quit attempt.74 Therefore, smokers with depression may respond better 

to smoking cessation interventions augmented with mood management techniques. Our results 

support this hypothesis. Pooled results from our meta-analysis demonstrate a small, positive 

effect of adding behavioral mood management therapy to smoking cessation cotreatments. 

The number needed to treat with mood management therapy plus NRT or antidepressants is 12 

persons to get 1 additional person to quit smoking for at least 6 months. The strength of evidence 

is moderate. Only six identified trials provided enough detail to assess cessation rates among 
26

Comparative Effectiveness of Smoking Cessation Treatments 

for Patients With Depression Evidence-based Synthesis Program

smokers with depression. Moreover, we found significant heterogeneity in intensity of mood 

management therapy across studies, which may influence estimates of effectiveness. 

All of the included antidepressant trials showed small, positive effects on smoking cessation, 

but a summary estimate of effect was not statistically significant. However, the strength of 

evidence for the lack of benefit for antidepressants as a smoking cessation aid for smokers with 

depression is low. Sample sizes were small and the number achieving cessation few, which limits 

precision of estimates of effects and our ability to detect statistically significant differences. 

Also, we were able to include only five trials, of which there was significant heterogeneity in 

antidepressant type. Only bupropion and nortriptyline have proven efficacy as smoking cessation 

pharmacotherapies.36,76 Meta-analysis results show little smoking cessation benefit for selective 

serotonin reuptake inhibitors such as sertraline and fluoxetine in the general population of 

smokers.36 Because results may differ by pharmacotherapy used, caution should be taken in 

applying our findings to other antidepressants that may be used to aid smokers with depression in 

quitting smoking. 

Offering NRT to smokers with depression appears to have a small, positive effect on smoking 

cessation rates among depressed smokers. Cessation rates ranged from 14 to 22% in the three 

included studies that reported outcomes of 12 months or longer.44,57,64 These cessation rates are 

higher than the 3 to 5% of smokers who successfully maintain quit attempts a year later without 

treatment aids77 and are comparable to NRT quit rates in the general population of smokers.35 Yet, 

long-term cessation rates were lower for patients with current depressive symptoms57 than for 

those who are history positive for MDD44 (14% versus 22%, respectively). Smokers with current 

depressive symptoms may have greater difficulty quitting due to more issues with nicotine 

withdrawal or worsening of depressive symptoms during a quit attempt.78 Smokers with current 

depressive symptoms may need additional support to make and maintain a quit attempt. The 

strength of evidence for NRT use among smokers with depression is moderate. Data were sparse; 

we were able to include only four trials. However, studies were of good quality and reported 

consistent results.

Strengths and Limitations

Our systematic review has a number of strengths that are consistent with the QUORUM 

reporting statement and the AMSTAR quality assessment of systematic reviews. These include 

a protocol-driven approach, a comprehensive literature search of multiple electronic databases, 

double data abstraction, quality assessment of the primary studies, and appropriate methods for 

combining estimates of effect. Despite these strengths, our review has several limitations. 

Foremost is that few RCTs exist that test smoking cessation interventions among smokers with 

depression. The paucity of literature has important implications for this evidence review. First, 

in order to make meaningful comparisons, we created broad intervention categories that used 

different types of counseling modes (e.g., group, individual) and pharmacotherapies. Within each 

category, there is considerable heterogeneity. For example, we identified few medication trials 

and fewer with the same type of medication. Ideally, we would have wanted to analyze trials by 

specific medications since treatment effects may vary within broad classes of medications. 

Second, few trials recruited smokers with current depression. In fact, many trials excluded 

patients with current or recent histories of depression. Therefore, many reports based 
27

Comparative Effectiveness of Smoking Cessation Treatments 

for Patients With Depression Evidence-based Synthesis Program

classifications of depression on self-reported screening criteria (e.g., CES-D, BDI) for significant 

depressive symptoms. Self-report scales may be measures of general emotional distress or 

negative affect rather than specific depressive symptoms. In primary care settings, a positive 

depression screen has a positive predictive value of ≤ 50% for MDD.79 Thus, our review contains 

heterogeneity among the group of subjects included in trials classified as depressed. To address 

this heterogeneity, our protocol specified a stratified analysis by type of depression (e.g., history 

of MDD, current depressive symptoms, current MDD), but there were too few trials in any 

intervention category to follow this planned approach. Also, time since last episode, chronicity 

of depression, and other important variations in depressive disorders may be associated with 

outcomes. For example, some evidence supports that those with recurrent MDD compared to 

a single episode have worse outcomes6

 and may differentially respond to certain interventions 

that target their depressive symptoms during a quit attempt. Our review is unable to address this 

issue. Moreover, most studies included in this report excluded participants with comorbid alcohol 

or substance abuse. Results are likely not generalizable to groups with these comorbidities. 

