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Effects of varenicline on cognitive function in non-smokers with schizophrenia
SCHRES-07216; No of Pages 2 Schizophrenia Research xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Schizophrenia Research journal homepage: www.elsevier.com/locate/schres
Letter to the Editor Effects of varenicline on cognitive function in non-smokers with schizophrenia Keywords: Schizophrenia Non-smokers Varenicline Cognition Visuospatial working memory
Dear Editor, Schizophrenia (SZ) is associated with cognitive deficits and higher rates of tobacco smoking (72–90%) compared to the general population (~ 16%) that are linked to dysregulated nicotinic acetylcholine receptors (nAChR) (Wing et al., 2012). Moreover, smoking may improve (Sacco et al., 2005) while tobacco abstinence worsens cognition (George et al., 2002; Wing et al., 2013) in SZ. Thus, nAChR-based treatments remediating cognitive deficits are warranted. Varenicline, a nAChR partial agonist, is the most effective smoking cessation medication in SZ (Pachas et al., 2012; Williams et al., 2012), and may have pro-cognitive effects (Wing et al., 2013). Given that most studies have been conducted in smokers, the effects of varenicline on cognition may relate to withdrawal symptom reversal. Studies in non-smokers may avoid confounding effects of nicotine withdrawal on cognition. The results of these studies have been mixed (Hong et al., 2011; Shim et al., 2012; Roh et al., 2014). We evaluated the effects of varenicline on cognition in nonsmokers with and without SZ. A randomized, double-blind, placebo-controlled, cross-over laboratory study design was employed. Varenicline (0, 0.5 or 1 mg twice daily × 3 days) was administered in a counterbalanced manner across participants over 3 consecutive study weeks with a 1-week washout period between dose weeks in non-smoking SZ (n = 15) and non-psychiatric controls (n = 15). Weekly testing included three cognitive testing sessions (day 2 morning, day 3 morning, day 3 afternoon (day 3 PM)). Non-smoking status was verified by plasma cotinine (b15 ng/ml) and expired breath carbon monoxide level b 10 ppm. Varenicline plasma levels were collected on day 3 PM and effects on cognitive outcomes were evaluated. Plasma varenicline, and nicotine/cotinine levels were analyzed by liquid chromatography/mass spectroscopy (Tanner et al., 2015). Our primary outcome was visuospatial working memory (VSWM) as measured using the spatial delay recall task (Hershey et al., 1998), while secondary analyses examined relationships between varenicline plasma levels and other cognitive measures. Thirty participants (15 SZ, 15 controls) completed the protocol. Significantly lower Shipley IQ scores were found in SZ versus controls (p = 0.011). At baseline, controls performed better in VSWM, verbal memory and executive function than SZ (p b 0.05); a consistent main effect of diagnosis during dose weeks on the cognitive battery outcomes was also
found. Two-way ANOVAs demonstrated no main effects of varenicline dose or diagnosis × dose interactions on cognitive performance in either SZ non-smokers or controls (p N 0.05); similar results were observed using Principal Components Analysis (PCA) where a three-component solution was retained: general cognitive functioning (Factor 1), working memory and executive functioning (Factor 2) and sustained attention (Factor 3). There were no changes in clinical and psychiatric symptoms in both groups. Preliminary results in a subsample suggested improved cognitive function with lower varenicline plasma levels in patients, and with higher varenicline plasma levels in controls, at 2.0 mg/day. Correlation analyses between plasma varenicline and VSWM performance revealed trends for improved VSWM performance with increased plasma levels among SZ non-smokers in the low dose condition (p b 0.08; Fig. 1A). For controls, plasma levels were positively related to VSWM (p = 0.013; Fig. 1B), verbal memory (p = 0.005) and Factor 1 (p = 0.025) in the high dose condition. Study limitations included failure to achieve steady state levels of varenicline over the 3-day dosing paradigm that is typically titrated over a one-week period (Faessel et al., 2010). Both diagnostic groups had lower plasma levels than expected in low dose and substantial variance within high dose varenicline. Moreover, VSWM deficits in patients were modest, which may have reduced varenicline responses. Finally, the study sample and subsample was small. This study provides evidence for complex effects of varenicline on cognition in SZ and control individuals under non-smoking conditions. Larger studies with longer duration of varenicline treatment are warranted to establish the relationships between varenicline plasma levels and cognition in non-smokers with and without SZ.
