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. Author manuscript; available in PMC: 2026 Jan 21.
Published in final edited form as: J Dual Diagn. 2017 Apr 17;13(3):168–178. doi: 10.1080/15504263.2017.1319585

Improved Depressive Symptoms in Adults with Schizophrenia During a Smoking Cessation Attempt with Varenicline and Behavioral Therapy

Corinne Cather a,b, Susanne Hoeppner a, Gladys Pachas a,b, Sarah Pratt c, Eric Achtyes d, Kristina M Cieslak a,b, A Eden Evins a,b
PMCID: PMC12817128  NIHMSID: NIHMS2135855  PMID: 28414583

Abstract

Objective:

Smoking prevalence rates are elevated in individuals with schizophrenia spectrum disorders (SSD) compared with the general population, with attendant disproportionate smoking-related morbidity and mortality. Pharmacotherapies that improve abstinence rates in this population are underutilized, partly due to concerns about neuropsychiatric safety, particularly for those with comorbid depression or prior suicide attempt. Prospective assessment of the psychiatric safety profile of varenicline in those with SSD is needed.

Methods:

Adult smokers with SSD entered a 12-week trial of varenicline and behavioral therapy for smoking cessation. Depressive symptoms were assessed with the Calgary Depression Scale for Schizophrenia (CDSS) at baseline and weekly thereafter. Participants with baseline and one or more postbaseline CDSS assessments, n = 179, were included in a secondary analysis of change in depressive symptoms with varenicline treatment, adjusting for abstinence status and baseline depressive symptoms.

Results:

Twenty-seven percent of participants had a CDSS score at baseline consistent with current major depressive disorder, and more than half had a prior suicide attempt. Forty-one percent (74/179) achieved two or more weeks of continuous abstinence at the end of treatment. CDSS scores declined 31% during the 12-week treatment period. Controlling for baseline CDSS scores, depressive symptoms declined over time in those who completed the trial, independent of abstinence status, and either declined or remained unchanged in those with major depressive disorder or prior suicide attempt or who were taking antidepressant medication. Those who did not complete the trial had no change in depressive symptoms.

Discussion:

Depressive symptoms declined in adults with schizophrenia during 12 weeks of varenicline treatment and cognitive behavioral therapy, independent of tobacco abstinence. Smokers with SSD who have significant depressive symptoms may be successful in smoking cessation attempts with pharmacotherapeutic aids such as varenicline while maintaining stable psychiatric symptoms. This is a secondary analysis of data collected as part of a clinical trial registered as NCT00621777, at www.clinicaltrials.gov.

Keywords: Schizophrenia, nicotine, smoking cessation, varenicline, major depressive disorder, depressive symptoms, abstinence

Introduction

Despite reports that smokers with serious mental illness are as likely as smokers in the general population to want to quit smoking (Siru, Hulse, & Tait, 2009) and that combined pharmacotherapy and behavioral therapy is recommended as standard of care for smokers with schizophrenia (Buchanan et al., 2010; Evins, Cather, & Laffer, 2015), smokers with serious mental illness do not routinely receive standard-of-care treatment for smoking cessation (Druss, Bradford, Rosenheck, Radford, & Krumholz, 2001; Goff et al., 2005; Heffner, Strawn, DelBello, Strakowski, & Anthenelli, 2011; Himelhoch & Daumit, 2003; Prochaska, 2011; Schroeder & Morris, 2010; Ziedonis et al., 2008). The premature mortality gap between those with serious mental illness and the general population, due primarily to cardiovascular disease (Lutterman et al., 2003), is the largest disparity in life expectancy in the United States (Everett, Mahler, Biblin, Ganguli, & Mauer, 2008). Despite evidence from controlled trials indicating that varenicline is effective (Anthenelli et al., 2016; Evins et al., 2014; Evins et al., 2017; Pachas et al., 2012; Weiner et al., 2011; Williams et al., 2012), is safe (Dutra, Stoeckel, Carlini, Pizzagalli, & 55 Evins, 2012; Evins et al., 2014; Hong et al., 2011; Pachas et al., 2012; Shim et al., 2012; Smith et al., 2016; Weiner et al., 2011; Williams et al., 2012), and reduces cardiovascular mortality risk (Thorndike et al., 2016) for adult smokers with schizophrenia spectrum disorders (SSD), it remains underutilized in this population (Huang, Lewis, & Britton, 2014), likely due to worries about neuropsychiatric adverse events in this group, who are viewed to be at high risk for psychiatric symptom exacerbation with both smoking cessation and varenicline treatment. Reluctance to provide pharmacotherapeutic cessation aids to smokers with SSD may contribute to their low smoking cessation rates (Cook et al., 2014) and excess morbidity and mortality (Callaghan et al., 2014, Olfson, Gerhard, Huang, Crystal, & Stroup, 2015).

Adults with SSD have high lifetime prevalence of major depressive disorder and suicide attempts (Cather, Barr, & Evins, 2008; Freudenreich et al., 2008). Depressive and anxiety symptoms have been reported to improve with smoking cessation (Taylor et al., 2014) and with varenicline treatment in smokers without psychotic illness (Anthenelli et al., 2013; Avery et al., 2014; Cinciripini et al., 2013), and treatment with bupropion with or without nicotine replacement therapy has not been associated with exacerbation in mood symptoms in those with SSD (Cinciripini et al., 2010; Evins et al., 2005; Tsoi, Porwal, & Webster, 2013). However, the course of depressive symptoms in those with SSD during varenicline treatment is not known.

To examine whether depressive symptom exacerbation occurred in smokers with SSD during a smoking cessation trial, we analyzed weekly clinician-rated and self-reported depressive symptoms from a 12-week, open-label smoking cessation trial of varenicline and weekly group cognitive behavioral therapy (CBT) for smoking cessation in adults with SSD in the overall sample and in subgroups at increased risk for depressive symptom exacerbation. Subgroups of interest were those with a baseline major depressive episode, those with a prior suicide attempt, those taking antidepressants at baseline, and those who failed to attain abstinence. We conducted a subgroup analysis of those who discontinued early to assess whether exacerbation in depressive symptoms during the trial led to early dropout. Further, we assessed transient but potentially clinically significant exacerbations in depressive symptoms by examining the distribution of the maximal change in depressive symptoms from baseline at any time point by abstinence and completer status and investigated whether antidepressant use at baseline moderated abstinence outcomes.

Methods

A 12-week, open-label trial of varenicline and weekly group CBT for smoking cessation was conducted as part of a larger trial in outpatient smokers with SSD from March 2008 to May 2013 (Evins et al., 2014). This study was conducted in compliance with the Declaration of Helsinki, U.S. Food and Drug Administration, and International Conference on Harmonization Good Clinical Practices guidelines. Oversight was provided by institutional review boards at each study site and an independent data safety and monitoring committee. A complete discussion of the study was held with all potential study participants prior to initiation of study procedures, and all participants provided written informed consent.

