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Effects of the Nicotinic Partial Agonist Varenicline on Smoking Lapse Behaviour in Schizophrenia

Kozak, Karolina MSc, PhD Candidate1,3; Dermody, Sarah S. PhD5; Sharif-Razi, Maryam BSc, MA1,2; Coles, Alexandria S. BA1,3; Morozova, Marya MSW, RSW1; Wing, Victoria C. PhD1; McKee, Sherry A. PhD4; George, Tony P. MD, FRCPC1,3

Canadian Journal of Addiction: June 2019 - Volume 10 - Issue 2 - p 27–35
doi: 10.1097/CXA.0000000000000052

Background: Varenicline, a nicotinic receptor partial agonist, is a first-line smoking cessation pharmacotherapy that may reduce smoking relapse in smokers with schizophrenia (SWS). The use of human laboratory models may allow the determination of potential mechanisms to improve treatment outcomes. The first instance of smoking during a quit attempt (a “smoking lapse”) is one of the best predictors of relapse. The aim of this study was to investigate effects of varenicline on smoking lapse in SWS and controls using a validated model of smoking lapse behaviours.

Methods: Varenicline was titrated up to 2 mg/d over 4 days and continued for a total of 6 days using a randomized, double-blind, placebo-controlled cross-over human laboratory lapse study design in SWS (n = 14) and nonpsychiatric control (n = 14) smokers.

Results: Varenicline nonsignificantly increased time to lapse in both SWS and control groups. However, these effects were most pronounced in SWS compared to controls with higher levels of nicotine dependence (Fagerström Test for Nicotine Dependence score ≥6; Cohen's d = 0.47 SWS; d = 0.24 controls). There were no medication effects related to cognitive function, withdrawal, craving, or smoking topography outcomes.

Conclusions: Our preliminary findings lack evidence in supporting the potential efficacy of varenicline on smoking relapse, particularly in SWS that may in part relate to our small sample size. Larger studies to further delineate the specific mechanisms by which varenicline ameliorates smoking relapse in SWS are needed, possibly in combination with adjunctive treatments to enhance overall relapse-prevention outcomes.


Contexte: La varénicline, sevrage partiel des récepteurs nicotiniques, est une pharmacothérapie de premier plan susceptible de réduire les rechutes du tabagisme chez les fumeurs atteints de schizophrénie (SWS). L’utilisation de modèles humains en laboratoire peut permettre de déterminer les mécanismes potentiels pour améliorer les résultats du traitement. La première occurrence de tabagisme au cours d’une tentative d’arrêt du tabac (un «manque de nicotine») est l’un des meilleurs annonciateurs de rechute. Le but de cette étude était d’étudier les effets de la varénicline sur les rechutes de tabagisme chez les patients SWS et les contrôles à l’aide d’un modèle validé de comportements lors de rechute de tabagisme.

Méthodes: La varénicline a été administrée jusqu’à 2 mg / jour sur 4 jours et poursuivie pendant 6 jours lors d’une étude aléatoire, ainsi qu’à double insu de contrôle placebo, en laboratoire, chez des patients atteints de schizophrénie (n = 14), ainsi que chez des sujets sous aucun contrôle psychiatrique (n = 14) fumeurs.

Résultats: La varénicline a démontré un effet non-significatif dans le temps de rechute chez les sujets des deux groupes. Toutefois les effets étaient plus prononcés chez les enfants SWS que chez les témoins présentant des niveaux plus élevés de dépendance à la nicotine (score FTND > 6; d Cohen = d 0,47, schizophrénie; d = 0,24). Aucun effet médicamenteux lié aux fonctions cognitives, au sevrage, à l’état de manque ou à la topographie du tabagisme n’a été observé.

Conclusions: Les résultats préliminaires n’ont démontré aucune efficacité significative de la varénicline dans la suppression des rechutes au tabagisme, surtout chez les sujets souffrants de schizophrénie. Cependant, ces résultats peuvent dépendre en partie du faible nombre de sujets. Des études plus vastes visant à définir plus précisément les mécanismes spécifiques par lesquels la varénicline améliore la rechute du tabagisme dans la schizophrénie sont nécessaires, éventuellement en association avec des traitements d’appoint pour améliorer les résultats globaux en matière de prévention des rechutes.

