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. 2013 Sep 20;16(2):197–207. doi: 10.1093/ntr/ntt134

Efficacy of Sequential Use of Fluoxetine for Smoking Cessation in Elevated Depressive Symptom Smokers

Richard A Brown 1,✉, Ana M Abrantes 1, David R Strong 2, Raymond Niaura 3, Christopher W Kahler 4, Ivan W Miller 1, Lawrence H Price 1
PMCID: PMC13411490  PMID: 24057928

Abstract

Introduction:

Fluoxetine, a selective serotonin reuptake inhibitor, was examined in the treatment of smokers with elevated depressive symptoms. Specifically, this randomized, open-label clinical trial was designed to evaluate the efficacy of three logical, real-world alternatives for providing smoking cessation treatment to smokers with elevated depressive symptoms.

Methods:

In a sample of 216 smokers (mean Center for Epidemiological Studies Depression Scale score = 11.41), participants were randomly assigned to (a) transdermal nicotine patch (TNP), beginning on quit date and continuing for 8 weeks thereafter; (b) standard administration of antidepressant pharmacotherapy with fluoxetine (20mg), beginning 2 weeks before quit date and continuing for 8 weeks following quit date + TNP (ST-FLUOX); or (c) sequential administration of fluoxetine (20mg), beginning 8 weeks before quit date and continuing for 8 weeks following quit date + TNP (SEQ-FLUOX). All participants received 5 sessions of brief behavioral smoking cessation treatment.

Results:

Findings indicate that SEQ-FLUOX resulted in significantly higher point prevalence abstinence than ST-FLUOX at 6-month follow-up (OR = 2.35; 95% CI = 1.10–5.02, p < .03), a difference that was reduced at the 12-month assessment. Furthermore, sequential fluoxetine treatment, compared with standard fluoxetine treatment, resulted in significantly lower levels of depressive symptoms throughout smoking cessation treatment (p < .025) and significantly lower nicotine withdrawal-related negative affect (p < .004) immediately after quitting.

Conclusions:

Findings suggest that if one is going to prescribe fluoxetine for smoking cessation in smokers with elevated depressive symptoms, it is best to begin prescribing fluoxetine well before the target quit date.

INTRODUCTION

The association between depressive symptoms and smoking behavior has been consistently demonstrated across population-based, psychiatric, and primary care samples (Benjet, Wagner, Borges, & Medina-Mora, 2004; Brown, Madden, Palenchar, & Cooper-Patrick, 2000; Finney Rutten, Wanke, & Augustson, 2005; Güleç et al., 2005; Kenney, Holahan, North, & Holahan, 2006; McCaffery, Niaura, Swan, & Carmelli, 2003). Not only are smokers characterized by higher levels of depressive symptoms than nonsmokers, depressive symptoms are associated with poorer smoking cessation outcomes among smokers trying to quit (Allen, Prince, & Dietz, 2009; Blondal et al., 1999; Cook, Spring, McChargue, & Doran, 2010; Kenney et al., 2006; Kinnunen, Korhonen, & Garvey, 2008; Leventhal, Ramsey, Brown, LaChance, & Kahler, 2008; Thorndike et al., 2008). Although clinical practice guidelines for the treatment of nicotine dependence suggest the need to address mental health issues such as elevated depressive symptoms among smokers (Fiore et al., 2000, 2008), no specialized drug treatments for nicotine dependence currently exist for this at-risk subpopulation of cigarette smokers. Indeed, recent evidence suggests that U.S. physicians are more likely to identify smoking status among patients with mental health problems but infrequently act on this information by counseling patients to quit or providing nicotine dependence treatment (Thorndike, Stafford, & Rigotti, 2001). The development of an efficacious, drug treatment of nicotine dependence for smokers with elevated depressive symptoms would address this need by providing physicians with an effective treatment alternative for the large numbers of smokers with depressive symptoms seen daily in their clinical practices (Brown et al., 2000).

Both cognitive behavioral therapy (CBT) and antidepressant (AD) pharmacotherapy have been examined as cessation treatment options for this at-risk subpopulation of cigarette smokers. The efficacy of CBT approaches in smokers with elevated depressive symptoms has been equivocal. For example, although intensive CBT mood-management treatments (e.g., 8–10 group sessions over 6–8 weeks) have demonstrated efficacy for smokers with recurrent major depressive disorder (MDD) (Brown et al., 2001; Haas, Muñoz, Humfleet, Reus, & Hall, 2004), no effect of this approach on negative mood or differential benefit for smokers with elevated depressive symptoms has been found (Brown et al., 2007). However, in a pilot study, MacPherson et al. (2010) found that eight sessions of group-based behavioral activation treatment for smoking (BATS) was associated with improved smoking cessation outcomes among primarily Black smokers with elevated depressive symptoms. Further, BATS was also associated with significantly greater reductions in depressive symptoms than the standard cessation treatment condition. Although BATS has demonstrated preliminary efficacy, even if replicated, the intensity, length, and group format of this approach will limit its generalizability and translation to current primary care settings.