Sample

Participants were women and men with schizophrenia or schizoaffective disorder, depressed type (SSD), aged 18 to 70 years, recruited from 10 community mental health centers across six U.S. states, who reported smoking ≥ 10 cigarettes per day for at least the past year; had an expired carbon monoxide (CO) concentration ≥ 9 parts per million (ppm) at screening; were taking a stable, clinically determined dose of an antipsychotic medication for at least 30 days prior to enrollment; expressed a desire to quit smoking and willingness to take varenicline; and set a smoking quit date within four weeks of enrollment. Exclusion criteria included current suicidal ideation, hospitalization for a major depressive episode in the past six months or for suicidal ideation or attempt in the past year, and comorbid active substance use disorder other than nicotine.

Design and intervention

Participants received varenicline 0.5 mg daily for three days, 0.5 mg twice daily for four days, and 1 mg twice daily for 11 weeks, along with weekly, one-hour manualized group CBT for smoking cessation tailored for smokers with severe mental illness (Evins et al., 2007; Evins et al., 2005). To assess the stability of psychiatric symptoms with the addition of varenicline while minimizing confounding effects of nicotine withdrawal, participants were asked to continue their usual smoking behavior for the first three weeks of the trial and to set a quit date the day before the fifth CBT group meeting (week 4 of the study), when they had been taking varenicline for four weeks, consistent with prescribing instructions to set a quit date between 8 and 35 days after starting varenicline (Prescriber’s Digital Reference, 2017).

Assessments

Baseline assessments included chart review, clinical interview, the Fagerstrom Test for Nicotine Dependence on Cigarettes (Heatherton, Kozlowski, Frecker, & Fagerstrom, 1991), and urine screening for drugs of abuse. Antipsychotic dosage at baseline was converted to chlorpromazine equivalents using standards provided by Buchanan et al. (2010) for first-generation antipsychotics and as per Leucht et al. (2014) for second-generation antipsychotics.

Assessments conducted at baseline and weekly included self-report of smoking behavior, expired CO, Calgary Depression Scale for Schizophrenia (CDSS), and Wisconsin Smoking Withdrawal Scale (WSWS; Welsch et al., 1999). The Brief Psychiatric Rating Scale (BPRS; Overall & Gorham, 1962) and the Scale for the Assessment of Negative Symptoms (Andreasen, 1989) were administered at baseline and week 12. Self-report of abstinence was biochemically verified with expired CO at each weekly CBT group visit. End-of-treatment abstinence was defined as at least two weeks of continuous abstinence at week 12, operationalized as self-report of smoking no cigarettes in the prior week, CO < 9 ppm at study weeks 11 and 12, and verification of abstinence at week 12 with semiqualitative urinary cotinine analysis.

Analysis

To evaluate changes in depressive symptoms (CDSS total scores and WSWS depression sub-scale scores) during the 12-week trial, we used hierarchical mixed models with time as a within-person factor and end-of-treatment abstinence as a between-person factor, using random intercepts and an autoregressive covariance structure, including baseline CDSS score as a time point in the model. Participants who dropped out of the study were included as a separate group within the model, resulting in three groups. We modeled time as a categorical predictor and tested linear effects of time through specific contrasts, fitting all available time points. To isolate the effect of varenicline on depressive symptoms without the complicating factor of nicotine withdrawal, we included a specific contrast of baseline visits prior to the first dose of varenicline (screening and baseline) with study visits after the initiation of varenicline but before the quit date (weeks 1–3). We used this model structure with seven-day point-prevalence abstinence added as a time-varying covariate to examine depressive symptom scores over time in subgroups (a) with a lifetime suicide attempt; and (b) with baseline depressive symptom ratings consistent with a current major depressive episode, defined as a CDSS total score > 6 at either screening or baseline (82% specificity and 85% sensitivity; Addington, Addington, & Maticka-Tyndale, 1993). In order to investigate the effect of baseline antidepressant use on mean depressive symptom severity and the trajectories of depressive symptoms in those who achieved abstinence, did not achieve abstinence, or dropped out, we ran an additional version of our main model in which we modeled baseline antidepressant use (yes vs. no) as a covariate and as a moderator of the effect of time on CDSS depressive symptom scores during the trial. If group by time interactions were significant, we tested simple effects of time within each group and then tested linear effects of time through specific contrasts.

To evaluate whether early abstinence was associated with a transient increase in depressive symptoms not evident in the main analysis, we conducted a separate one-way analysis of variance of CDSS change scores from baseline to the visit following the target quit date among the 141 (78.8%) participants who had pretreatment and week 4 assessments, comparing those who reported at least 24 hours of abstinence at the week 4 visit with those who did not.

We used univariate ordinal logistic regressions to evaluate whether baseline depressive symptoms were associated with dropout from the study and a multiple logistic regression to evaluate whether antidepressant use and greater baseline depression symptoms (CDSS scores > 6) at baseline predicted end-of-treatment abstinence. Means are presented as raw means ± standard deviation (SD) unless specifically identified as model-adjusted marginal means (i.e., least square means; LSM) ± standard error (SE). Data were managed using REDCap electronic data capture tools (Harris et al., 2009) hosted at Massachusetts General Hospital. Analyses were performed using SAS (Version 9.4 of the SAS System for Windows).

Results

One hundred seventy-nine smokers with SSD enrolled, had a baseline CDSS score, attended at least one postbaseline assessment, and were included in the analyses. Seventy-four of these participants (41.3%) attained two or more weeks of continuous abstinence at the end of 12-week treatment period, with an average duration of continuous abstinence of 42.7 ± 18.6 days at week 12. Those who did not achieve two weeks of continuous abstinence at week 12 (n = 34) had a mean 1.5 ± 2.9 days of abstinence at week 12, and those who dropped out prior to week 12 (n = 71) had a mean of 1.9 ± 6.9 days of abstinence at the time of dropout.

Twenty-seven percent of the sample (48/179) had CDSS scores > 6 at either the screening or baseline visits, consistent with a current major depressive episode (Addington et al., 1993). At enrollment, nearly 60% were taking an antidepressant, 32% were taking an anxiolytic medication, and all were taking antipsychotic medication. More than half of the sample had made a suicide attempt in their lifetime (Table 1).

Table 1.

Baseline demographic and clinical variables by end-of-treatment abstinence status.