1Addictions Division, Centre for Addiction and Mental Health (CAMH), Toronto, Ontario, Canada

2Department of Psychology, University of Calgary, Calgary, Alberta, Canada

3Division of Brain and Therapeutics, Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada

4Behavioral Pharmacology Laboratory, Division of Substance Abuse, Department of Psychiatry, Yale University School of Medicine, New Haven, CT

5School of Psychological Science, Oregon State University

Corresponding Author: Karolina Kozak, MSc, PhD Candidate, Addictions Division, Centre for Addiction and Mental Health (CAMH), Biobehavioural Addictions and Concurrent Disorders Research Laboratory (BACDRL), 33 Russell Street, Room 1120, Toronto, ON, Canada M5S 2S1. Tel: +1 416 535 8501x30463, fax: +1 416 260 4171, e-mail:

Received 9 January, 2019

Accepted 9 April, 2019

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Tobacco smoking continues to be the leading cause of preventable death in the Western world.1 Although smoking rates have declined to ∼18%, rates remain very high in people with schizophrenia (SWS) (58%–88%).2,3 These high smoking rates in SWS patients may relate to cognitive deficits (i.e., attention, working memory, and impulsivity) that have been found to improve with nicotine use4 and worsen with tobacco abstinence.5,6 In addition to being more likely to smoke, SWS patients initiate smoking at a younger age, smoke more cigarettes per day, have a preference for cigarettes with higher tar content, are more nicotine dependent, and have higher expired breath carbon monoxide (CO) and nicotine levels in comparison to smokers without a psychiatric diagnosis.3,7 Once initially abstinent, they are also prone to rapid smoking relapse (i.e., 50% relapse after only 35 days of discontinuation of a pharmacotherapy).8 One large multisite clinical trial has shown that the nicotinic partial agonist, varenicline, can protect against smoking relapse after initial smoking abstinence.8 However, rates of relapse at 1-year follow-up were substantial. Accordingly, better treatments are needed to prevent smoking relapse in SWS.

Relapse is defined as the return to regular smoking for at least 7 consecutive days.9 One of the best predictors of relapse is the “first lapse” to smoking. That is, the first time an individual “gives up” and smokes a cigarette during a quit attempt. While the Evins et al8 study was a smoking relapse-prevention trial, no studies have been conducted to determine the effects of varenicline on smoking lapse behaviour. McKee et al10 developed a validated human laboratory model of smoking lapse behaviour. The first aspect of the model is the availability to smoke cigarettes, which is related to relapse. The second aspect is an alternative reinforcer, which provides an incentive for not smoking, is similar to real-life situations, and increases the likelihood that the relative reinforcing effect of the cigarette would be detected. Importantly, the model is sensitive to known precipitants of smoking relapse10 such as tobacco abstinence,11 stress,12 and alcohol,13 and to clinically effective tobacco pharmacotherapies including sustained-release bupropion and varenicline.10 Moreover, a recent meta-analysis found that varenicline has been largely and continuously supported as an efficacious and safe treatment for tobacco use disorder in SWS.14 The focus on abstinence outcome is critical for tobacco research, as obtaining Food and Drug Administration approval for cessation medications requires demonstrating effects on smoking abstinence; however, failure to assess smoking behaviour in laboratory models has been identified as a limitation.15

To address this research gap, we investigated the effects of varenicline in smokers with and without SWS using the McKee et al10 smoking lapse paradigm. The use of this human laboratory model may elucidate the potential mechanisms by which varenicline exerts its effects to prevent relapse in SWS versus controls. We hypothesized that SWS would have a reduced ability to resist smoking during the placebo condition compared to controls, and that varenicline would increase the ability to resist cigarette smoking in both smokers with and without SWS. As an exploratory hypothesis, we predicted this related to differences in smoking reinforcement, attenuation of abstinence induced cognitive deficits, withdrawal, craving, and smoking behaviours (i.e., smoking topography).

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Based on the effect of 2 mg/d varenicline on smoking lapse in the McKee et al10 study, estimates from Cohen for a two-tailed comparison indicated a sample of n = 25 smokers in each diagnostic group would be able to detect an effect of medication (between effect with 99% power; within effect with 96%) and a medication by diagnosis interaction with 80% power. To this end, 18 outpatients with DSM-IV SWS or schizoaffective disorder and 15 nonpsychiatric control participants using the Structured Clinical Interview for the DSM-IV-TR (SCID-I/P),16 between the ages of 18 and 55 were recruited. Written informed consent (REB#225-2012) was obtained from all participants as approved by the Research Ethics Board at the Centre for Addiction and Mental Health and were compensated for their participation. All participants underwent a 2-day screening procedure to determine eligibility, including a physical and psychiatric examination with a registered nurse (ES) or physician (TPG). All participants were nontreatment seeking (i.e., not trying to quit as indicated by scores <7 on the Contemplation Ladder,17 smoked ≥10 cigarettes per day, had expired CO ≥ 10 ppm, Fagerström Test of Nicotine Dependence score ≥4,18 and an Intelligence quotient (IQ) ≥ 80 on the Wechsler Test of Adult Reading).19 Patients were receiving a stable dose of antipsychotics for at least a month and were clinically stable (total score <70 on the Positive and Negative Syndrome Scale).20 Control participants receiving psychotropic medications at the time of enrolment or who met diagnostic criteria for any Axis I disorder (except history of major depression or anxiety disorder if in remission for at least 1 yr) were excluded. Exclusion criteria for both groups included: substance use (except nicotine or caffeine) in the past month, history of alcohol/drug abuse 3 months before study enrolment, current use of smoking cessation aids (i.e., nicotine replacement therapy, bupropion sustained-release, or varenicline), pregnancy or nursing, history of renal insufficiency, hypersensitivity to varenicline, and history of neurological or medical conditions known to significantly influence cognitive function.