With respect to AD pharmacotherapy, buproprion, nortriptyline, and fluoxetine have each been examined for smoking cessation. Although studies demonstrate that bupropion and nortriptyline have greater overall efficacy for smoking cessation (Hughes, Stead, & Lancaster, 2007), fluoxetine, a selective serotonin reuptake inhibitor (SSRI), has provided modest benefits in general population smokers (Niaura et al., 2002) but specific smoking cessation benefits in smokers who were compliant and remained in treatment (Hitsman, Spring, Borrelli, Niaura, & Papandonatos, 2001) and in smokers with elevated depressive symptoms (Blondal et al., 1999; Dalack, Glassman, Rivelli, Covey, & Stetner, 1995). On the other hand, in a randomized, placebo-controlled trial of fluoxetine (60mg) in smokers with and without a history of MDD, Spring et al. (2007) found a significant effect on smoking cessation for depression history-positive compared with history-negative smokers during the treatment phase of the study. However, regardless of depression history, fluoxetine was associated with poorer smoking cessation outcomes at 6 months postquit

When utilizing mood-management treatment for smokers with elevated depressive symptoms, it is possible that starting the treatment in proximity to the target quit date may not be optimal. There is some evidence that the simultaneous onset of multiple behavior changes may require too much effort and be associated with poorer success rates of either behavior (Baumeister, Vohs, & Tice, 2007; Joseph, Willenbring, Nugent, & Nelson, 2004; Spring et al., 2004). For example, in a smoking cessation trial examining concurrent versus sequential weight control treatment, results favored a sequential approach (Spring et al., 2004). Therefore, sequencing the mood-management treatment to begin well ahead of the smoking cessation treatment phase may yield better outcomes in terms of mood changes and effects for smokers with elevated depressive symptoms.

There currently does not exist a smoking cessation trial comparing concurrent versus sequential mood management among smokers with elevated depressive symptoms. Elevated pretreatment depressive symptoms, in general, may lead to poor engagement in smoking cessation treatment. Indeed, in a previous study, we found that elevated levels of pretreatment depressive symptoms were predictive of treatment attrition prior to quit date (Curtin, Brown, & Sales, 2000). Thus, sequential treatment of depressive symptoms may reduce attrition and facilitate treatment engagement for smoking cessation

This clinical trial was intended to test the three most logical, real-world treatment alternatives for clinicians providing smoking cessation intervention to smokers with elevated depressive symptoms. In a sample of smokers with elevated depressive symptoms (Center for Epidemiological Studies Depression Scale [CES-D] score > 6), we utilized an additive, randomized design with participants receiving (a) transdermal nicotine patch (TNP), beginning on quit date and continuing for 8 weeks thereafter, (b) standard administration of AD pharmacotherapy with fluoxetine (20mg), beginning 2 weeks before quit date and continuing for 8 weeks following quit date + TNP (ST-FLUOX), or (c) sequential administration of fluoxetine (20mg), beginning 8 weeks before quit date and continuing for 8 weeks following quit date + TNP (SEQ-FLUOX). All participants received five sessions of brief behavioral smoking cessation treatment.

The primary objectives of the study were to examine whether (a) AD pharmacotherapy with fluoxetine (ST-FLUOX and SEQ-FLUOX) would result in superior short- and long-term smoking cessation outcomes compared with TNP alone and (b) SEQ-FLUOX would result in superior short- and long-term smoking cessation outcomes compared with ST-FLUOX. Secondary objectives were to examine whether (c) AD pharmacotherapy with fluoxetine (ST-FLUOX and SEQ-FLUOX) would result in reduced depressive symptoms and negative affect compared with TNP alone; (d) SEQ-FLUOX would result in reduced depressive symptoms and negative affect compared with ST-FLUOX; and (e) reductions in depressive symptoms and negative affect would mediate the relationship between treatment condition and improved short- and long-term smoking cessation outcomes.

METHOD

Participants

Participants were 216 adult smokers who were recruited via newspaper, radio, and television advertisements. The number of participants was determined a priori and based upon power analysis to detect rates of point prevalence abstinence, which were 10% higher with two-sided p < .05 and power of 80%. We anticipated that 78 subjects equally allocated to each condition would be necessary with an anticipated dropout rate of 15%. Participants were deemed eligible to participate in the study if they met the following inclusion criteria: (a) between 18 and 65 years of age, (b) regular cigarette smoker for at least 1 year, (c) currently smoking at least 10 cigarettes per day, (d) elevated depressive symptoms as indicated by CES-D score ≥ 6 (the median CES-D score in our large, randomized controlled trial of bupropion; Brown et al., 2007), and (e) use no other tobacco products. In addition, participants were excluded from study participation for any of the following: (a) current MDD or other Axis I disorder, (b) psychoactive substance abuse or dependence (excluding nicotine dependence) within the past year, (c) current use of psychotropic medication, (d) use of AD medication within the past 6 months, (e) current suicidal risk, (f) a history of significant medical illness, such as cardiovascular, neurological, gastrointestinal, or other systemic illness, pregnancy or breastfeeding, and (g) current use of nicotine replacement therapy or other medication for smoking cessation