≥2 weeks abstinence at week 12 (n = 74) <2 weeks abstinence at week 12 (n = 34) Early discontinuation (n = 71)
Variables %/M (SD) %/M (SD) %/M (SD)
Demographics
  Age, mean (SD), y 47.9 (10.4) 46.9 (10.0) 47.2 (10.0)
  Sex, % female 32.4 35.3 45.1
  White, % 73.0 61.8 77.5
  Black, % 17.6 23.5 16.9
  Other, %  9.5 14.7  5.6
  Hispanic ethnicity, %  2.8  6.3  4.2
  Less than high school education, % 23.0 30.3 29.6
  Single, never married, % 64.9 79.4 64.8
Smoking characteristics
  Expired CO, mean (SD), ppm† 21.9 (10.0) 24.1 (11.0) 24.0 (13.2)
  Cigarettes/day, mean (SD)† 20.6 (12.7)a 24.1 (10.8)a,b 25.2 (11.9)b**
  FTND score, mean (SD)  5.9 (2.0)  6.4 (1.8)  6.3 (1.7)
  Age first smoked, mean (SD), y 17.1 (5.4)a 20.4 (8.4)b 16.9 (4.6)a*
  Years of smoking, mean (SD), y 28.5 (12.1) 25.6 (11.9) 27.5 (11.7)
  No prior quit attempts, % 6.8 20.6 14.1
  5+ prior quit attempts, % 31.1 35.3 32.4
Psychiatric medication
  First-generation antipsychotic, % 10.8 8.8 15.5
  Second-generation antipsychotic (excluding clozapine), % 66.2 76.5 60.6
  Clozapine, % 23.0 14.7 23.9
  Two or more antipsychotic medications, % 24.3 38.2 32.9
  Chlorpromazine equivalents, mean (SD) 558.4 (404.7) 709.7 (480.2) 645.1 (479.4)
  Anxiolytics, % 27.4 27.3 38.6
Clinical symptom ratings
  CDSS total score, mean (SD)  4.4 (3.6)  4.2 (3.4)  3.7 (3.0)
  CDSS total score > 6, %‡ 29.7 35.3 19.7
  BPRS total score, mean (SD) 53.0 (13.6) 51.7 (14.3) 49.8 (12.6)
  SANS composite score, mean (SD) 34.2 (15.3) 35.5 (15.6) 35.6 (13.8)
  Suicide attempt (lifetime), % 53.4 47.1 54.4
  Alcohol and/or drug use (past 7 days), % 16.2 14.7 23.9
  Binge drinking (past month), %  8.1 11.8  7.1
  Alcohol dependence (lifetime, self-report), % 53.5 29.4 45.7
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Note. Group differences of prevalence (percentages) were tested with chi-square tests, those in continuous variables with one-way analyses of variance; different letters in the superscripts indicate significant group differences.

*

p < .05.

**

p< .01.

***

p < .001.

†

Group difference analysis based on log-transformed values.

‡

At either screen or baseline.

M = mean; SD = standard deviation; FTND = Fagerstrom Test for Nicotine Dependence (6 items, score range: 0–10); CDSS = Calgary Depression Scale for Schizophrenia (total score range: 0–27); BPRS = Brief Psychiatric Rating Scale (24 items, scale range: 24–168); SANS = Scale for the Assessment of Negative Symptoms [in Schizophrenia] (19 items, composite total score range: 0–95); y = years; ppm = parts per million.

Those with greater depressive symptoms at baseline were older, had been smoking for longer in their lives, had more severe nicotine dependence and psychiatric symptoms, and were more likely to have made a suicide attempt (Table 2). Neither greater depressive symptoms nor use of antidepressant medication at baseline was associated with the likelihood of attaining end of treatment abstinence (CDSS scores > 6 OR = 1.17, 95% CI [0.59, 2.31]; Wald × 2 = 0.20, p = .656; antidepressant use OR = 1.67, 95% CI [0.90, 3.13]; Wald × 2 = 2.62, p = .106).

Table 2.

Participant characteristics by depressive symptom severity.

CDSS ≤ 6 (n = 131) CDSS > 6 (n = 48)
Variables %/M (SD) %/M (SD)
Age, mean (SD), y 46.5 (10.7) 50.2 (7.7)*
Sex, % female 39.7 33.3
Expired carbon monoxide, ppm, mean (SD)† 22.4 (15.0) 25.1 (16.6)
Cigarettes per day at screening, mean (SD)† 22.5 (12.6) 24.8 (10.9)
FTND score, mean (SD)  5.9 (1.8)  6.9 (1.7)***
Years of smoking, mean (SD), y 26.1 (12.2) 31.3 (10.3)**
CDSS total score, mean (SD)  2.6 (1.8)  8.3 (3.0)***
BPRS total score, mean (SD) 47.7 (12.4) 61.3 (10.6)***
SANS composite score, mean (SD) 32.7 (14.9) 41.1 (12.5)***
Prior suicide attempt (lifetime), % 44.5 74.5***
Alcohol dependence (lifetime, self-report), % 41.7 56.3
End of treatment abstinence, %‡ 39.7 45.8
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Note. Group differences of prevalence (percentages) were tested with chi-square tests, those in continuous variables with one-way analyses of variance.

*

p < .05.

**

p < .01.

***

p < .001.

†

Group difference analysis based on log-transformed values.

‡

≥ weeks continuous abstinence at group 12, where dropouts are assumed to be smoking.

M = mean; SD = standard deviation; FTND = Fagerstrom Test for Nicotine Dependence (6 items, score range: 0–10); CDSS = Calgary Depression Scale for Schizophrenia (total score range: 0–27); BPRS = Brief Psychiatric Rating Scale (24 items, scale range: 24–168); SANS = Scale for the Assessment of Negative Symptoms [in Schizophrenia] (19 items, composite total score range: 0–95); Hx ETOH dep = history of alcohol dependence (lifetime), self-reported; y = years.

Ratings of depressive symptoms decreased over time in participants who completed the 12-week open-label treatment with varenicline, regardless of whether they attained end-of-treatment abstinence, and did not change in those who dropped out. There was no main effect of end-of-treatment abstinence on CDSS scores. There was a main effect of time on CDSS scores in the entire sample, F(13, 1227) = 4.41, p = < .001, such that depressive symptoms decreased linearly over time, specific contrast of a linear effect of time F(1, 511) = 15.30, p < .001, decreasing from a mean (LSM ± SE) CDSS score of 4.11 ± 0.25 at baseline to 2.88 ± 0.36 at week 11, a 31% reduction (Figure 1A). There was a group by time interaction, F(25, 1149) = 1.62, p = .028, which indicated that the CDSS symptom score changes differed between at least two groups. CDSS scores decreased over time in the abstinent, group-specific effect of time F(13, 816) = 6.22, p < .001, and non-abstinent completers, group-specific effect of time F(13, 841) = 2.48, p = .003, and did not change significantly in the those who terminated the study early, group-specific effect of time F(12, 1349) = 1.48, p = .125 (see Figure 1A). There was also a reduction in depressive symptom scores of 1.51 ± 0.31 points, LSM difference ± SE, specific contrast F(1, 1059) = 23.15, p < .001, from the visits prior to initiation of varenicline (screening and baseline) to visits after initiation of varenicline but prior to the quit date (weeks 1–3).

Figure 1.

Figure 1.

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Weekly depressive symptom severity ratings during 12-week smoking cessation attempt. Note. CDSS = Calgary Depression Scale for Schizophrenia (total score range: 0–27); M = mean; SD = standard deviation. Weekly depressive symptom ratings are presented by A: end of treatment abstinence status; B: severity of depressive symptoms at baseline; and C: lifetime suicide attempt.