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Study medication

Varenicline was administered using a randomized, counter-balanced, placebo-controlled, double-blind cross-over experimental design (Fig. 1). Participants received placebo or varenicline over the course of 2 distinct test weeks, separated by a 1-week wash-out period. Capsules composed only of lactose monohydrate were recompounded by Centre for Addiction and Mental Health Pharmacy and matching placebo capsules were produced. Based on the typical prequit pretreatment period used in clinical practice, varenicline was titrated to steady-state levels of 2 mg/d over 4 days (0.5 mg BID for day 1 and 1.0 mg BID for days 2–4) before craving and withdrawal were assessed on day 5 (satiated state, i.e., ad lib smoking) and day 6 (abstinent state).10 Medication compliance was assessed by pill counts and adverse events were assessed using the Systematic Assessment for Treatment Emergent Events.21

Figure 1

Figure 1

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Smoking measures

Daily smoking was assessed using self-report timeline follow back methods.22 The Tiffany Questionnaire for Smoking Urges (TQSU)23 was used to evaluate cravings in response to positive affect related to expectancy of reinforcement (Factor 1) and negative affect related to relief of nicotine withdrawal (Factor 2). The Minnesota Nicotine Withdrawal Scale (MNWS),24 an 8-item self-report questionnaire was used to assess nicotine withdrawal symptoms (i.e., nicotine craving, irritability, anxiety, difficulty concentrating, restlessness, increased appetite or weight gain, depressed mood, and insomnia). The internal consistency and test-retest reliability of the MNWS and TQSU in SWS and control smokers are comparable.25

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Smoking topography

Smoking topography of the favoured cigarette brand of individual participants was assessed using the Clinical Research Support System (CReSS; Borgwaldt KC, Richmond, VA) in a dedicated reverse airflow room with external ventilation of expired cigarette smoke. Smoking topography was assessed at baseline, smoking satiation (day 5) and in the smoking lapse period (day 6). We used a similar paradigm to that employed in our previous studies at Yale University.26 Briefly, cigarettes were smoked through a plastic mouthpiece connected by tubing to an analog–digital converter. The CReSS system calculated and stored a number of measures including average puff volume, average interpuff interval, and average puff duration.

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Smoking lapse paradigm

At the end of day 5, participants were asked to refrain from smoking for ∼16 hours before their day 6 assessment. Most SWS relapse within 24 hours of initiating abstinence thus we used 16-hour abstinence and that time is both time and resource efficient (our previous studies demonstrated optimal retention of participants; ∼95%).4,27 On day 6, abstinence was biochemically verified by expired CO levels <10 ppm. The smoking lapse procedure took place in a reverse airflow smoking room where participants were exposed to their preferred brand of cigarettes with a lighter and ashtray. Participants had the option to initiate a tobacco self-administration session or to delay initiation for up to 50 minutes in exchange for monetary reinforcement. A fixed level of monetary reinforcement ($1) was provided for each 5-minute increment that they could resist smoking during the delay period. After the 50-minute delay or once participants indicated a preference to smoke over waiting for the 50 minutes to elapse, a 60-minute tobacco self-administration session was initiated. During this ad lib phase, participants could choose to smoke up to 8 of their preferred brand of cigarettes or receive monetary reinforcement for cigarettes not smoked in the form of a $4 “smoking tab” from which $0.50 was taken for each cigarette lit.10 The lapse behaviour outcomes were (1) the length of the delay period (i.e. ability to resist smoking), and (2) the number of cigarettes smoked during the ad lib smoking period.28

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Neuropsychological assessments

A cognitive battery was administered at the training session and was repeated twice in each treatment week (day 5 satiated; day 6 abstinent). The Spatial Delay Response (SDR) task is an index visuospatial working memory29 and previously described.30 The Continuous Performance Test (CPT-X) and Kirby Delay Discounting Task are an index of sustained attention and impulsivity, respectively, and both been described previously.6 The Balloon Analogue Risk Task (BART) models real-world risk behaviour through the conceptual frame of balancing the potential for reward versus loss.