All prospective participants were screened by phone according to the inclusion and exclusion criteria above. Individuals deemed ineligible based upon phone screening were offered a self-help booklet on smoking cessation (Clearing the Air; United States Department of Health and Human Services, 1995) and referrals to community smoking cessation programs. Individuals deemed eligible based upon phone screening were scheduled for a baseline assessment, which included completing a physical examination with the study physician to ensure that use of the nicotine patch and fluoxetine would be safe. Once medical clearance/final eligibility was established, participants were randomly assigned to one of the three treatment conditions using urn randomization (Wei, 1978) to assure a balanced distribution according to gender, current level of depressive symptoms (CES-D), and level of nicotine dependence (Fagerström Test for Nicotine Dependence; FTND, Heatherton, Kozlowski, Frecker, & Fagerström, 1991). Figure 1 displays the treatment timelines for the three treatment conditions.

Figure 1.

Figure 1.

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Treatment timeline.

Treatment Conditions

Brief Behavioral Smoking Cessation Treatment

Participants in all three of the following medication conditions received brief standard smoking cessation treatment on an individual basis, consistent with the most recent clinical practice guideline for “Treating Tobacco Use and Dependence” (Fiore et al., 2000, 2008). Treatment was delivered in five sessions over a 4-week period. Session 1 took place the day before quit date and focused on preparation for quitting and instruction in using the patch and was approximately 30min in duration. All other sessions were 20min in duration. Session 2, the only session to be conducted by phone, took place 1 day after quit date. Session 3 was conducted 7 days after quit date, Session 4 occurred 14 days after quit date, and Session 5 occurred 28 days after quit date.

TNP Treatment Condition

Participants received a supply of Nicoderm CQ®, 24-h TNP and were educated about the use of the patch at Session 1, the day before quit date. They were instructed to apply the patch beginning on quit date and then to apply one patch each day thereafter. Participants used the full-strength 21-mg patch for 4 weeks, tapered to the 14-mg patch for the next 2 weeks, and then to the 7mg patch for the remaining 2 weeks of treatment. The patch was discontinued at the end of treatment, 8 weeks after quit date. A meta-analysis found no differences in outcome between 16- and 24-h patches and no benefit to extending patch treatment beyond 8 weeks (Fiore, Smith, Jorenby, & Baker, 1994). Smokers who lapsed during treatment were encouraged to set a new quit date and continue to attempt to quit.

Standard Fluoxetine Treatment Condition

In addition to receiving TNP as described above, participants in the standard fluoxetine treatment (ST-FLUOX) received the fluoxetine at the initial physician visit 14 days prior to their quit date and were instructed to take one 20-mg fluoxetine capsule each morning, and they remained on this dose for 8 weeks following quit date (a total of 10 weeks). Subsequently, the study physician saw participants 4 weeks after initiating medication and for a termination visit 8 weeks after quit date (end of treatment) to assure safety upon medication discontinuation.

Sequential Fluoxetine Treatment Condition

In addition to receiving TNP as described above, participants in the sequential condition (SEQ-FLUOX) were instructed to take one 20-mg fluoxetine capsule each morning, beginning 8 weeks prior to their quit date and continuing for 8 weeks following quit date (a total of 16 weeks). Participants met with the study physician at an initial visit and subsequently on two occasions, 4 weeks after initiating medication, and for a termination visit 8 weeks after quit date (end of treatment) to assure safe medication discontinuation.

Measures

Structured Clinical Interview for DSM-IV

Diagnostic exclusions and lifetime prevalence of Axis I diagnoses were determined by the Structured Clinical Interview for DSM-IV (SCID-NP, nonpatient version; (First, Spitzer, Gibbon, & Williams, 1995).

Center for Epidemiological Studies Depression Scale

The CES-D was administered for assessing level of depressive symptoms. The CES-D has demonstrated good reliability and validity (Radloff, 1977). Each of the 20 items are rated using four response options (0–3), summed total scores range from 0 to 60, and a cutoff of 16 or higher is used typically to identify individuals at risk for MDD.

Smoking History and Patterns

Smoking history and patterns were assessed at baseline using smoking history and current status indices, which included rate, brand, nicotine content, previous quit attempts and duration, household smokers, age of onset, and other factors.

Nicotine Dependence

Severity of nicotine dependence was assessed using the FTND (Heatherton et al., 1991), a six-item measure, with higher scores indicating higher levels of nicotine dependence. The FTND has shown good internal consistency, a single-dimension factor structure, and positive relationships with degree of nicotine intake as assessed by saliva cotinine (Heatherton et al., 1991).