Splitting the study sample by baseline major depressive episode (i.e., baseline CDSS score > 6 vs. CDSS score ≤ 6; Table 2) or prior suicide attempt, depressive symptoms either declined or remained unchanged over time in all groups. Participants with a baseline major depressive episode had higher CDSS scores throughout the trial than those, LSM difference ± SE: 4.26 ± 0.30, F(1, 202) = 205.18, p < .001 (Figure 1B). There was a time-by-baseline major depressive episode interaction, F(13, 984) = 4.84, p < .001, such that CDSS scores decreased linearly over time in participants with a baseline major depressive episode and did not change in those with low baseline CDSS scores, specific contrast of linear slope difference F(1, 639) = 14.08, p < .001 (Figure 1B). Participants with a prior suicide attempt (n = 92) had higher CDSS scores throughout the treatment period, LSM: 1.43 ± 0.39, F (1, 186) = 13.06, p < .001 (Figure 1C). There was no interactive effect of prior suicide by time on CDSS scores, F(13, 940) = 1.29, p = .215, indicating that the overall linear effect of decreasing depressive symptoms throughout the study identified by the previous models held for participants regardless of prior suicide attempt. In addition, abstinence at any given visit was associated with lower CDSS scores at that visit, major depressive episode model LSM difference ± SE: −0.44 ± 0.18, F(1, 1304) = 6.14, p = .013; suicide history model LSM difference ± SE: −0.37 ± 0.16, F(1, 1236) = 5.10, p = .024, a relationship that did not differ by baseline major depressive episode, F(1, 1304) = 1.16, p = .282, or prior suicide attempt, F(1, 1236) < .01, p = .976, respectively.

We repeated the primary analysis with the depression subscale of the self-reported WSWS. There was no significant main effect of time in WSWS depression scores in the group as a whole, F(13, 1216) = 1.68, p = .060. Subsequent tests of simple effects of time within each group indicated that WSWS depression scores decreased over time in those who attained end-of-treatment abstinence, group-specific effect of time F(13, 820) = 1.76, p = .046, but not among non-abstinent completers, group-specific effect of time F(13, 850) = 1.29, p = .210, or those who dropped out, group-specific effect of time F(12, 1340) = 1.09, p = .368.

Effect of early abstinence on depressive symptoms

To evaluate whether early abstinence was associated with a transient increase in depressive symptoms not evident in the main analysis, we evaluated change in CDSS scores among the 141 (78.8%) participants who had pretreatment and week 4 assessments, comparing those who reported at least 24 hours of abstinence at the week 4 visit n = 50 (35.5%; mean duration of abstinence at week 4 = 7.3 ± 7.6 days, mean CO = 3.1 ± 7.5) with those who did not (0.2 ± 0.3 days of abstinence, mean CO = 14.6 ± 13.0; see Figure 2). Pretreatment depressive symptoms did not differ by early abstinence status, t (139) = 0.63, p = .527. From pretreatment to week 4, depressive symptoms remained largely unchanged in those with early abstinence, LSM ± SE: −0.74 ± 0.41, t (138) = −1.79, p = .076, and decreased in those without early abstinence, LSM ± SE: −1.34 ± 0.31, t(138) = −4.34, p < .001. The group difference between the depression symptom mean change scores was not significant, F(1, 138) = 1.34, p = .249.

Figure 2.

Figure 2.

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Severity of depressive symptoms at screening and one week following the quit date (study week 4) by abstinence status in the week following the quit date. Note. CDSS = Calgary Depression Scale for Schizophrenia (total score range: 0–27); SE = standard error.

Effect of antidepressant use on course of depressive symptoms and abstinence rates

Participants taking antidepressants at enrollment reported higher depressive symptom ratings throughout the study than those who did not use antidepressants, F (1, 175) = 8.19, p = .005, but antidepressant use did not moderate the effect of time on depressive symptom ratings during treatment, F(13, 933) = 1.39, p = .157. The main effect of time on depressive symptom ratings remained in the overall sample, F(13, 1187) = 4.09, p < .001; depressive symptom ratings decreased linearly over time, decreasing from a mean CDSS score of 3.99 ± 0.25 (LSM ± SE) at baseline to 2.81 ± 0.36 (LSM ± SE) at week 11, a 30% reduction, specific contrast of a linear effect of time, F(1, 495) = 14.26, p < .001. The group by time interaction reported in the main model also remained significant, F(25, 1137) = 1.58, p = .035). CDSS scores decreased over time in the abstinent, group-specific effect of time F(13, 804) = 5.49, p < .001, and non-abstinent completers, group-specific effect of time F(13, 827) = 2.33, p = .005, and did not change significantly in the those who terminated the study early, group-specific effect of time F(12, 1329) = 1.45, p = .135.

Distribution of depression-related adverse events by study week

Depression-related adverse events were calculated as events in which a participant had an increase in CDSS score of ≥ 3 points, the point value increase that would convert the group mean CDSS score to > 6. While average ratings of depressive symptoms declined in the sample as a whole and in the high-risk subgroups evaluated, at each study visit, 2% to 12% of participants reported an increase in depressive symptom ratings of ≥ 3 points over baseline, and more than one-third (37%) of participants met this criterion on at least one study visit (Figure 3). Participants who had a an increase in CDSS scores of 3 or more points over baseline at one study visit may have had a mean decline in their depressive symptoms during the study period.

Figure 3.

Figure 3.

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Weekly incidence of depressive symptom worsening compared to baseline. Note. CDSS = Calgary Depression Scale for Schizophrenia (total score range: 0–27).

Depression and attrition

Prior to the target quit date, 21% (38/179) of participants dropped out. Between weeks 4 and 12, 18% (33/179) of participants dropped out. Neither pretreatment CDSS scores, Wald χ2(df = 1) = 1.13, p = .288, OR = 1.05, 95% CI [0.96, 1.15], nor BPRS depression–anxiety scores, Wald χ2(df = 1) = 1.04, p = .308, (OR) = 1.18, 95% CI [0.86, 1.61], were associated with dropout before or after the quit date in univariate ordinal logistic regressions (Table 1). See Appendix A for a table showing timing and reason for dropout for the sample.

Discussion

We report in this secondary analysis in smokers with schizophrenia that neither a smoking cessation attempt with varenicline and CBT nor abstinence was associated with worsening in depressive symptoms. This finding was present in the group as a whole and in subgroups with significant depressive symptoms at baseline or a prior suicide attempt that constituted more than half of the sample. In fact, depressive symptom severity either remained stable or declined during the 12-week trial in these groups. High baseline depressive symptoms were not associated with failure to attain abstinence, and depressive symptoms declined during the smoking cessation trial, independent of abstinence. This is consistent with reports in other at-risk populations (Anthenelli et al., 2013; Capron, Allan, Norr, Zvolensky, & Schmidt, 2014; Hall et al., 2006; McClure et al., 2009; Prochaska et al., 2008; Torres et al., 2010), but is the first report of its kind to our knowledge in individuals with psychotic disorders.