Declaration of funding source • Investigator-Initiated Pfizer, Inc. Grant (WI171136) • Canadian Institutes of Health Research Operating Grant (MOP#115145)
Declaration of conflicts Dr. George reports that he has funding support from the Canadian Institutes of Health Research (CIHR) and Pfizer, and is a consultant to Novartis. Ms. Kozak, Dr. Dermody, Dr. Tyndale, Dr. Zack, and Dr. Barr report no conflicts of interest. The authors alone are responsible for the content and writing of this paper.
Acknowledgements This study was support by an Institute of Medical Sciences Graduate Fellowship from the University of Toronto (to Ms. Kozak), an investigator-initiated grant from Pfizer, Inc. (WI171136) and CIHR Operating Grant MOP#115145 (to Dr. George).
Appendix A. Supplementary data Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.schres.2017.03.023.
http://dx.doi.org/10.1016/j.schres.2017.03.023 0920-9964/© 2017 Published by Elsevier B.V.
Please cite this article as: Kozak, K., et al., Effects of varenicline on cognitive function in non-smokers with schizophrenia, Schizophr. Res. (2017), http://dx.doi.org/10.1016/j.schres.2017.03.023
2
Letter to the Editor
Karolina Kozak Institute of Medical Sciences (IMS), University of Toronto, Toronto, Ontario, Canada Addictions Division, Centre for Addiction and Mental Health (CAMH), Toronto, Ontario, Canada Corresponding author at: Addictions Division, Centre for Addiction and Mental Health (CAMH), Biobehavioural Addictions and Concurrent Disorders Research Laboratory (BACDRL), 33 Russell Street, Room 1120, Toronto, ON M5S 2S1, Canada. E-mail address: [email protected]. Sarah S. Dermody Addictions Division, Centre for Addiction and Mental Health (CAMH), Toronto, Ontario, Canada Rachel A. Rabin Institute of Medical Sciences (IMS), University of Toronto, Toronto, Ontario, Canada Addictions Division, Centre for Addiction and Mental Health (CAMH), Toronto, Ontario, Canada
Fig. 1. Varenicline plasma levels and VSWM performance. Bivariate correlations with outcomes parsed by varenicline plasma and diagnosis; SZ patients (Panel 1A) controls (Panel 1B).