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Statistical analyses

Demographic and clinical data between diagnostic groups were analyzed using independent t tests, Chi-square or Fisher Exact tests as appropriate. The primary outcome measures in this study was the time to lapse (i.e., ability to resist smoking during a 0–3000 s time period). In light of the distribution of the dependent variable (time to lapse; data not shown) with high skewness and kurtosis, we used dichotomous outcomes as the majority of participants lapsed [both immediate lapsers, i.e., 0 s (23.21%) and delayed lapsers (55.36%)] or did not lapse at all (44.64%). A logistic regression was conducted with diagnosis (SWS vs controls) and medication group (varenicline vs placebo) as predictors of time to lapse. Odds ratio were converted to Cohen's d. Individuals were classified in high versus low dependent groups based on Fagerström Test for Nicotine Dependence (FTND) ≥ 6 from baseline.31 A 2 (diagnosis) × 2 (treatment group) analysis of variance (ANOVA) was also used to determine differences on time to lapse.

As an exploratory analysis, we determined effects of varenicline versus placebo on cognitive outcomes (SDR; CPT-X; BART), MNWS total score (withdrawal), and TQSU Factors 1 and 2 scores (craving). This was completed using 2 (SWS/control) × 2 (varenicline/placebo) × 2 (day 5 satiated; day 6 abstinent) mixed ANOVA, with diagnosis and treatment groups as the between-subject factors and time as the within-subject factor. We investigated whether baseline cognitive performance in both diagnostic groups would correlate with time to lapse in either treatment group, using Pearson's product-moment correlations. We also assessed topographical outcomes considering reinforcement (i.e., average smoking puff volume; average interpuff intervals) on day 5 (satiated) using 2 (diagnosis) by 2 (treatment) ANOVAs. Differences were considered significant at P < 0.05.

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Participant demographics

In total, fourteen participants per diagnostic group successfully completed the study. Participants were well matched on all demographic characteristics, with the exception of current IQ scores on the Shipley (Table 1). The diagnostic groups were comparable on most baseline measures and displayed high levels of nicotine dependence (∼6.5), smoking about 1 pack/d for ∼20 years.

Table 1

Table 1

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Varenicline versus placebo effects on time to lapse

A 2 (diagnosis) × 2 (treatment group) ANOVA demonstrated no significant differences on time to lapse [F(1,52) = 0.008, P = 0.93] (Fig. 2); this indicated not enough evidence to supporting the hypothesis. Calculation of effect sizes (Cohen's d) suggested small effects in both patient (d = 0.35) and control (d = 0.28) smokers in the total sample. However, when only heavy nicotine dependent (FTND ≥ 6) smokers with (n = 11) and without SWS (n = 9) were included in the analysis (Fig. 3), there were more pronounced effects of varenicline versus placebo in SWS (Cohen's d = 0.47) versus control (Cohen's d = 0.24) smokers. However, the diagnosis by treatment group interaction was not significant [F(1,36) = 0.074, P = 0.79].

Figure 2

Figure 2

Figure 3

Figure 3

A logistic regression was performed to ascertain the effects of diagnosis and medication group on the likelihood of lapse. In the low dependent group (FTND < 6), there was a medium effect of treatment × diagnosis (d = 0.67), and a large effect of diagnosis (d = 0.83) and treatment (d = 1.21). In the high dependent group (FTND ≥ 6), there were small effects of treatment × diagnosis (d = 0.09), and treatment (d = 0.22) and medium effect of diagnosis (d = 0.47). However, none of these effects were significant (P > 0.05), therefore indicating neither diagnosis nor treatment predict time to lapse. Based on prior research we also examined dependence level as a moderator (e.g., third factor), and these effects were also nonsignificant (data not shown). As such, our negative findings indicate a lack of evidence for our prediction that SWS would have a reduced ability to resist smoking during the placebo condition compared to controls, and that varenicline would increase the ability to resist cigarette smoking in both diagnostic groups.