In order to distinguish adverse events associated with pharmacotherapy from nicotine withdrawal symptoms, the trial was designed with a one-month medication lead-in prior to the quit date. Much of the observed decrease in depressive symptoms occurred in the month prior to the target quit date. While this is an open-label trial and reduction in depressive symptoms during the first weeks of the trial could have been due to the weekly CBT—although the CBT did not have a mood modulation focus, or unmeasured factors—the finding of reduced depressive symptoms in the first weeks of treatment is consistent with prior reports of antidepressant effects of nicotinic acetylcholine receptor antagonists such as mecamylamine hydrochloride (George, Sacco, Vessicchio, Weinberger, & Shytle, 2008) and partial nicotinic agonists, including varenicline (Phillip, Carpenter, Tyrka, Whiteley, & Price, 2009).

We observed no trend for worsening depressive symptoms in this sample of smokers with SSD, whom many clinicians may expect to be especially vulnerable to psychiatric symptom perturbation during a smoking cessation attempt. Sensitivity analyses indicate that this was not due to early attrition selectively in those who experienced exacerbation in depressive symptoms. Further, we did not observe worsening of depressive symptoms immediately following the target quit date; rather, depressive symptoms one week following the quit date were lower in those who had attained brief abstinence on the quit date and unchanged in those who did not. This finding is consistent with prior reports of an association of longer-term abstinence with significantly improved depression and anxiety symptoms (Taylor et al., 2014).

While there was a clear and consistent overall pattern of decreasing depressive symptoms over time, independent of abstinence status or baseline antidepressant use, roughly 2% to 12% of active study participants in any given week of the trial and 37% of participants over the 12-week trial had a transient increase in depressive symptom ratings. This is consistent with a report of overall significantly reduced depressive symptom severity over time, rated with the Hospital Anxiety and Depression Scale, during a 12-week smoking cessation attempt with varenicline, bupropion, nicotine patch, or placebo in a large cohort with psychiatric illness, but with approximately 15% of the sample, independent of treatment, reporting a transient increase in depressive symptoms (Evins et al., 2017b). Worsening of depressive symptoms appeared more prevalent in those who dropped out or did not attain abstinence, providing support for the “struggling quitters” hypothesis (Berlin, Chen, & Covey, 2010), which posits that demoralization and/or withdrawal contribute to increased depressive symptoms in the wake of an unsuccessful quit attempt. These exacerbations appeared to be transient events, not associated with a clear trend over time, and could represent underlying fluctuations in depressive symptoms independent of smoking cessation attempt or treatment. Of potential clinical interest, abstinence at any given visit was associated with significantly lower CDSS scores at that visit, irrespective of baseline major depressive episode or prior suicide attempt. We cannot rule out the possibility that this effect could be due to slower metabolism of certain psychiatric medications with tobacco abstinence (Kroon, 2007; Zevin & Benowitz, 1999).

Consistent with prior reports in those with schizophrenia (Evins et al., 2005; Evins et al., 2008), but in contrast to reports in samples without serious mental illness, higher baseline depressive symptoms were not associated with lower cessation rates (Weinberger, Pilver, Desai, Mazure, & McKee, 2013), and although the depressed subgroup in this analysis had factors that are generally associated with lower abstinence rates, such as older age, more severe psychopathology, and greater severity of nicotine dependence, abstinence rates did not differ between the depressed (46%) and nondepressed subgroups (40%). Similarly, abstinence rates also did not differ between those taking and those not taking an antidepressant medication at baseline. This may be due to the high overall symptom burden in the participants, such that depressive symptoms may not have posed a significant impediment to abstinence over that posed by psychotic or cognitive symptoms associated with schizophrenia.

Limitations

In the absence of a placebo comparison group, it is impossible to determine whether the reduction in depressive symptoms observed over time with varenicline and CBT treatment for smoking cessation in this sample is attributable to either the treatment or to smoking reduction/cessation. Moreover, neither raters nor participants were blind to treatment or abstinence status, leaving the possibility that either may have been systematically biased to underrate psychopathology. However, given the media attention paid to adverse depression outcomes with varenicline, a negative rater and self-rating bias may have been expected. It is reassuring that clinician ratings with the CDSS and self-ratings with the WSWS depression subscale were congruent, did not reveal worsening in any subgroup, and showed improvement among the abstinent group. Reduced depressive symptoms over time could additionally be interpreted as regression to the mean, since those with higher pretreatment CDSS scores showed reduction and those with lower pretreatment CDSS scores showed no change in CDSS scores over the course of the trial. However, pretreatment CDSS scores were stably elevated at both pretreatment visits (screening and baseline) such that we did not see an early indication of regression to the mean over the one- to three-week pretreatment period, suggesting that the CDSS was reliably assessed and stable pretreatment.

Also of note, although 27% of the sample had CDSS scores > 6, consistent with a major depressive episode diagnosis, the mean baseline CDSS score was 4.11 for this sample, and smokers with current suicidal ideation or hospitalization for a major depressive episode in the past six months or for suicidal ideation or attempt in the past year were excluded; thus, the patterns of abstinence and trajectory of depressive symptoms observed in this sample may not generalize to cohorts with more severe depressive symptoms. However, participants were recruited from community mental health centers and one-third of participants had a current major depressive episode on a screening instrument and one-half had a prior suicide attempt, making the sample highly generalizable to community samples.

Antidepressant and anxiolytic medication may have masked an effect of varenicline on worsening depressive symptoms for the subgroup taking these medications, but medication dosages had been stable for at least one month prior to enrollment, and improvement over time in depressive symptom severity would not be expected if antidepressant medications were simply preventing worsening of depressive symptoms with varenicline or smoking cessation.

Participants were not randomized to abstinence status, and it is possible that those who experienced depression with early abstinence did not remain abstinent or dropped out. We conducted a sensitivity analysis to address this question and found that those who were not abstinent at the end of treatment had reduction in depressive symptoms over time and those who discontinued the study did not have increased depressive symptoms over time while in the study.

Conclusions

We conclude that smokers with schizophrenia and schizoaffective disorder who have significant depressive symptoms may be successful in smoking cessation attempts with varenicline while maintaining stable psychiatric symptoms. This adds to a growing evidence base that supports offering pharmacotherapeutic cessation aids to smokers with psychiatric illness as standard of care, as there is ample evidence for efficacy and little evidence of harm (Buchanan et al., 2010; Chengappa et al., 2014; Dutra et al., 2012; Evins et al., 2005; Evins et al., 2014; Hall, 2007; Pachas et al., 2012; Tsoi et al., 2013), while the risks of continued smoking are substantial (Callaghan et al., 2014).

Acknowledgments

We would like to acknowledge Ivan Montoya, MD, acting director of the National Institute on Drug Abuse Division of Therapeutics and Medical Consequences, for his unflagging support for this project.