References Faessel, H.M., Obach, R.S., Rollema, H., Ravva, P., Williams, K.E., Burstein, A.H., 2010. A review of the clinical pharmacokinetics and pharmacodynamics of varenicline for smoking cessation. Clin. Pharmacokinet. 49 (12), 799–816. George, T.P., Vessicchio, J.C., Termine, A., Sahady, D.M., Head, C.A., Pepper, W.T., Kosten, T.R., Wexler, B.E., 2002. Effects of smoking abstinence on visuospatial working memory function in schizophrenia. Neuropsychopharmacology 26 (1), 75–85. Hershey, T., Craft, S., Glauser, T.A., Hale, S., 1998. Short-term and long-term memory in early temporal lobe dysfunction. Neuropsychology 12 (1), 52–64. Hong, L.E., Thaker, G.K., McMahon, R.P., Summerfelt, A., Rachbeisel, J., Fuller, R.L., Wonodi, I., Buchanan, R.W., Myers, C., Heishman, S.J., Yang, J., Nye, A., 2011. Effects of moderate-dose treatment with varenicline on neurobiological and cognitive biomarkers in smokers and nonsmokers with schizophrenia or schizoaffective disorder. Arch. Gen. Psychiatry 68 (12), 1195–1206. Pachas, G.N., Cather, C., Pratt, S.A., Hoeppner, B., Nino, J., Carlini, S.V., Achtyes, E.D., Lando, H., Mueser, K.T., Rigotti, N.A., Goff, D.C., Evins, A.E., 2012. Varenicline for smoking cessation in schizophrenia: safety and effectiveness in a 12-week, open-label trial. J. Dual Diagn. 8 (2), 117–125. Roh, S., Hoeppner, S.S., Schoenfeld, D., Fullerton, C.A., Stoeckel, L.E., Evins, A.E., 2014. Acute effects of mecamylamine and varenicline on cognitive performance in non-smokers with and without schizophrenia. Psychopharmacology 231 (4), 765–775. Sacco, K.A., Termine, A., Seyal, A., Dudas, M.M., Vessicchio, J.C., Krishnan-Sarin, S., Jatlow, P.I., Wexler, B.E., George, T.P., 2005. Effects of cigarette smoking on spatial working memory and attentional deficits in schizophrenia: involvement of nicotinic receptor mechanisms. Arch. Gen. Psychiatry 62 (6), 649–659. Shim, J.C., Jung, D.U., Jung, S.S., Seo, Y.S., Cho, D.M., Lee, J.H., Lee, S.W., Kong, B.G., Kang, J.W., Oh, M.K., Kim, S.D., McMahon, R.P., Kelly, D.L., 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. Tanner, J.A., Novalen, M., Jatlow, P., Huestis, M.A., Murphy, S.E., Kaprio, J., Kankaanpaa, A., Galanti, L., Stefan, C., George, T.P., Benowitz, N.L., Lerman, C., Tyndale, R.F., 2015. Nicotine metabolite ratio (3-hydroxycotinine/cotinine) in plasma and urine by different analytical methods and laboratories: implications for clinical implementation. Cancer Epidemiol. Biomark. Prev. 24 (8), 1239–1246. Williams, J.M., Anthenelli, R.M., Morris, C.D., Treadow, J., Thompson, J.R., Yunis, C., George, T.P., 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. J. Clin. Psychiatry 73 (5), 654–660. Wing, V.C., Wass, C.E., Soh, D.W., George, T.P., 2012. A review of neurobiological vulnerability factors and treatment implications for comorbid tobacco dependence in schizophrenia. Ann. N. Y. Acad. Sci. 1248, 89–106. Wing, V.C., Wass, C.E., Bacher, I., Rabin, R.A., George, T.P., 2013. Varenicline modulates spatial working memory deficits in smokers with schizophrenia. Schizophr. Res. 149 (1–3), 190–191.
