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.
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).
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.
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).
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.
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.
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.
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
3. Tidey JW, Miller ME. Smoking cessation and reduction in people with chronic mental illness. Br Med J
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
5. George TP, Vessicchio JC, Termine A, et al. Effects of smoking abstinence on visuospatial working memory function in schizophrenia
6. Wing VC, Wass CE, Bacher I, et al. Varenicline
modulates spatial working memory deficits in smokers with schizophrenia
. Schizophr Res
7. Mackowick KM, Lynch MJ, Weinberger AH, et al. Treatment of tobacco dependence in people with mental health and addictive disorders. Curr Psychiat Rep
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
9. Hughes JR, Peters EN, Naud S. Relapse to smoking after 1 year of abstinence: a meta-analysis. Addict Behav
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
11. Leeman RF, O’Malley SS, White MA, et al. Nicotine
and food deprivation decrease the ability to resist smoking. Psychopharmacology
12. McKee SA, Sinha R, Weinberger AH, et al. Stress decreases the ability to resist smoking and potentiates smoking intensity and reward. J Psychopharmacol
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
14. Ahmed S, Virani S, Kotapati VP, et al. Efficacy and safety of varenicline
for smoking cessation in schizophrenia
: a meta-analysis. Front Psychiatry
15. Perkins KA, Lerman C. Early human screening of medications to treat drug addiction: novel paradigms and the relevance of pharmacogenetics. Clin Pharmacol Therap
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
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
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
21. Levine J, Schooler NR. General versus specific inquiry with SAFTEE. J Clin Psychoparmacol
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
23. Tiffany ST, Drobes DJ. The development and initial validation of a questionnaire on smoking urges. Addiction
24. Hughes JR, Hatsukami DK. Signs and symptoms of tobacco withdrawal. Arch Gen Psychiatry
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
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
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
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
29. Hershey T, Craft S, Glauser TA, et al. Short-term and long-term memory in early temporal lobe dysfunction. Neuropsychology
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
32. George TP, Vessicchio JC, Termine A, et al. A placebo controlled trial of bupropion for smoking cessation in schizophrenia
. Biol Psychiatry
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
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
35. Smith RC, Lindenmayer JP, Davis JM, et al. Cognitive and antismoking effects of varenicline
in patients with schizophrenia
or schizoaffective disorder. Schizophr Res
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
37. Sacco KA, Bannon KL, George TP. Nicotinic receptor mechanisms and cognition in normal states and neuropsychiatric disorders. J Psychopharmacol
38. D'Souza MS, Markou A. Schizophrenia
and tobacco smoking comorbidity: nAChR agonists in the treatment of schizophrenia
-associated cognitive deficits. Neuropharmacology
39. Tidey JW, Rohsenow DJ, Kaplan GB, et al. Cigarette smoking topography in smokers with schizophrenia
and matched non-psychiatric controls. Drug Alcohol Depend
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
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
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
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
44. Perkins KA, Lerman C. An efficient early phase 2 procedure to screen medications for efficacy in smoking cessation. Psychopharmacology
45. Annamalai A, Singh N, O’Malley SS. Smoking use and cessation among people with serious mental illness. Yale J Biol Med
Keywords:© 2019 by Lippincott Williams & Wilkins, Inc.
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