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Varenicline versus placebo effects on cognitive functions

In an exploratory analysis, no baseline cognitive differences were found between the diagnostic groups across all neuropsychological assessments (P > 0.05; data not shown). Two (diagnosis) × 2 (treatment) × 2 (time) mixed ANOVAs indicated a significant effect of diagnosis for the 30-second delay period (P = 0.038) on visuospatial working memory, and CPT % Hits and % Omission (P = 0.035) regardless of treatment group within time. No significant treatment or diagnosis × treatment interaction was found on SDR, CPT subset variables, and BART within time (Table 2). Order of varenicline dose did not significantly alter cognition in either group (data not shown).

Table 2

Table 2

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Correlations of baseline cognitive deficits with smoking relapse

We found that increased/slower-hit rate (milliseconds, ms), which is indicative of inattentiveness (especially when error rates are high), was significantly correlated with decreased time to lapse in controls during the placebo treatment week (r = −0.622, n = 14, P = 0.018). Larger Kirby Delay Discounting Task medium scores, which are indicative of greater impulsivity for medium monetary rewards, demonstrated trend level associations with decreased time to lapse in controls during the placebo treatment week (r = −0.465, n = 14, P = 0.094). Interestingly, larger average number of pumps in BART, which are indicative of greater risk-taking tendency, showed trend level associations with increased time to lapse in controls during the placebo treatment week (r = 0.503, n = 14, P = 0.067). All other cognitive deficits were nonsignificant within both diagnostic and treatment groups.

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Varenicline versus placebo effects on withdrawal and craving

A 2 (diagnosis) × 2 (treatment) × 2 (time) mixed ANOVA on the MNWS total score found no significant diagnosis [F(1,52) = 2.806, P = 0.100], treatment [F(1,52) = 1.101, P = 0.299], or diagnosis × treatment interactions [F(1,52) = 0.627, P = 0.432] within the satiation and abstinence period.

There were no significant diagnosis [F(1,50) = 0.102, P = 0.751; F(1,50) = 0.766, P = 0.386], treatment [F(1,50) = 0.107, P = 0.745; F(1,50) = 0.841, P = 0.363], or diagnosis × treatment interactions [F(1,50) = 0.206, P = 0.652; F(1,50) = 1.288, P = 0.262] on positive affect related to expectancy of reinforcement (TQSU Factor 1) and negative affect related to relief of nicotine withdrawal (TQSU Factor 2), respectively, across time. Order of varenicline dose did not significantly alter cognition in either group (data not shown).

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Varenicline versus placebo effects on smoking topography measures

There were no baseline diagnostic differences in topographical outcomes (i.e., average puff volume, average interpuff intervals, and average puff duration) (P > 0.05, data not shown). A total of n = 11 SWS and n = 10 control smokers completed all topographical assessments. There were no significant diagnosis [F(1,38) = 0.635, P = 0.43], treatment [F(1,38) = 0.544, P = 0.47], or diagnosis × treatment [F(1,38) = 0.090, P = 0.77] interactions on average puff volume (mL). There were no significant diagnosis [F(1,38) = 0.047, P = 0.83], treatment [F(1,38) = 0.247, P = 0.62], or diagnosis × treatment [F(1,38) = 0.074, P = 0.79] interactions on average puff duration. Interestingly, there was a trend for a diagnosis effect [F(1,38) = 3.814, P = 0.06] on average interpuff interval (seconds) regardless of treatment group, and no significant treatment [F(1,38) = 0.001, P = 0.974] or diagnosis × treatment [F(1,38) = 0.007, P = 0.935] interactions (SWS mean = 16.27; controls mean = 23.98). Notably, the descriptive data showed that SWS had shorter interpuff intervals.

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Tobacco SWS have a higher smoking prevalence (58%–88%) than the general population (∼18%), and lower rates of smoking cessation.28,32–34 After achievement of initial abstinence, SWS are known to relapse rapidly.3,8 However, the determinants for tobacco smoking relapse in SWS compared to controls have not been well established. The nicotinic partial agonist, varenicline, may prevent smoking relapse in SWS and other smokers with serious mental illness.8 The present study sought to determine the effects of varenicline at an optimal clinical dose (2.0 mg/d × 7 d of treatment) compared to placebo, using a validated model of smoking lapse10 in SWS versus nonpsychiatric control smokers.

The results of this preliminary human laboratory study suggested that while varenicline tended to increase the ability of SWS to resist smoking lapse, the clinical effects are modest (Cohen's d = 0.35), but comparable to the magnitude of effects observed in control smokers (Cohen's d = 0.28). The level of nicotine dependence in our study groups was very high (FTND ∼ 6.6–6.9). As such, the effects of varenicline on prolonging time to smoking relapse appeared to be more robust in more highly dependent SWS (FTND ≥ 6; d = 0.47) versus controls (d = 0.24); Figure 3. However, given the small subsamples (SWS = 11; controls = 9), these results should be considered preliminary and replicated in larger samples. This finding however is of great importance, given that SWS are a group of “hardcore” smokers for which current smoking cessation strategies have limited efficacy.