Martin Zack Institute of Medical Sciences (IMS), University of Toronto, Toronto, Ontario, Canada Molecular Brain Science Department, Centre for Addiction and Mental Health, Toronto, Ontario, Canada Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada Mera S. Barr Institute of Medical Sciences (IMS), University of Toronto, Toronto, Ontario, Canada Addictions Division, Centre for Addiction and Mental Health (CAMH), Toronto, Ontario, Canada Division of Brain and Therapeutics, Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada Rachel F. Tyndale Division of Brain and Therapeutics, Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada Molecular Brain Science Department, Centre for Addiction and Mental Health, Toronto, Ontario, Canada Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada Tony P. George Institute of Medical Sciences (IMS), University of Toronto, Toronto, Ontario, Canada Addictions Division, Centre for Addiction and Mental Health (CAMH), Toronto, Ontario, Canada Division of Brain and Therapeutics, Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada 3 January 2017 Available online xxxx
Please cite this article as: Kozak, K., et al., Effects of varenicline on cognitive function in non-smokers with schizophrenia, Schizophr. Res. (2017), http://dx.doi.org/10.1016/j.schres.2017.03.023
Contents lists available at ScienceDirect
Schizophrenia Research journal homepage: www.elsevier.com/locate/schres
Letter to the Editor Effects of varenicline on cognitive function in non-smokers with schizophrenia Keywords: Schizophrenia Non-smokers Varenicline Cognition Visuospatial working memory
Dear Editor, Schizophrenia (SZ) is associated with cognitive deficits and higher rates of tobacco smoking (72–90%) compared to the general population (~ 16%) that are linked to dysregulated nicotinic acetylcholine receptors (nAChR) (Wing et al., 2012). Moreover, smoking may improve (Sacco et al., 2005) while tobacco abstinence worsens cognition (George et al., 2002; Wing et al., 2013) in SZ. Thus, nAChR-based treatments remediating cognitive deficits are warranted. Varenicline, a nAChR partial agonist, is the most effective smoking cessation medication in SZ (Pachas et al., 2012; Williams et al., 2012), and may have pro-cognitive effects (Wing et al., 2013). Given that most studies have been conducted in smokers, the effects of varenicline on cognition may relate to withdrawal symptom reversal. Studies in non-smokers may avoid confounding effects of nicotine withdrawal on cognition. The results of these studies have been mixed (Hong et al., 2011; Shim et al., 2012; Roh et al., 2014). We evaluated the effects of varenicline on cognition in nonsmokers with and without SZ. A randomized, double-blind, placebo-controlled, cross-over laboratory study design was employed. Varenicline (0, 0.5 or 1 mg twice daily × 3 days) was administered in a counterbalanced manner across participants over 3 consecutive study weeks with a 1-week washout period between dose weeks in non-smoking SZ (n = 15) and non-psychiatric controls (n = 15). Weekly testing included three cognitive testing sessions (day 2 morning, day 3 morning, day 3 afternoon (day 3 PM)). Non-smoking status was verified by plasma cotinine (b15 ng/ml) and expired breath carbon monoxide level b 10 ppm. Varenicline plasma levels were collected on day 3 PM and effects on cognitive outcomes were evaluated. Plasma varenicline, and nicotine/cotinine levels were analyzed by liquid chromatography/mass spectroscopy (Tanner et al., 2015). Our primary outcome was visuospatial working memory (VSWM) as measured using the spatial delay recall task (Hershey et al., 1998), while secondary analyses examined relationships between varenicline plasma levels and other cognitive measures. Thirty participants (15 SZ, 15 controls) completed the protocol. Significantly lower Shipley IQ scores were found in SZ versus controls (p = 0.011). At baseline, controls performed better in VSWM, verbal memory and executive function than SZ (p b 0.05); a consistent main effect of diagnosis during dose weeks on the cognitive battery outcomes was also
found. Two-way ANOVAs demonstrated no main effects of varenicline dose or diagnosis × dose interactions on cognitive performance in either SZ non-smokers or controls (p N 0.05); similar results were observed using Principal Components Analysis (PCA) where a three-component solution was retained: general cognitive functioning (Factor 1), working memory and executive functioning (Factor 2) and sustained attention (Factor 3). There were no changes in clinical and psychiatric symptoms in both groups. Preliminary results in a subsample suggested improved cognitive function with lower varenicline plasma levels in patients, and with higher varenicline plasma levels in controls, at 2.0 mg/day. Correlation analyses between plasma varenicline and VSWM performance revealed trends for improved VSWM performance with increased plasma levels among SZ non-smokers in the low dose condition (p b 0.08; Fig. 1A). For controls, plasma levels were positively related to VSWM (p = 0.013; Fig. 1B), verbal memory (p = 0.005) and Factor 1 (p = 0.025) in the high dose condition. Study limitations included failure to achieve steady state levels of varenicline over the 3-day dosing paradigm that is typically titrated over a one-week period (Faessel et al., 2010). Both diagnostic groups had lower plasma levels than expected in low dose and substantial variance within high dose varenicline. Moreover, VSWM deficits in patients were modest, which may have reduced varenicline responses. Finally, the study sample and subsample was small. This study provides evidence for complex effects of varenicline on cognition in SZ and control individuals under non-smoking conditions. Larger studies with longer duration of varenicline treatment are warranted to establish the relationships between varenicline plasma levels and cognition in non-smokers with and without SZ.