Nicotine Withdrawal Symptoms

Nicotine withdrawal symptoms were assessed using the Minnesota Withdrawal Scale, a reliable and sensitive 10-item scale (Hughes & Hatsukami, 1986). This measure has been used successfully to capture withdrawal dynamics (Piasecki et al., 2000) and assesses the frequency, duration, severity, and temporal variability in withdrawal symptoms.

Smoking Status

Self-reports of smoking status were collected from participants by phone at Session 2 and in person at Sessions 3, 4, and 5, and at 8-week, 26-week and 52-week follow-ups. The main outcome analyses were based upon 7-day point prevalence abstinence (i.e., reported abstinence of at least 7 days prior to each scheduled follow-up). Self-report is always overridden by objective verification in the conservative direction, that is, smoking (SRNT Subcommittee on Biochemical Verification, 2002).

The timeline followback (TLFB) procedure was utilized for assessing the longitudinal course of smoking outcomes. This retrospective, calendar-aided assessment provides self-reported data on daily cigarette use over extended time periods (Brown et al., 1998). The TLFB was administered at follow-ups to assess cigarette use since the previous assessment.

Biochemical Verification

Self-reported abstinence at 26-week and 52-week follow-ups was verified by saliva cotinine (cutoff value = 10ng/ml) for stated abstinence of 2 weeks or more (cotinine may be incompletely metabolized before this time) and at 2, 4, and 8 weeks post quit date by carbon monoxide analysis of breath samples (8 ppm cutoff) for stated abstinence of 24h to 2 weeks (Jarvis, Tunstall-Pedoe, Feyerabend, Vesey, & Saloojee, 1987; SRNT Subcommittee on Biochemical Verification, 2002). Detected values above the stated cutoff scores were considered indicative of smoking.

Data Analysis Plan

To examine the effects of treatments on point prevalence abstinence 2, 4, 8, 26, and 52 weeks after the planned quit day, we conducted repeated measures analysis for categorical outcomes using generalized estimating equations (GEE). The GEE allows for appropriate modeling of covariance structures when observations are correlated across time (Liang & Zeger, 1986). Statistical analyses were powered for primary aims assessing differences in biochemically verified point prevalence abstinence at each follow-up across the planned comparisons of (ST-FLUOX and SEQ-FLUOX) versus TNP and SEQ-FLUOX versus ST-FLUOX comparisons. Statistical power was estimated using 19% abstinence for ST-FLUOX at 26 and 52 weeks, based upon the only study at the time of fluoxetine combined with nicotine replacement therapy (Blondal et al., 1999). SEQ-FLUOX was estimated at 29% abstinence, as a 10% increase in abstinence over ST-FLUOX was considered to be clinically relevant and less than 10% may not warrant the added inconvenience and expense of the SEQ-FLUOX treatment. Analyses were conducted within R Statistical Software (R Core Team, 2011) using library “geeglm” (Højsgaard, Halekoh, & Yan, 2006) with the logit link function and an unstructured correlation matrix specified.

Planned covariates included level of nicotine dependence, baseline depressive symptoms, gender, and race (dichotomized to indicate White and non-White participants). Unconditional GEE models were used to evaluate changes in rates of abstinence over time and the significance of linear and quadratic trends prior to including planned covariates. The primary between-groups independent variable in the analysis was treatment group assignment, with two a priori planned comparisons: (a) the two fluoxetine conditions were compared with standard treatment (ST-FLUOX + SEQ-FLUOX vs. TNP) and (b) sequential fluoxetine was compared with concurrent fluoxetine (SEQ-FLUOX vs. ST-FLUOX). After testing the main effects of treatments, we tested interactions between treatment effects and time (centered by coding time in weeks from 26-week assessment) to determine if the relative effects weakened over the 52-week period. We then examined simultaneously interactions of the two planned treatment contrasts with the four covariates.

In this intention-to-treat analysis, all participants allocated to treatments were included in primary analyses, and self-reports required confirmation prior to considering participants to be abstinent. Missing self-reports were considered to be nonabstinent. In this way, our reported abstinence rates correspond to standard reporting practices (Hughes et al., 2003) and represent a conservative representation of treatment outcomes.

RESULTS

Of the 216 participants randomized to treatment, 83 were women (38.4%), 190 identified themselves as White (88.0%), and the mean age was 45.91 (SD = 10.01) years. Prior to treatment, participants reported smoking 21.08 (SD = 7.71) cigarettes per day and had a mean FTND of 5.64 (SD = 2.03), indicating a moderate level of nicotine dependence. At baseline assessment, the mean CES-D was 11.41 (SD = 7.56). Screening and recruitment flow throughout the clinical trial are reflected in the CONSORT diagram in Figure 2, and Table 1 includes demographic, smoking, and depressive symptom characteristics for each treatment group. Treatment groups did not differ on demographic, smoking, or depressive symptoms.

Figure 2.

Figure 2.