In many instances, we examined subgroup data for this evidence review. Including studies that 

reported on subgroups of individuals with depression has limitations. By doing so, we introduce 

the possibility of false-negative studies because many of these studies were not powered to detect 

clinically important treatment effects in depressed subgroups. Meta-analysis helps to address 

this limitation, but with relatively few studies of small sample sizes, our analyses may remain 

underpowered. In addition, subgroup analyses, unless specified a priori and part of a limited 

number of subgroups evaluated, may produce false-positive or spurious results.80

Data were limited on the majority of our key questions. No studies tested differential effects 

of smoking cessation interventions by treatment sequencing among smokers with depression. 

Literature on treatment differences by gender and depression status was also sparse. Our results 

on adverse effects are limited as well. Ideally, we would have conducted a separate search for 

adverse effects in the observational literature. However, it is unlikely that much literature exists 

on these types of interventions specific to our population of interest—smokers with a history of 

depression or with current depression. Lastly, few of the trials in this evidence review included 

VA users. Although veterans have higher rates of depression and smoking compared to the 

general population,8-12 results should be generalizable to the VA population. 

Conclusions

We identified only 16 trials, encompassing 1756 smokers with depression. Just three of these 

trials actively recruited participants with elevated depressive symptoms.57,58,67 Most patients 

included in this review were history positive for depression; findings best apply to this 

population. For patients with current depression, we have little data. We were able to conduct 

meta-analyses of only two contrasts: (1) addition of any type of antidepressant and (2) treatment 

augmented by behavioral mood management counseling. Results of this systematic review 

indicate promising smoking cessation strategies for smokers with depression. 

Table 11 summarizes the strength of evidence for each of our key questions and contrasts. Our 

results support a small, positive effect for adding mood management counseling for smoking 

cessation among patients with depression. However, it is uncertain if the effects of mood 

management counseling may differ by therapy mode (individual versus group therapy). We did not 
28

Comparative Effectiveness of Smoking Cessation Treatments 

for Patients With Depression Evidence-based Synthesis Program

find adequate support for adding antidepressants; we may be underpowered to detect statistically 

significant differences. Evidence suggests support for adding NRT; however, included trials were 

too varied to be analyzed quantitatively. While most trials included in this evidence review were 

of good quality and had consistent results, data were sparse. We expect that future research will 

likely have an important impact on our confidence in the estimates of effectiveness of smoking 

cessation treatments for smokers with depression. However, evidence suggests that depression does 

not need to be resolved before tobacco cessation treatment is initiated. Smokers with depression 

can successfully maintain smoking cessation. To improve the likelihood of success, health care 

providers should consider encouraging their depressed patients who smoke to seek smoking 

cessation services that include behavioral mood management treatment and NRT.

Table 11. Summary of the Strength of Evidence for Key Questions 1 to 5 

Number 

of studies 

(subjects)a

Domains pertaining to strength of evidence Magnitude of effect 

and strength of 

evidence

Risk of Bias:

Design/

Quality

Consistency Directness Precision Percentage abstinent 

from smoking at least 

6 months

postrandomization or 

relative risk ratio

Key Question 1: NRT Moderate SOE

Moderate SOE 4 (699) RCT/

Good

Consistent Direct Imprecise 14 to 22%

Key Question 1: Antidepressant therapy Low SOE

5 (484) RCT/Good Consistent Direct Imprecise 1.48 (95% CI 0.86 to 

2.54)b

Key Question 1: Mood management treatment Moderate SOE

6 (466) RCT/Good Consistent Direct Imprecise 1.45 (95% CI 1.01 to 

2.07)c

Key Question 1: Other intervention strategies Low SOE

3 (202) RCT/ Fair Inconsistent Direct Imprecise 17 to 39%

Key Question 2: Differential effects by depression status Insufficient SOE

2 (305) RCT/ Good Inconsistent Direct Imprecise 18 to 39%

Key Question 3: Differential effects by gender Insufficient SOE

1 (36) RCT/ Good Consistent Direct Imprecise 22%

Key Question 4: Differential effects by treatments delivered concurrently or 

sequentially

Insufficient SOE

0 (0) --- --- --- --- ---

Key Question 5: Adverse effects Insufficient SOE

5 (1,652) RCT/ Good Inconsistent Indirect Imprecise

a Numbers reflect participants with depression only for KQs 1 to 4 and all study participants for KQ 5.

b Magnitude of effect calculated from 3 trials included in meta-analysis (n = 255).

c Magnitude of effect calculated from 5 trials included in meta-analysis (n = 402).

Abbreviations: CI = confidence interval, RCT = randomized controlled trial, SOE = strength of evidence
29

Comparative Effectiveness of Smoking Cessation Treatments 

for Patients With Depression Evidence-based Synthesis Program

FUTURE RESEARCH

While this review provides some evidence about smoking cessation strategies for patients with 

depression, more work is needed in this area. First, we found very little trial data on intervening 

with smokers who are currently depressed. Persons with depression are about twice as likely 

to be smokers than persons without depression.5 Moreover, smokers with depression may 

experience more challenges when trying to make and maintain a quit attempt, such as greater 

negative mood symptoms from withdrawal, higher nicotine dependence, and greater likelihood 

of relapse, than smokers without depression.17,18,21,22,24,81 Secondary analysis of existing smoking 

cessation trial data could advance our understanding of smoking cessation strategies for patients 

with depression. Future studies should be designed to test smoking cessation interventions for 

this vulnerable population. Next, within the trials we identified, we found little research on 

key moderators that may influence treatment effectiveness (e.g., gender, depression status). 

Moderator analysis will facilitate subgroup identification, which may lead to better treatment 

matching.6

Evidence is growing that combination pharmacotherapy is effective for the general population 

of smokers.82 In 2009, the VA Pharmacy Benefits Management (PBM) Services released 

recommendations for the use of combination pharmacotherapy for tobacco use cessation. The 

VA PBM recommends combination NRT that involves the use of a longer acting NRT such 

as the patch in conjunction with a short-acting NRT (e.g., gum, inhaler, nasal spray) (http://

www.pbm.va.gov). Future studies should be designed to allow for direct comparisons between 

combinations of likely efficacious NRT therapies for smokers with depression. Also, it is not 

known how to combine depression and smoking pharmacotherapies. Take, for example, a patient 

with depression who is improving on sertraline but wants to stop smoking. Should the provider 

add bupropion or change from sertraline to bupropion, which may risk worsening of depression? 

Future trials should investigate combination smoking cessation and depression pharmacotherapy 

among smokers with depression. 

Behavioral counseling plus pharmacotherapy is considered the gold standard of care for effective 

smoking cessation interventions.29,37,39 Smokers with psychiatric comorbidities may benefit 

from combined behavioral counseling and pharmacotherapy with longer therapeutic approaches 

(i.e., exceeding 8 to 12 weeks) to reduce likelihood of dropout and depression relapse.41 Thus, 

future research should be designed to optimize dose, duration, and frequency of both behavioral 

counseling and pharmacotherapies. In addition, it is likely that patients with depression need 

strategies that target both depressive symptoms and smoking. Future research should seek to 

answer questions about the optimal sequencing of depression and smoking treatment content of 

smoking cessation interventions. Moreover, we were unable to tease apart the active components 

of individual therapies. Thus, important issues, such as mode of therapy (e.g., individual, 

group, telephone) and key therapeutic components (e.g., goal setting, monitoring of thoughts 

and moods, social support), cannot be answered by this systematic review. Future studies 

should be designed to disentangle active ingredients of behavioral counseling and the effects of 

delivery channels. Beyond scanning the reports included in this review, no attempt was made to 

synthesize information about adverse effects from observational studies and other data sources. 

Future research should be conducted to characterize adverse effects of treatment, including 

changes in negative affect and depressive symptoms. 
30

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for Patients With Depression Evidence-based Synthesis Program

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