Declaration of funding source • Investigator-Initiated Pfizer, Inc. Grant (WI171136) • Canadian Institutes of Health Research Operating Grant (MOP#115145)
Declaration of conflicts Dr. George reports that he has funding support from the Canadian Institutes of Health Research (CIHR) and Pfizer, and is a consultant to Novartis. Ms. Kozak, Dr. Dermody, Dr. Tyndale, Dr. Zack, and Dr. Barr report no conflicts of interest. The authors alone are responsible for the content and writing of this paper.
Acknowledgements This study was support by an Institute of Medical Sciences Graduate Fellowship from the University of Toronto (to Ms. Kozak), an investigator-initiated grant from Pfizer, Inc. (WI171136) and CIHR Operating Grant MOP#115145 (to Dr. George).
Appendix A. Supplementary data Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.schres.2017.03.023.
http://dx.doi.org/10.1016/j.schres.2017.03.023 0920-9964/© 2017 Published by Elsevier B.V.
Please cite this article as: Kozak, K., et al., Effects of varenicline on cognitive function in non-smokers with schizophrenia, Schizophr. Res. (2017), http://dx.doi.org/10.1016/j.schres.2017.03.023
2
Letter to the Editor
Karolina Kozak Institute of Medical Sciences (IMS), University of Toronto, Toronto, Ontario, Canada Addictions Division, Centre for Addiction and Mental Health (CAMH), Toronto, Ontario, Canada Corresponding author at: Addictions Division, Centre for Addiction and Mental Health (CAMH), Biobehavioural Addictions and Concurrent Disorders Research Laboratory (BACDRL), 33 Russell Street, Room 1120, Toronto, ON M5S 2S1, Canada. E-mail address: [email protected]. Sarah S. Dermody Addictions Division, Centre for Addiction and Mental Health (CAMH), Toronto, Ontario, Canada Rachel A. Rabin Institute of Medical Sciences (IMS), University of Toronto, Toronto, Ontario, Canada Addictions Division, Centre for Addiction and Mental Health (CAMH), Toronto, Ontario, Canada
Fig. 1. Varenicline plasma levels and VSWM performance. Bivariate correlations with outcomes parsed by varenicline plasma and diagnosis; SZ patients (Panel 1A) controls (Panel 1B).