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CONSORT flow diagram.

Table 1.

Baseline Demographic, Smoking, and Depression Vulnerability Across Conditions

SEQ-FLUOX (n = 71) ST-FLUOX (n = 73) TNP (n = 72) p value
M SD M SD M SD
Age 45.95 8.98 46.38 10.47 45.40 10.59 .84
Femalea 38% – 38% – 39% – .99
Whitea 90% – 86% – 88% – .77
Cigarettes per day 22.17 7.26 20.88 7.85 20.22 7.97 .31
FTND 5.77 2.00 5.60 1.95 5.54 2.16 .78
CES-D 11.58 7.55 10.61 7.65 12.05 7.51 .51
CES-D > 16a 27% – 29% – 35% .57
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Note. SEQ-FLUOX = sequential fluoxetine treatment; ST-FLUOX = standard fluoxetine treatment; TNP = transdermal nicotine patch treatment; FTND = Fagerström Test for Nicotine Dependence; CES-D = Center for Epidemiological Studies Depression Scale.

aFrequency within each group.

Of the 216 participants allocated to a treatment condition, 152 (70.4%) completed all follow-ups, 50 (23.1%) missed 1, 5 (2.3%) missed 2, and 9 (4.2%) missed 3 or more assessments. The odds of missing follow-ups were not related to treatment condition (ps > .50). No serious adverse events occurred throughout the course of the study.

Does Fluoxetine ([ST-FLUOX and SEQ-FLUOX] vs. TNP) Improve Effect of Treatment on Smoking Outcomes?

Table 2 lists results from analysis, and Figure 3 displays model-adjusted 7-day point prevalence abstinence rates for the three conditions at 2 and 4 weeks after quit date, at the end of treatment (8 weeks), and 6 and 12 months after quit date. Seven-day biochemically verified point prevalence abstinence rates were 62.5%, 66.7%, 38.9%, 27.8%, and 25.0% for TNP; 68.5%, 58.9%, 39.7%, 21.9%, and 21.9% for ST-FLUOX; and 66.2%, 62.0%, 43.7%, 38%, and 26.8% for SEQ-FLUOX, respectively. The unconditional GEE model suggested a significant linear decrease (B = −0.75; SE = 0.09, p < .001) and quadratic change in the rate (B = 0.12; SE = 0.02, p < .001) of decreases in abstinence rates over the 52-week period. Model terms reflecting the linear and quadratic trends were included in subsequent covariate-adjusted models that evaluated treatment main effects and changes in treatment effects over time.

Table 2.

Results From Generalized Estimating Equations Model of 7-Day Point Prevalence Abstinence at 4, 8, 26, and 52 Weeks After Quitting

Estimate SE Wald p value
Intercept 0.83 0.37 4.94 .03
Caucasian 0.29 0.13 5.32 .02
FTND −0.19 0.06 10.22 .00
CES-D (baseline) 0.00 0.01 0.13 .72
Female −0.18 0.11 2.93 .09
Linear time −0.83 0.10 73.05 .00
Quadratic time 0.13 0.02 35.44 .00
SEQ-FLUOX vs. ST-FLUOX 0.16 0.14 1.26 .26
(SEQ-FLUOX/ST-FLUOX) vs. TNP −0.02 0.08 0.05 .82
SEQ-FLUOX vs. ST-FLUOX by linear time 0.28 0.12 5.62 .02
SEQ-FLUOX vs. ST-FLUOX by quadratic time −0.06 0.03 5.76 .02
(SEQ-FLUOX/ST-FLUOX) vs. TNP by linear time −0.01 0.07 0.02 .88
(SEQ-FLUOX/ST-FLUOX) vs. TNP by quadratic time 0.00 0.02 0.06 .81
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Note. SEQ-FLUOX = sequential fluoxetine treatment; ST-FLUOX = standard fluoxetine treatment; TNP = transdermal nicotine patch treatment; FTND = Fagerström Test for Nicotine Dependence; CES-D = Center for Epidemiological Studies Depression Scale.

Figure 3.

Figure 3.

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Model-adjusted 7-day point prevalence abstinence rates for the three conditions at 2 and 4 weeks after quit date, at the end of treatment (8 weeks), and at 6 and 12 months after quit date. SEQ-FLUOX = sequential fluoxetine treatment; ST-FLUOX = standard fluoxetine treatment; TNP = transdermal nicotine patch treatment.