The results of this study also found no effects of varenicline compared to placebo on cognitive outcomes across time (satiated and abstinent) in either diagnostic group. This is in contrast to the predicted abstinence induced impairment in cognition in SWS,5 and previous studies indicating the prevention of cognitive impairment during abstinence in SWS by varenicline.35,36 Moreover, we found no differences of medication on craving or withdrawal in either diagnostic group across time. However, given there were no baseline cognitive differences between SWS and controls, and that we found that baseline deficits in controls in the placebo week correlated with time to lapse, perhaps our SWS sample was a more high-functioning subgroup. This may also demonstrate the procognitive effects of nicotine greatly supported in the literature.37,38

We found no significant treatment effects on smoking topographic outcomes across the diagnostic groups. However, our trend (P < 0.06) toward shorter inter puff intervals in SWS regardless of treatment week, is in line with current research suggesting higher levels smoking reinforcement in people with SWS.26,39 Several studies have found that SWS smoke more intensely than nonpsychiatric smokers (i.e., group differences on interpuff intervals specifically).39–43 Given our small sample size, a greater difference may have been required in order to observe any treatment effects on time to lapse and topographic outcomes between the diagnostic groups.

Results of this study should be interpreted in light of several limitations. The study sample and subsample (more highly nicotine dependent FTND ≥ 6) were modest, thus these results should be considered preliminary. Moreover, our small sample size (n = 14 SWS; n = 14 controls) recruited was lower than our calculated power, thus was a major limitation in detecting statistically significant findings. Second, only nontreatment seeking smokers were recruited, which may contributed to the reduced efficacy of varenicline in preventing smoking lapse.44 Third, we did not have a full reinstatement period for smoking but rather a set time to smoke between 0 and 50 minutes (i.e., the smoking lapse paradigm) that was highly variable across smokers in both diagnostic groups. This restricted lapse period may have contributed to the lacking sensitivity of detecting a lapse in smokers with SWS in an ad lib phase; future studies may consider replicating this design with longer duration lapse periods. Moreover, the brief duration of varenicline treatment (7 d) may limited its overall efficacy in this paradigm in smokers with SWS.45 Fourthly, topographical data on the abstinence day (day 6) was not reliable, and was not used when comparing the treatment effects between diagnostic groups (only day 5, satiated was used). A more robust approach, which would consider this discrepancy across smokers, may be applicable to observe smoking behaviours affected by this validated model of smoking lapse behaviours. For example, McKee's laboratory at Yale26 used a reinstatement period for smoking topography reinforcement measures, which showed increased smoking intensity (i.e., increased average puff volume, puff duration, and peak puff volume) in SWS in the mecamylamine pretreatment compared to placebo, while no such changes were found in controls. Therefore, perhaps using a similar design of a reinstatement period after the lapse paradigm in SWS may lead to a better understand the effects of varenicline on smoking behaviours. Finally, no baseline differences were found on cognitive outcomes between the diagnostic groups, which may have ultimately limited the procognitive effects of varenicline as well as the severity of SWS to relapse.

In conclusion, there were modest effects of varenicline on time to lapse in both SWS and control smokers, with comparable effects on reinforcement, craving, or cognition compared to placebo. When examining the more highly dependent smokers, our findings supported a relapse prevention effect of varenicline, which may suggests varenicline's ability to reduce rewarding effects of smoking during abstinence lapses (i.e., Evins et al8). As such, larger, longitudinal studies of varenicline on cognition in SWS are warranted. Furthermore, given the relatively small effect sizes, which were moderated by nicotine dependence levels, augmentation of varenicline effects with combined novel therapeutics are warranted.

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TPG reports that he has funding support from the Canadian Institutes of Health Research (CIHR) and Pfizer, and is a consultant to Novartis and compensated for scientific roles at the Canadian Centre for Substance Use and Addiction (CCSUA) and The American College of Neuropsychopharmacology (Deputy Editor, Neuropsychopharmacology). KK, SSD, MS-R, ASC, MM, VCW, and SAM report no conflicts of interest. The authors alone are responsible for the content and writing of this paper.

This study was support by a 2012 Pfizer GRAND Award (to TPG), the Chair in Addiction Psychiatry at the University of Toronto (to TPG) and Canadian Institutes of Health Research (CIHR) grant MOP#115145 (to TPG). We thank Ms. Emily Simpkin, R.N. for providing medical support to this clinical study.