Disclosures

Dr. Evins, within the past five years, has received research study support to her institution from Pfizer, Forum Pharmaceuticals, GlaxoSmithKline, National Institute of Mental Health (NIMH), National Institute on Drug Abuse (NIDA), and Patient-Centered Outcomes Research Institute (PCORI) and has provided consulting and/or advisory board services to Pfizer and Reckitt Benckiser. Dr. Achtyes has received research grant support from Assurex, Janssen, Michigan State University, Pine Rest Foundation, Priority Health, University of Chicago, American Recovery and Reinvestment Act, Avanir, Centers for Medicare & Medicaid Services, Dartmouth College, Janssen, National Institute on Alcohol Abuse and Alcoholism, NIDA, NIMH, North Shore Long Island Jewish Health System, Otsuka, Pfizer, Vanguard Research Group, and University of Texas Southwestern. He has served on advisory boards to Roche and Vanguard Research Group. No other authors have conflicts of interest to declare.

Funding

This work was funded by the National Institute of Health–R01 DA021245 (Evins) and K24 DA030443 (Evins).

Appendix A. Reason for early termination and week of termination.

Last study week attended Number of participants Reason for early termination
0 1 Adverse event
1 Discontinued by study staff
3 Lost to follow-up
6 Withdrew consent
1 1 Adverse event
1 Discontinued by study staff
2 Lost to follow-up
3 Withdrew consent
2 4 Adverse event
1 Discontinued by study staff
1 Lost to follow-up
3 Withdrew consent
3 1 Adverse event
2 Discontinued by study staff
1 Other
7 Withdrew consent
4 1 Adverse event
1 Lost to follow-up
2 Withdrew consent
5 2 Adverse event
1 Withdrew consent
6 1 Discontinued by study staff
2 Withdrew consent
7 2 Discontinued by study staff
1 Lost to follow-up
2 Withdrew consent
8 1 Lost to follow-up
3 Withdrew consent
9 1 Adverse event
1 Discontinued by study staff
1 Nonabstinence
4 Withdrew consent
11 5 Nonabstinence
2 Withdrew consent
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References