The covariate-adjusted GEE model suggested significantly lower odds of abstinence for non-White race (odds ratio [OR] = 0.75, 95% CI = 0.59–0.96, p < .03), higher nicotine dependence (OR = 0.83, 95% CI = 0.74–0.93, p < .001), and at trend level, women (OR = 0.83, 95% CI = 0.67–1.02, p < .09). We also examined the potential influence of having a history of MDD on abstinence (B = 0.17, SE = 0.12, p < 0.15) and did not include this term further given planned adjustment for current depressive symptoms. Table 2 presents results of primary outcomes from covariate-adjusted GEE models in which we observed a significant treatment by time interaction (cu). This interaction was confined to the comparison of the SEQ-FLUOX versus ST-FLUOX groups (see below). In comparisons of the fluoxetine conditions (ST-FLUOX and SEQ-FLUOX) versus TNP, there were no significant differences in abstinence rates and no significant differences in rates of abstinence over time (ps > .80). Table 3 presents results of planned comparisons of 7-day point prevalence abstinence rates among participants receiving each of the three treatments.

Table 3.

Planned Comparisons of 7-Day Point Prevalence Abstinence Rates Among Participants Receiving Transdermal Nicotine Patch, Standard Fluoxetine, or Sequential Fluoxetine Treatment

OR Lower 0.95 Upper 0.95
End of treatment
    SEQ-FLUOX vs. ST-FLUOX 1.20 0.60 2.40
    SEQ-FLUOX/ST-FLUOX vs. TNP 0.98 0.80 1.20
6 months
    SEQ-FLUOX vs. ST-FLUOX 2.35 1.10 5.02
    SEQ-FLUOX/ST-FLUOX vs. TNP 0.99 0.80 1.23
12 months
    SEQ-FLUOX vs. ST-FLUOX 1.37 0.63 2.99
    SEQ-FLUOX/ST-FLUOX vs. TNP 1.03 0.83 1.29
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Note. SEQ-FLUOX = sequential fluoxetine treatment; ST-FLUOX = standard fluoxetine treatment; TNP = transdermal nicotine patch treatment.

Does SEQ-FLUOX Versus ST-FLUOX Improve Effect of Treatment on Smoking Outcomes?

The above-noted significant treatment by time interaction (p < .03) of primary outcomes from covariate-adjusted GEE models reflected that abstinence rates in the SEQ-FLUOX treatment group declined more slowly (B = 0.28; 95% CI = 0.04–0.51, p < .03), and rates of decline were held off longer (B = −0.06, 95% CI = –0.12 to −0.01, p < .03) when compared with rates of declining abstinence in ST-FLUOX over the 12-month assessment period. Rates of point prevalence abstinence among participants who received SEQ-FLUOX were not significantly different from participants receiving ST-FLUOX at the end of treatment (OR = 1.20; 95% CI = 0.64–2.40). However, participants in SEQ-FLUOX had significantly higher rates of abstinence than participants in the ST-FLUOX treatment at the 6-month assessment (OR = 2.35; 95% CI = 1.10–5.02, p < .03), a difference that was reduced at the 12-month assessment (OR = 1.37; 95% CI = 0.63–2.99, p < .44). In a final step of the GEE analysis, interactions of treatment group with gender, White race, FTND, and baseline CES-D were entered simultaneously to the model described above. None of the interactions was significant, with p values ranging from 0.16 to 0.94.

In post hoc comparison at the 6-month assessment where between-group differences were largest, point prevalence abstinence rates among participants in SEQ-FLUOX (38%) were not significantly different than rates (27.8%) among participants in TNP (OR = 1.56; 95% CI = 0.76–3.20, p < .24). Seven-day biochemically verified point prevalence continuous abstinence rates at end-of-treatment, 6-, and 12-month assessments were 31.9%, 20.8%, and 13.9% for TNP; 30.1%, 17.8%, and 12.3% for ST-FLUOX; and 33.8%, 23.9%, and 16.9% for SEQ-FLUOX, respectively. This pattern of results was mirrored in analyses that required continuous abstinence across the three assessments although results did not support significant differences between treatments (p > .05).

Secondary Aims: Effect of Treatments on Depressive Symptoms

We examined the effects of treatments on measures of depressive symptoms prior to and following (Figure 4) smoking cessation. Depressive symptoms were assessed using the CES-D at baseline, at the beginning of treatment (Session 1), and during treatment at 1, 2, 4, and 8 weeks after quitting. In linear regression models with covariates mirroring outcome analyses, we did not observe any significant differences (ps > .18) in levels of depressive symptoms prior to the scheduled quit day, with mean CES-D scores of 8.66 (SD = 7.15), 9.19 (SD = 7.79), and 10.16 (SD = 7.70) for SEQ-FLUOX, ST-FLUOX, and TNP, respectively. We next used random-effects regression models to examine CES-D scores following cessation, with control for baseline levels of depressive symptoms and mirroring planned covariates of White race, level of nicotine dependence, and gender. There was no significant difference when comparing the two fluoxetine conditions (SEQ-FLUOX and ST-FLUOX) to the TNP condition through the end of treatment (B = 0.05; SE = 0.28; 95% CI = −0.50 to 0.50; p < .86). However, participants in the SEQ-FLUOX condition maintained significantly lower levels of depressive symptoms than ST-FLUOX (B = −1.05, SE = .49; 95% CI = −1.99 to −0.11; p < .03) through the end of treatment, amounting to differ ences (d = 0.30) between fluoxetine conditions by the end of treatment (See Figure 4).