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1. George TP. Goldstein L, Schafer A. Nicotine and tobacco (Chapter 32). Cecil Medicine Elsevier, 25th edNew York, NY:2015.
2. Kalman D, Morrisette SB, George TP. Co-morbidity of smoking in psychiatric and substance use disorders. Am J Addict 2005; 14:106–123.
3. Tidey JW, Miller ME. Smoking cessation and reduction in people with chronic mental illness. Br Med J 2015; 351:h4065.
4. Sacco KA, Termine A, Seyal A, et al. Effects of cigarette smoking on spatial working memory and attentional deficits in schizophrenia: involvement of nicotinic receptor mechanisms. Arch Gen Psychiatry 2005; 62:649–659.
5. George TP, Vessicchio JC, Termine A, et al. Effects of smoking abstinence on visuospatial working memory function in schizophrenia. Neuropsychopharmacology 2002; 26:75–85.
6. Wing VC, Wass CE, Bacher I, et al. Varenicline modulates spatial working memory deficits in smokers with schizophrenia. Schizophr Res 2013; 149:190–191.
7. Mackowick KM, Lynch MJ, Weinberger AH, et al. Treatment of tobacco dependence in people with mental health and addictive disorders. Curr Psychiat Rep 2012; 14:478–485.
8. Evins A, Cather C, Pratt SA, et al. Maintenance treatment with varenicline for smoking cessation in patients with schizophrenia and bipolar disorder a randomized clinical trial. JAMA 2014; 311:145–154.
9. Hughes JR, Peters EN, Naud S. Relapse to smoking after 1 year of abstinence: a meta-analysis. Addict Behav 2008; 33:1516–1520.
10. McKee S, Weinberger AH, Shi J, et al. Developing and validating a human laboratory model to screen medications for smoking cessation. Nicotine Tob Res 2012; 14:1362–1371.
11. Leeman RF, O’Malley SS, White MA, et al. Nicotine and food deprivation decrease the ability to resist smoking. Psychopharmacology 2010; 212:25–32.
12. McKee SA, Sinha R, Weinberger AH, et al. Stress decreases the ability to resist smoking and potentiates smoking intensity and reward. J Psychopharmacol 2011; 25:490–502.
13. Kahler CW, Metrik J, Spillane NS, et al. Acute effects of low and high dose alcohol on smoking lapse behavior in a laboratory analogue task. Psychopharmacology 2014; 231:4649–4657.
14. Ahmed S, Virani S, Kotapati VP, et al. Efficacy and safety of varenicline for smoking cessation in schizophrenia: a meta-analysis. Front Psychiatry 2018; 9:428.
15. Perkins KA, Lerman C. Early human screening of medications to treat drug addiction: novel paradigms and the relevance of pharmacogenetics. Clin Pharmacol Therap 2001; 89:460–463.
16. First MB, Spitzer RI, Gibbon M, et al. Structured Clinical Interview for DSM-IV Axis I Disorders. New York, NY:Biometrics Research. New York State Psychiatric Institute; 1996.
17. Biener L, Abrams DB. The contemplation ladder: validation of a measure of readiness to consider smoking cessation. Health Psychol 1991; 10:360–365.
18. Heatherton TF, Kozlowski LT, Frecker RC, et al. The Fagerstrom Test for nicotine dependence: a revision of the Fagerstrom Tolerance Questionnaire. Br J Addict 1991; 86:1119–1127.
19. Wechsler D. Wechsler Test of Adult Reading (WTAR). San Antonio, TX:The Psychological Corporation; 2001.
20. Kay SR, Fiszbein A, Opler LA. The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophr Bull 1987; 13:261–276.
21. Levine J, Schooler NR. General versus specific inquiry with SAFTEE. J Clin Psychoparmacol 1992; 12:3–10.
22. Sobell LC, Sobell MB, Leo GI, et al. Reliability of a timeline method: assessing normal drinkers′ reports of recent drinking and a comparative evaluation across several populations. Br J Addict 1988; 83:393–402.
23. Tiffany ST, Drobes DJ. The development and initial validation of a questionnaire on smoking urges. Addiction 1991; 86:1467–1476.
24. Hughes JR, Hatsukami DK. Signs and symptoms of tobacco withdrawal. Arch Gen Psychiatry 1986; 43:289–294.
25. Weinberger AH, Reutenauer EL, Allen TM, et al. Reliability of the Fagerstr[Combining Diaeresis]om test for nicotine dependence, Minnesota Nicotine Withdrawal Scale, and Tiffany Questionnaire for Smoking Urges in smokers with and without schizophrenia. Drug Alcohol Depend 2007; 86:278–282.