References Faessel, H.M., Obach, R.S., Rollema, H., Ravva, P., Williams, K.E., Burstein, A.H., 2010. A review of the clinical pharmacokinetics and pharmacodynamics of varenicline for smoking cessation. Clin. Pharmacokinet. 49 (12), 799–816. George, T.P., Vessicchio, J.C., Termine, A., Sahady, D.M., Head, C.A., Pepper, W.T., Kosten, T.R., Wexler, B.E., 2002. Effects of smoking abstinence on visuospatial working memory function in schizophrenia. Neuropsychopharmacology 26 (1), 75–85. Hershey, T., Craft, S., Glauser, T.A., Hale, S., 1998. Short-term and long-term memory in early temporal lobe dysfunction. Neuropsychology 12 (1), 52–64. Hong, L.E., Thaker, G.K., McMahon, R.P., Summerfelt, A., Rachbeisel, J., Fuller, R.L., Wonodi, I., Buchanan, R.W., Myers, C., Heishman, S.J., Yang, J., Nye, A., 2011. Effects of moderate-dose treatment with varenicline on neurobiological and cognitive biomarkers in smokers and nonsmokers with schizophrenia or schizoaffective disorder. Arch. Gen. Psychiatry 68 (12), 1195–1206. Pachas, G.N., Cather, C., Pratt, S.A., Hoeppner, B., Nino, J., Carlini, S.V., Achtyes, E.D., Lando, H., Mueser, K.T., Rigotti, N.A., Goff, D.C., Evins, A.E., 2012. Varenicline for smoking cessation in schizophrenia: safety and effectiveness in a 12-week, open-label trial. J. Dual Diagn. 8 (2), 117–125. Roh, S., Hoeppner, S.S., Schoenfeld, D., Fullerton, C.A., Stoeckel, L.E., Evins, A.E., 2014. Acute effects of mecamylamine and varenicline on cognitive performance in non-smokers with and without schizophrenia. Psychopharmacology 231 (4), 765–775. Sacco, K.A., Termine, A., Seyal, A., Dudas, M.M., Vessicchio, J.C., Krishnan-Sarin, S., Jatlow, P.I., Wexler, B.E., George, T.P., 2005. Effects of cigarette smoking on spatial working memory and attentional deficits in schizophrenia: involvement of nicotinic receptor mechanisms. Arch. Gen. Psychiatry 62 (6), 649–659. Shim, J.C., Jung, D.U., Jung, S.S., Seo, Y.S., Cho, D.M., Lee, J.H., Lee, S.W., Kong, B.G., Kang, J.W., Oh, M.K., Kim, S.D., McMahon, R.P., Kelly, D.L., 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. Tanner, J.A., Novalen, M., Jatlow, P., Huestis, M.A., Murphy, S.E., Kaprio, J., Kankaanpaa, A., Galanti, L., Stefan, C., George, T.P., Benowitz, N.L., Lerman, C., Tyndale, R.F., 2015. Nicotine metabolite ratio (3-hydroxycotinine/cotinine) in plasma and urine by different analytical methods and laboratories: implications for clinical implementation. Cancer Epidemiol. Biomark. Prev. 24 (8), 1239–1246. Williams, J.M., Anthenelli, R.M., Morris, C.D., Treadow, J., Thompson, J.R., Yunis, C., George, T.P., 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. J. Clin. Psychiatry 73 (5), 654–660. Wing, V.C., Wass, C.E., Soh, D.W., George, T.P., 2012. A review of neurobiological vulnerability factors and treatment implications for comorbid tobacco dependence in schizophrenia. Ann. N. Y. Acad. Sci. 1248, 89–106. Wing, V.C., Wass, C.E., Bacher, I., Rabin, R.A., George, T.P., 2013. Varenicline modulates spatial working memory deficits in smokers with schizophrenia. Schizophr. Res. 149 (1–3), 190–191.
Martin Zack Institute of Medical Sciences (IMS), University of Toronto, Toronto, Ontario, Canada Molecular Brain Science Department, Centre for Addiction and Mental Health, Toronto, Ontario, Canada Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada Mera S. Barr Institute of Medical Sciences (IMS), University of Toronto, Toronto, Ontario, Canada Addictions Division, Centre for Addiction and Mental Health (CAMH), Toronto, Ontario, Canada Division of Brain and Therapeutics, Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada Rachel F. Tyndale Division of Brain and Therapeutics, Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada Molecular Brain Science Department, Centre for Addiction and Mental Health, Toronto, Ontario, Canada Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada Tony P. George Institute of Medical Sciences (IMS), University of Toronto, Toronto, Ontario, Canada Addictions Division, Centre for Addiction and Mental Health (CAMH), Toronto, Ontario, Canada Division of Brain and Therapeutics, Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada 3 January 2017 Available online xxxx
Please cite this article as: Kozak, K., et al., Effects of varenicline on cognitive function in non-smokers with schizophrenia, Schizophr. Res. (2017), http://dx.doi.org/10.1016/j.schres.2017.03.023