Figure 4.

Figure 4.

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Changes in Center for Epidemiological Studies Depression Scale (CES-D) after quit day and through the end of treatment. SEQ-FLUOX = sequential fluoxetine treatment; ST-FLUOX = standard fluoxetine treatment; TNP = transdermal nicotine patch treatment.

Effects of Treatments on Withdrawal Symptoms Immediately After Quitting

The pattern of results observed with depressive symptoms was also seen in measures of withdrawal following quitting. The withdrawal scale [100] has three factors: Urges, Negative Affect, and Sleep Disturbance. There were no differences in any of the three withdrawal subscale scores across conditions, either at baseline or at the beginning of treatment (ps > .05). In models that controlled for levels of withdrawal scales at the beginning of treatment and included planned covariates as above, the level of Urges and Negative Affect in the fluoxetine conditions (SEQ-FLUOX and ST-FLUOX) in the weeks after quitting was not different from the TNP condition (ps > .05). Participants in the SEQ-FLUOX treatment had significantly lower Negative Affect (B = −0.56, SE = .0.18; 95% CI = −0.91 to −0.21; p < .004) but did not have different levels of Urges (B = −0.53, SE = 0.43, 95% CI = −1.37 to 0.31, p < .23) than participants in the ST-FLUOX treatment. There were no differences across the SEQ-FLUOX, ST-FLUOX, or TNP conditions in levels of Sleep Disturbance during the weeks following quitting (p >.05).

Given no statistically significant differences in primary smoking outcomes within the active treatment period, we did not explore mediational analyses.

DISCUSSION

This study is the first to examine a sequential treatment approach to pharmacotherapy for depressive symptoms prior to smoking cessation. The results of primary smoking outcomes comparing the two fluoxetine conditions (SEQ-FLUOX vs. ST-FLUOX) showed a significant difference in abstinence rates over time in the SEQ-FLUOX treatment group relative to ST-FLUOX, and the decline in abstinence rates was faster in ST-FLUOX than in SEQ-FLUOX over the 12-month follow-up. The participants in SEQ-FLUOX fluoxetine treatment showed a greater point prevalence abstinence than participants in ST-FLUOX treatment at 6-month follow-up (38% vs. 21.9%; OR = 2.35), a difference that was both statistically and clinically significant. However, this difference was reduced at 12-month follow-up. The models did not show differences between AD pharmacotherapy with fluoxetine combined with TNP (ST-FLUOX and SEQ-FLUOX) versus TNP alone, in either abstinence rates or in rates of abstinence over time.

During the active 8-week treatment period, participants in SEQ-FLUOX treatment with fluoxetine maintained significantly lower levels of depressive symptoms and negative affect withdrawal symptoms than participants in ST-FLUOX. No significant between-group differences were found in smoking urges or sleep disturbance. The two fluoxetine conditions were not significantly different from TNP in depressive symptoms, negative affect, urges, or sleep disturbance during smoking cessation treatment.

The pattern of results observed in this study (i.e., SEQ-FLUOX outperforming ST-FLUOX, but the fluoxetine conditions not differing from TNP), as depicted in Figure 4, adds to findings that show a lack of treatment effects for fluoxetine when used concurrently for smoking cessation. Indeed, recent work (e.g., Spring et al., 2007) has suggested that the use of fluoxetine for smoking cessation can be deleterious and should be discouraged in smokers with depressive vulnerabilities. However, unlike the current study, the study by Spring et al. (2007) and all other previous studies have utilized fluoxetine concurrently with smoking cessation. The results of the current study suggest that the temporal sequencing of mood treatment, in this case pharmacotherapy with the SSRI fluoxetine, with standard smoking cessation treatment may be an important factor in the development and implementation of an efficacious mood-management treatment for smokers with elevated depressive symptoms. It is clear from the results of this study that if one is going to prescribe fluoxetine for smoking cessation in smokers with elevated depressive symptoms, it is best to begin prescribing fluoxetine well before the target quit date.

Post hoc comparisons between SEQ-FLUOX and TNP did not reveal statistically significant differences in abstinence rates over the course of the study. However, by the 6-month timepoint, participants in the SEQ-FLUOX were 1.6 times more likely to be abstinent than participants in TNP, with a 10% differences in abstinent rates (OR = 1.56; 38% vs. 27.8%). Given that we initially hypothesized that the combined fluoxetine conditions (i.e., SEQ-FLUOX and ST-FLUOX), but not either alone, would result in better smoking cessation outcomes than the TNP condition, the study was not sufficiently powered to detect a statistically significant difference between one of the fluoxetine conditions (either SEQ-FLUOX or ST-FLUOX) and TNP. However, the observed OR and differences in abstinence rates at 6 months between SEQ-FLUOX and TNP suggest the need for a well-designed, placebo-controlled, and sufficiently powered clinical trial that would more definitively address questions about the potential efficacy of the sequential use of fluoxetine relative to standard smoking cessation treatment for smokers with elevated depressive symptoms.