26. McKee SA, Weinberger AH, Harrison EL, et al. Effects of the nicotinic receptor antagonist mecamylamine on ad-lib smoking behavior, topography, and nicotine levels in smokers with and without schizophrenia: a preliminary study. Schizophr Res 2009; 115:317–324.
27. Weinberger AH, Sacco KA, Creeden CL, et al. Effects of acute abstinence, reinstatement, and mecamylamine on biochemical and behavioral measures of cigarette smoking in schizophrenia. Schizophr Res 2007; 91:217–225.
28. Evins AECC, Culhane MA, Birnbaum A, et al. 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. J Cin Psychopharmacol 2007; 27:380–386.
29. Hershey T, Craft S, Glauser TA, et al. Short-term and long-term memory in early temporal lobe dysfunction. Neuropsychology 1998; 12:52–64.
30. Kozak K, Dermody SS, Rabin RA, et al. Effects of varenicline on cognitive function in non-smokers with schizophrenia. Schizophr Res 2017; pii: S0920-9964(17)30143-3. [Epub ahead of print].
31. Perez-Rios M, Santiago-Perez MI, Alonso B, et al. Fagerstrom test for nicotine dependence vs heavy smoking index in a general population survey. BMC public health 2009; 9:493.
32. George TP, Vessicchio JC, Termine A, et al. A placebo controlled trial of bupropion for smoking cessation in schizophrenia. Biol Psychiatry 2002; 52:53–61.
33. George TP, Vessicchio JC, Sacco KA, et al. A placebo-controlled trial of bupropion combined with nicotine patch for smoking cessation in schizophrenia. Biol Psychiatry 2008; 63:1092–1096.
34. Williams JM, Anthenelli RM, Morris CD, et al. A randomized, double-blind, placebo-controlled study evaluating the safety and efficacy of varenicline for smoking cessation in patients with schizophrenia or schizoaffective disorder. J Clin Psychiatry 2012; 73:654–660.
35. Smith RC, Lindenmayer JP, Davis JM, et al. Cognitive and antismoking effects of varenicline in patients with schizophrenia or schizoaffective disorder. Schizophr Res 2009; 110:149–155.
36. Liu ME, Tsai SJ, Jeang SY, et al. Varenicline prevents affective and cognitive exacerbation during smoking abstinence in male patients with schizophrenia. Psychiatry Res 2011; 190:79–84.
37. Sacco KA, Bannon KL, George TP. Nicotinic receptor mechanisms and cognition in normal states and neuropsychiatric disorders. J Psychopharmacol 2004; 18:457–474.
38. D'Souza MS, Markou A. Schizophrenia and tobacco smoking comorbidity: nAChR agonists in the treatment of schizophrenia-associated cognitive deficits. Neuropharmacology 2012; 62:1564–1573.
39. Tidey JW, Rohsenow DJ, Kaplan GB, et al. Cigarette smoking topography in smokers with schizophrenia and matched non-psychiatric controls. Drug Alcohol Depend 2005; 80:259–265.
40. Tidey JW, Rohsenow DJ, Kaplan GB, et al. Effects of smoking abstinence, smoking cues and nicotine replacement in smokers with schizophrenia and controls. Nicotine Tob Res 2008; 10:1047–1056.
41. Williams JM, Ziedonis DM, Abanyie F, et al. Increased nicotine and cotinine levels in smokers with schizophrenia and schizoaffective disorder is not a metabolic effect. Schizophr Res 2005; 79:323–335.
42. Williams JM, Gandhi KK, Lu SE, et al. Shorter interpuff interval is associated with higher nicotine intake in smokers with schizophrenia. Drug Alcohol Depend 2011; 118:313–319.
43. Tidey JW, Colby SM, Xavier EM. Effects of smoking abstinence on cigarette craving, nicotine withdrawal, and nicotine reinforcement in smokers with and without schizophrenia. Nicotine Tob Res 2014; 16:326–334.
44. Perkins KA, Lerman C. An efficient early phase 2 procedure to screen medications for efficacy in smoking cessation. Psychopharmacology 2014; 231:1–11.
45. Annamalai A, Singh N, O’Malley SS. Smoking use and cessation among people with serious mental illness. Yale J Biol Med 2015; 88:271–277.

human laboratory study; nicotine; nicotinic acetylcholine receptor; schizophrenia; smoking lapse; tobacco use disorder; varenicline; Mots clés; étude en laboratoire chez l’humain; nicotine; récepteur de l’acétylcholine nicotinique; rechute au tabagisme; schizophrénie; trouble lié à l’usage du tabac; varénicline

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