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 

for Patients With Depression Evidence-based Synthesis Program

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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EXECUTIVE SUMMARY

BACKGROUND

Smoking is disproportionately higher among persons with depression (45% versus 22%). 

Furthermore, 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. Despite 

the complex relationship between tobacco use and depression, smokers with depression are 

motivated to quit smoking and should be offered cessation services. Several evidence-based 

smoking cessation treatments are effective for the general population of smokers. Yet the 

comparative effectiveness of these strategies in smokers with depression is uncertain. Also, it is 

uncertain if factors that may facilitate targeted interventions, such as depression status, gender, 

and treatment sequencing (i.e., concurrent versus sequential) for mood and smoking cessation, 

differentially impact the effectiveness of smoking cessation interventions. We conducted a 

systematic review of the peer-reviewed literature to answer the following key questions:

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?

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. 
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Comparative Effectiveness of Smoking Cessation Treatments 

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METHODS

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. Titles, abstracts, and articles 

were reviewed in duplicate by trained researchers. A trained researcher abstracted data from 

published reports into evidence tables; a second reviewer overread the evidence tables. When 

study designs and outcomes reported were similar, we estimated pooled risk ratios (RR) with 

95% confidence intervals (CI) 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. All 

other data were narratively summarized.

RESULTS

We screened 884 titles, rejected 792, and performed full-text reviews on 92 articles. We manually 

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. The 

23 included reports encompassed 16 unique trials, of which only three recruited participants with 

current depression. 

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?

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 exercise behavioral counseling plus 

NRT, mailed self-help materials, or long-acting opiate antagonist plus behavioral counseling as 

smoking cessation interventions.

Pooled results from our meta-analysis demonstrate a small, positive effect of adding behavioral 

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

2.07). All of the included antidepressant trials showed small, positive effects when comparing 

antidepressants plus behavioral counseling to placebo plus behavioral counseling, but a summary 

estimate of effect from meta-analysis was not statistically significant (RR = 1.31, 95% CI 0.73 

to 2.34). We were unable to conduct a meta-analysis of NRT trials. Three of the four NRT trials 

showed positive effects with clinically significant abstinence. Two of these NRT trials reported 

statistically significant differences. Results from three of the four included studies suggest that 

offering NRT appears to have a small, positive effect on smoking cessation rates among smokers 

who are depressed. We found insufficient evidence to support exercise behavioral counseling, 

mailed self-help materials, or naltrexone, although both naltrexone and mailed self-help materials 

showed positive effects in single trials. 

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 
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Comparative Effectiveness of Smoking Cessation Treatments 

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

Only two studies provided information on differential effectiveness of smoking cessation 

intervention strategies by depression status. Study researchers conducted subgroup analysis 

only; no treatment by depression interaction effects were directly tested. Among participants 

who were history positive for unipolar depression in Evins (2008), 39% in the bupropion plus 

behavioral counseling plus NRT arm and 32% in the placebo plus behavioral counseling plus 

NRT control arm were abstinent at the end of trial (p-value NS). Bupropion did not significantly 

improve smoking cessation rates compared to active control condition for participants with 

current depression (33% versus 31%; p-value NS). In Munoz and colleagues (1997), the addition 

of mailed mood management content improved cessation rates over a mailed smoking cessation 

guide (38.5% versus 7.4%; p = 0.01) at 6 months postrandomization for participants with a 

history of major depressive episode (MDE). Smokers with current MDE did not experience 

significant differences (17.9% versus 8.0%; p = 0.15).

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. Covey and colleagues (1999) found a 

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

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. Men who were MDD history positive did not have higher quit rates 

on naltrexone.

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?

Most included trials 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. 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 compared 

to placebo control.

FUTURE RESEARCH RECOMMENDATIONS

While this review provided some evidence of smoking cessation strategies for patients with 

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

intervening with smokers with current depression. Future studies should be designed to test 

smoking cessation interventions for this vulnerable population. Next, within the trials we 
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Comparative Effectiveness of Smoking Cessation Treatments 

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identified, we found little research on key moderators that may influence treatment effectiveness 

(e.g., gender, depression status). Moderator analysis will facilitate subgroup identification 

and may lead to better treatment matching. In many instances, we were able to address only 

the incremental benefit of adding one strategy to an intervention package (e.g., behavioral 

counseling with or without antidepressant). Future studies should be designed to allow for direct 

comparisons between combinations of likely efficacious therapies for smokers with depression 

such as combination NRT therapy. Also, we were unable to disaggregate multicomponent 

interventions. Future research should be designed to disentangle active ingredients of 

interventions and optimize dose, duration, frequency, and sequencing of smoking cessation 

strategies. Finally, future research should be conducted to characterize adverse effects of 

treatments, including changes in negative affect and depressive symptoms.

CONCLUSIONS

In conclusion, the peer-reviewed literature contained few randomized controlled trials of 

smoking cessation interventions for patients with depression. Most trials excluded patients with 

current or recent MDD. Thus, most of the data for this evidence review were from subgroup 

analyses of patients with depressive symptoms or remote histories of depressive disorder. 

However, the majority of reports included in this evidence review were of good quality and had 

consistent results. We found insufficient evidence to characterize adverse effects of treatments 

and examine moderator effects of gender, depression status, and treatment delivery sequencing. 

However, this evidence review lends support for several promising interventions. Our results 

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

cessation cotreatments. Smokers with depression may respond better to smoking cessation 

interventions augmented with mood management techniques. Evidence also shows support 

for adding NRT; however, included trials were too varied to be analyzed quantitatively. All of 

the included antidepressant trials showed small, positive effects, but a summary estimate of 

effect was not statistically significant. However, there was heterogeneity in antidepressant type 

across studies. Effects likely vary with medication type. Health care providers should consider 

encouraging their patients with depression who smoke to seek smoking cessation services that 

include NRT and also address behavioral mood management counseling.