Interestingly, contrary to what was expected, SEQ-FLUOX did not demonstrate decreased depressive symptoms prior to quitting. It appears that the effect of SEQ-FLUOX on depressive symptoms was most evident after smoking cessation. In addition, negative affect–related withdrawal symptoms were also lower for SEQ-FLUOX participants relative to ST-FLUOX participants. Indeed, the period immediately following initial cessation is characterized by significant mood disturbance, with acute increases in depressive symptoms (Burgess et al., 2002; Piasecki et al., 2000) and both acute and persistent decreases in positive mood (Cook et al., 2004; Lerman et al., 2002). In a sample of nondepressed adult smokers, fluoxetine resulted in a reduction in negative affect and a rise in positive affect in the period immediately following smoking cessation (Cook et al., 2004). The results of the current study are consistent with these findings and suggest that fluoxetine, when used sequentially for 8 weeks prior to quitting, may be particularly suited to ameliorate mood disturbance in the period immediately following cessation.

Although previous studies of fluoxetine for smoking cessation have utilized doses of 30 and 60mg (Lerman et al., 2002), this study examined fluoxetine for smoking cessation at a lower dose of 20mg. The decision to use a 20-mg dose was based, in part, on findings from a randomized placebo-controlled trial for subthreshold MDD, which found that the standard starting dose of fluoxetine 20mg was effective in significantly reducing depressive symptoms (Judd et al., 2004). As prior smoking cessation work with fluoxetine at 30 and 60mg has shown an increased incidence of side effects and dose-dependent treatment discontinuation due to adverse events (Hitsman et al., 1999; Lerman et al., 2002), our findings of beneficial effects using the lower 20mg dose hold significant advantages for potential dissemination. If the efficacy of sequential fluoxetine at 20mg for elevated depressive symptoms can be more definitively established in future studies, this lower starting dose will clearly be a positive factor in the decisions of primary care physicians and other providers to utilize sequential fluoxetine treatment for smokers with elevated depressive symptoms

Given the novelty associated with sequencing fluoxetine treatment for smokers with elevated depressive symptoms, replication is clearly warranted. One important limitation of this study design is that these findings may have been due to placebo effects or the effects of additional contact time. A logical next step would be a randomized, double-blind, placebo-controlled trial of fluoxetine, used sequentially as in this study, in combination with ST/TNP for smoking cessation in smokers with elevated depressive symptoms. Also, a measure of positive affect was not included. Given the evidence that low levels of positive mood prior to cessation were predictive of poor long-term smoking cessation and that smokers with low levels of prequit positive mood benefit significantly from pharmacotherapy with fluoxetine (Doran et al., 2006), examining the effects of sequential use of fluoxetine on changes in positive mood is of considerable interest. Finally, it should be noted that because smokers with current MDD were excluded from this study, these findings might not generalize this subpopulation of smokers.

Overall, these findings suggest potential benefits of sequentially treating depressive symptoms with fluoxetine prior to initiating smoking cessation in smokers with elevated depressive symptoms. The further significance of this project lies in the potential for future dissemination of this approach to primary care and other clinical settings, which will have high public health significance. The results of this study contribute useful knowledge regarding the use and timing of AD pharmacotherapy, and further work with sequential approaches is warranted. Given recent evidence of the benefits of extending TNP treatment beyond 8 weeks (Schnoll et al., 2010), future studies to examine the benefit of fluoxetine as an adjunct to extended TNP or other nicotine replacement therapy may be warranted.

FUNDING

Supported in part by the American Cancer Society (PBP-104347) to RAB.

DECLARATION OF INTERESTS

LHP reports receiving grant/research support from Medtronic, Neuronetics, HRSA, and NeoSync; serving on an advisory panel for Abbott; and serving as a consultant for Wiley, Springer, Qatar National Research Fund, and Abbott. The other authors have no competing interests to declare.

Contributor Information

Richard A. Brown,  Department of Psychiatry and Human Behavior, Butler Hospital/Alpert Medical School of Brown University, Providence, RI;.

Ana M. Abrantes,  Department of Psychiatry and Human Behavior, Butler Hospital/Alpert Medical School of Brown University, Providence, RI;.

David R. Strong,  Department of Family and Preventive Medicine, University of California San Diego, La Jolla, CA;.

Raymond Niaura,  Schroeder Institute, American Legacy Foundation, Washington, DC;.

Christopher W. Kahler,  Brown University Center for Alcohol and Addiction Studies, Providence, RI.

Ivan W. Miller,  Department of Psychiatry and Human Behavior, Butler Hospital/Alpert Medical School of Brown University, Providence, RI;.

Lawrence H. Price,  Department of Psychiatry and Human Behavior, Butler Hospital/Alpert Medical School of Brown University, Providence, RI;.

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