  1. Addington D, Addington J, & Maticka-Tyndale E (1993). Assessing depression in schizophrenia: The Calgary Depression Scale. The British Journal of Psychiatry, Supplement, (22), 39–44. [PubMed] [Google Scholar]
  2. Andreasen NC (1989). Scale for the Assessment of Negative 605 Symptoms (SANS). The British Journal of Psychiatry, 155(7), 53–58. [PubMed] [Google Scholar]
  3. Anthenelli RM, Benowitz NL, West R, Aubin L, McRae T, Lawrence D, … Evins AE (2016). Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES): A double-blind, randomised, placebocontrolled clinical trial. The Lancet, 387(10037), 2507–2520. doi: 10.1016/S0140-6736(16)30272-0 [DOI] [PubMed] [Google Scholar]
  4. Anthenelli RM, Morris C, Ramey TS, Dubrava SJ, Tsilkos K, Russ C, & Yunis C (2013). Effects of varenicline on smoking cessation in adults with stably treated current or past major depression: A randomized trial. Annals of Internal Medicine, 159(6), 390–400. doi: 10.7326/0003-4819-159-6-201309170-00005 [DOI] [PubMed] [Google Scholar]
  5. Avery N, Kenny AM, Kleppinger A, Brindisi J, Litt MD, & Oncken CA (2014). Effects of varenicline, nicotine or placebo on depressive symptoms in postmenopausal smokers. The American Journal on Addictions, 23(5), 459–465. doi: 10.1111/j.1521-0391.2014.12130.x [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Berlin I, Chen H, & Covey LS (2010). Depressive mood, suicide ideation and anxiety in smokers who do and smokers who do not manage to stop smoking after a target quit day. Addiction, 105(12), 2209–2216. doi: 10.1111/j.1360-0443.2010.03109.x [DOI] [PubMed] [Google Scholar]
  7. Buchanan RW, Kreyenbuhl J, Kelly DL, Noel JM, Boggs DL, Fischer BA, … Keller W (2010). The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements. Schizophrenia Bulletin, 36(1), 71–93. doi: 10.1093/schbul/sbp116 [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Callaghan RC, Veldhuizen S, Jeysingh T, Orlan C, Graham C, Kakouris G, … Gatley J (2014). Patterns of tobacco-related mortality among individuals diagnosed with schizophrenia, bipolar disorder, or depression. Journal of Psychiatric Research, 48(1), 102–110. doi: 10.1001/jama.2013.284985 [DOI] [PubMed] [Google Scholar]
  9. Capron DW, Allan NP, Norr AM, Zvolensky MJ, & Schmidt NB (2014). The effect of successful and unsuccessful smoking cessation on short-term anxiety, depression, and suicidality. Addictive Behaviors, 39(4), 782–788. doi: 10.1016/j.addbeh.2013.12.014 [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Cather C, Barr R, & Evins A (2008). Smoking and schizophrenia: Prevalence, mechanisms and implications for treatment. Clinical Schizophrenia & Related Psychoses, 2(1), 70–78. doi: 10.3371/CSRP.2.1.5 [DOI] [Google Scholar]
  11. Chengappa KNR, Perkins KA, Brar JS, Schlicht PJ, Turkin SR, Hetrick ML, … George TP (2014). Varenicline for smoking cessation in bipolar disorder: A randomized, double-blind, placebo-controlled study. Journal of Clinical Psychiatry, 75(07), 765–772. doi: 10.4088/JCP.13m08756 [DOI] [PubMed] [Google Scholar]
  12. Cinciripini PM, Blalock JA, Minnix JA, Robinson JD, Brown VL, Lam C, … Dolan-Mullen P (2010). Effects of an intensive depression-focused intervention for smoking cessation in pregnancy. Journal of Consulting and Clinical Psychiatry, 78(1), 44–54. doi: 10.1037/a0018168 [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Cinciripini PM, Robinson JD, Karam-Hage M, Minnix JA, Lam C, Versace F, … Wetter DW (2013). Effects of varenicline and bupropion sustained-release use plus intensive smoking cessation counseling on prolonged abstinence from smoking and on depression, negative affect, and other symptoms of nicotine withdrawal. Journal of the American Medical Association–Psychiatry, 70(5), 522–533. doi: 10.1001/jamapsychiatry.2013.678 [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Cook B, Wayne G, Kafali E, Liu Z, Shu C, & Flores M (2014). Trends in smoking among adults with mental illness and association between mental health treatment and smoking cessation. Journal of the American Medical Association, 311(2), 172–182. doi: 10.1001/jama.2013.28498 [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Druss BG, Bradford WD, Rosenheck RA, Radford MJ, & Krumholz HM (2001). Quality of medical care and excess mortality in older patients with mental disorders. Archives of General Psychiatry, 58(6), 565–572. doi: 10.1136/bmjopen-2011-000778 [DOI] [PubMed] [Google Scholar]
  16. Dutra S, Stoeckel L, Carlini S, Pizzagalli D, & Evins AE (2012). Varenicline as a smoking cessation aid in schizophrenia: Effects on smoking behavior and reward sensitivity. Psychopharmacology, 219(1), 25–34. doi: 10.1007/s00213-011-2373-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Everett A, Mahler J, Biblin J, Ganguli R, & Mauer B (2008). Improving the health of mental health consumers: Effective policies and practices. International Journal of Mental Health, 37(2), 8–48. doi: 10.2753/IMH0020-7411370201 [DOI] [Google Scholar]
  18. Evins AE, Cather C, Culhane MA, Birnbaum A, Horowitz J, Hsieh E, … Goff DC (2007). A 12-week double-blind, placebo-controlled study of bupropion SR added to high-dose dual nicotine replacement therapy for smoking cessation or reduction in schizophrenia. Journal of Clincial Psychopharmacology, 27(4), 380–386. doi: 10.1097/01.jcp.0b013e3180ca86fa [DOI] [PubMed] [Google Scholar]
  19. Evins AE, Cather C, Deckersbach T, Freudenreich O, Culhane MA, Olm-Shipman CM, … Rigotti NA (2005). A double-blind placebo-controlled trial of bupropion sustained-release for smoking cessation in schizophrenia. Journal of Clincial Psychopharmacology, 25(3), 218–225. [DOI] [PubMed] [Google Scholar]
  20. Evins AE, Cather C, Pratt SA, Pachas GN, Hoeppner SS, Goff DC, … Schoenfeld DA (2014). Maintenance treatment with varenicline for smoking cessation in patients with schizophrenia and bipolar disorder: A randomized clinical trial. Journal of the American Medical Association, 311(2), 145–154. doi: 10.1001/jama.2013.285113 [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Evins AE, Culhane MA, Alpert JE, Pava J, Liese BS, Farabaugh A, & Fava M (2008). A controlled trial of bupropion added to nicotine patch and behavioral therapy for smoking cessation in adults with unipolar depressive disorders. Journal of Clinical Psychopharmacology, 28(6), 660–666. doi: 10.1097/JCP.0b013e31818ad7d6 [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Evins AE, Cather C, & Laffer A (2015). Treatment of tobacco use disorders in smokers with serious mental illness: Toward clinical best practices. Harvard Review of Psychiatry, 23(2), 90–98. doi: 10.1097/HRP.0000000000000063 [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Evins AE, Maravic MC, Russ C, McRae T, Dubrava S, Benowitz N, … Anthenelli R (2017a). Efficacy and neuropsychiatric safety of varenicline, bupropion, and nicotine patch for smoking cessation in smokers with psychiatric disorders. American Psychiatric Association Annual Meeting, San Diego, CA, USA. [Google Scholar]
  24. Evins AE, Maravic MC, Russ C, McRae T, Dubrava S, Benowitz N, … Anthenelli R (2017b). Change in anxiety and depression symptoms as measured by the hospital anxiety and depression scale in a study of varenicline, bupropion and nicotine patch in non-psychiatric and psychiatric cohorts (EAGLES study). Society for Research on Nicotine and Tobacco. 23rd Annual Meeting, Florence, Italy. [Google Scholar]
  25. Freudenreich O, Tranulis C, Cather C, Henderson D, Evins A, & Goff D (2008). Depressive symptoms in schizophrenia outpatients—prevalence and clinical correlates. Clinical Schizophrenia & Related Psychoses, 2(2), 127–135. doi: 10.3371/CSRP.2.2.2 [DOI] [Google Scholar]
  26. George TP, Sacco KA, Vessicchio JC, Weinberger AH, & Shytle RD (2008). Nicotinic antagonist augmentation of selective serotonin reuptake inhibitor-refractory major depressive disorder: A preliminary study. Journal of Clinical Psychopharmacology, 28(3), 340–344. doi: 10.1097/JCP.0b013e318172b49e [DOI] [PubMed] [Google Scholar]
  27. Goff DC, Cather C, Evins AE, Henderson DC, Freudenreich O, Copeland PM, … Sacks FM (2005). Medical morbidity and mortality in schizophrenia: Guidelines for psychiatrists. Journal of Clinical Psychiatry, 66(2), 183–194. [DOI] [PubMed] [Google Scholar]
  28. Hall SM (2007). Nicotine interventions with comorbid populations. American Journal of Preventive Medicine, 33(6), S406–S413. doi: 10.1016/j.amepre.2007.09.004 [DOI] [PubMed] [Google Scholar]
  29. Hall SM, Tsoh JY, Prochaska JJ, Eisendrath S, Rossi JS, Redding CA, … Gorecki JA (2006). Treatment for cigarette smoking among depressed mental health outpatients: A randomized clinical trial. American Journal of Public Health, 96(10), 1808–1814. doi: 10.2105/AJPH.2005.080382 [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, & Conde JG (2009). Research electronic data capture (RED-Cap)—a metadata-driven methodology and workflow process for providing translational research informatics support. Journal of Biomedical Informatics, 42(2), 377–381. doi: 10.1016/j.jbi.2008.08.010 [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Heatherton TF, Kozlowski LT, Frecker RC, & Fagerstrom KO (1991). The Fagerström Test for Nicotine Dependence: A revision of the Fagerstrom Tolerance Questionnaire. British Journal of Addiction, 86(9), 1119–1127. [DOI] [PubMed] [Google Scholar]
  32. Heffner JL, Strawn JR, DelBello MP, Strakowski SM, & Anthenelli RM (2011). The co-occurrence of cigarette smoking and bipolar disorder: Phenomenology and treatment considerations. Bipolar Disorders, 13(5–6), 439–453. doi: 10.1111/j.1399-5618.2011.00943.x [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Himelhoch S, & Daumit G (2003). To whom do psychiatrists offer smoking-cessation counseling? American Journal of Psychiatry, 160(12), 2228–2230. doi: 10.1176/appi.ajp.160.12.2228 [DOI] [PubMed] [Google Scholar]
  34. Hong LE, Thaker GK, McMahon RP, Summerfelt A, Rachbeisel J, Fuller RL, … Nye A (2011). Effects of moderate-dose treatment with varenicline on neurobiological and cognitive biomarkers in smokers and nonsmokers with schizophrenia or schizoaffective disorder. Archives of General Psychiatry, 68(12), 1195–1206. doi: 10.1001/archgenpsychiatry.2011.83 [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Huang Y, Lewis S, & Britton J (2014). Use of varenicline for smoking cessation treatment in UK primary care: An association rule mining analysis. BMC Public Health, 14(1), 1024. doi: 10.1186/1471-2458-14-1024 [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Kroon LA (2007). Drug interactions with smoking. American Journal of Health-System Pharmacy, 64(18), 1917–1921. doi: 10.2146/ajhp060414 [DOI] [PubMed] [Google Scholar]
  37. Leucht S, Samara M, Heres S, Patel MX, Woods SW, & Davis JM (2014). Dose equivalents for second-generation antipsychotics: The minimum effective dose method. Schizophrenia Bulletin, 40(2), 314–326. doi: 10.1093/schbul/sbu001 [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Lutterman T, Ganju V, Schacht L, Shaw R, Monihan K, & Huddle M (2003). Sixteen state study on mental health performance measures. Rockville, MD: Center for Mental Health Services, Substance Abuse and Mental Health Services Administration. [Google Scholar]
  39. McClure JB, Swan GE, Jack L, Catz SL, Zbikowski SM, McAfee TA, … Javitz H (2009). Mood, side-effects and smoking outcomes among persons with and without probable lifetime depression taking varenicline. Journal of General Internal Medicine, 24(5), 563–569. doi: 10.1007/s11606-009-0926-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Olfson M, Gerhard T, Huang C, Crystal S, & Stroup TS (2015). Premature mortality among adults with schizophrenia in the United States. JAMA Psychiatry, 72(12), 1172–1181. doi: 10.1001/jamapsychiatry.2015.1737 [DOI] [PubMed] [Google Scholar]
  41. Overall JE, & Gorham DR (1962). The brief psychiatric rating scale. Psychological Reports, 10(3), 799–812. [Google Scholar]
  42. Pachas GN, Cather C, Pratt SA, Hoeppner B, Nino J, Carlini SV, … Evins AE (2012). Varenicline for smoking cessation in schizophrenia: Safety and effectiveness in a 12-week, open-label trial. Journal of Dual Diagnosis, 8(2), 117–125. doi: 10.1080/15504263.2012.663675 [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Philip NS, Carpenter LL, Tyrka AR, Whiteley LB, & Price LH (2009). Varenicline augmentation in depressed smokers: An 8-week, open-label study. The Journal of Clinical Psychiatry, 70(7), 1026–1031. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Pfizer Inc. (n.d.). Chantix™ (varenicline) tablets: Prescribing information. Retrieved from http://www.chantix.com [Google Scholar]
  45. Prescriber’s Digital Reference. (2017). Varenicline–drug summary. Retrieved from http://www.pdr.net/drug-summary/chantix?druglabelid=466 [Google Scholar]
  46. Prochaska JJ (2011). Smoking and mental illness–breaking the link. New England Journal of Medicine, 365(3), 196–198. doi: 10.1056/NEJMp1105248 [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Prochaska JJ, Hall SM, Tsoh JY, Eisendrath S, Rossi JS, Redding CA, … Gorecki JA (2008). Treating tobacco dependence in clinically depressed smokers: Effect of smoking cessation on mental health functioning. American Journal of Public Health, 98(3), 446–448. doi: 10.2105/AJPH.2006.101147 [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Schroeder SA, & Morris CD (2010). Confronting a neglected epidemic: Tobacco cessation for persons with mental illnesses and substance abuse problems. Annual Review of Public Health, 31(1), 297–314. doi: 10.1146/annurev.publhealth.012809.103701 [DOI] [PubMed] [Google Scholar]
  49. Shim JC, Jung DU, Jung SS, Seo YS, Cho DM, Lee JH, … Kelly DL (2012). Adjunctive varenicline treatment with antipsychotic medications for cognitive impairments in people with schizophrenia: A randomized double-blind placebo-controlled trial. Neuropsychopharmacology, 37(3), 660–668. doi: 10.1038/npp.2011.238 [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Siru R, Hulse GK, & Tait RJ (2009). Assessing motivation to quit smoking in people with mental illness: A review. Addiction, 104(5), 719–733. doi: 10.1111/j.1360-0443.2009.02545.x [DOI] [PubMed] [Google Scholar]
  51. Smith RC, Amiaz R, Si TM, Maayan L, Jin H, Boules S, … Youseff M (2016). Varenicline effects on smoking, cognition, and psychiatric symptoms in schizophrenia: A double-blind randomized trial. PloS one, 11(1), e0143490. doi: 10.1371/journal.pone.0143490 [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Taylor G, McNeill A, Girling A, Farley A, Lindson-Hawley N, & Aveyard P (2014). Change in mental health after smoking cessation: Systematic review and meta-analysis. British Medical Journal, 348. doi: 10.1136/bmj.g1151 [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Thorndike AN, Achtyes ED, Cather C, Pratt S, Pachas GN, Hoeppner SS, & Evins AE (2016). Weight gain and 10-year cardiovascular risk with sustained tobacco abstinence in smokers with serious mental illness: A subgroup analysis of a randomized trial. The Journal of Clinical Psychiatry, 77(3), 320–326. doi: 10.4088/JCP.15m10074 [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Torres L, Barrera A, Delucchi K, Penilla C, Perez-Stable E, & Muñoz R (2010). Quitting smoking does not increase the risk of major depressive episodes among users of Internet smoking cessation interventions. Psychological Medicine, 40(3), 441–449. doi: 10.1017/S0033291709990560 [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Tsoi DT, Porwal M, & Webster AC (2013). Interventions for smoking cessation and reduction in individuals with schizophrenia. The Cochrane Database of Systematic Reviews, 2(2), CD007253. doi: 10.1002/14651858.CD007253.pub3 [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Weinberger AH, Pilver CE, Desai RA, Mazure CM, & McKee SA (2013). The relationship of dysthymia, minor depression, and gender to changes in smoking for current and former smokers: Longitudinal evaluation in the US population. Drug and Alcohol Dependence, 127(1), 170–176. doi: 10.1016/j.drugalcdep.2012.06.028 [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Weiner E, Buchholz A, Coffay A, Liu F, McMahon RP, Buchanan RW, & Kelly DL (2011). Varenicline for smoking cessation in people with schizophrenia: A double blind randomized pilot study. Schizophrenia Research, 129(1), 94–95. doi: 10.1016/j.schres.2011.02.003 [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Welsch SK, Smith SS, Wetter DW, Jorenby DE, Fiore MC, & Baker TB (1999). Development and validation of the Wisconsin Smoking Withdrawal Scale. Experimental and Clinical Psychopharmacology, 7(4), 354–361. [DOI] [PubMed] [Google Scholar]
  59. Williams JM, Anthenelli RM, Morris CD, Treadow J, Thompson JR, Yunis C, & George TP (2012). A randomized, double-blind, placebo-controlled study evaluating the safety and efficacy of varenicline for smoking cessation in patients with schizophrenia or schizoaffective disorder. Journal of Clinical Psychiatry, 73(5), 654–660. doi: 10.4088/JCP.11m07522 [DOI] [PubMed] [Google Scholar]
  60. Zevin S, & Benowitz NL (1999). Drug interactions with tobacco smoking. Clinical Pharmacokinetics, 36(6), 425–438. [DOI] [PubMed] [Google Scholar]
  61. Ziedonis D, Hitsman B, Beckham JC, Zvolensky M, Adler LE, Audrain-McGovern J, … Riley WT (2008). Tobacco use and cessation in psychiatric disorders: National Institute of Mental Health Report. Nicotine and Tobacco Research, 10(12), 1691–1715. doi: 10.1080/14622200802443569 [DOI] [PubMed] [Google Scholar]

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