The Effects of Varenicline on Working Memory and Long-Term Potentiation in Non-Smokers with Schizophrenia by Alanna Christina Bridgman A thesis submitted in conformity with the requirements for the degree of Master of Science Institute of Medical Sciences University of Toronto © Copyright by Alanna Christina Bridgman 2015 The Effects of Varenicline on Working Memory and Long-Term Potentiation in Non-Smokers with Schizophrenia Alanna Christina Bridgman Master of Science Institute of Medical Sciences University of Toronto 2015 Background: Deficits in the nicotinic acetylcholine receptor (nAChR) system are proposed to underlie vulnerability to nicotine dependence and cognitive impairment in schizophrenia. Varenicline is a smoking cessation medication that enhances cognition in schizophrenia while treating nicotine dependence, possibly through the modulation of neuroplasticity. Methods: This study assessed the effects of varenicline (1 mg/day) versus placebo on neuroplasticity and working memory in 11 schizophrenia non-smokers and 11 non-smoker healthy subjects, to eliminate the confounding effects of tobacco smoking. Results: Patients with schizophrenia performed worse on the 3-back task compared to healthy subjects. Varenicline enhanced working memory in low-performers only, regardless of diagnosis. Deficits in neuroplasticity were found in patients with schizophrenia compared to healthy subjects, which were enhanced with varenicline compared to placebo. Conclusions: Varenicline may be a potential therapeutic option for the remediation of cognitive and neuroplasticity deficits in patients with schizophrenia regardless of smoking status. ii Acknowledgments This work is dedicated to Thomas Joseph Mullin and Patricia Rose Gates. First and foremost, I’d like to acknowledge the participants that made this work possible. Thank you for your time, honesty, and genuine enthusiasm. I’d like to express the utmost gratitude to my supervisor, Dr. Tony P. George, for the opportunity to take this study on as my own. Through your guidance, I have learned how to think critically and independently, and have grown as a scientist and an individual. I thoroughly enjoyed my 4 years in this lab, and will miss the close-knit community that you’ve built. I sincerely thank you for patience and support, and I hope I have made you proud. I would not have succeeded in this study if not for Dr. Mera Barr. You didn’t just teach me all the fiddly techniques required for this degree, but you also pushed me to be a better graduate student, friend, and scientist. Thank you for being patient with me, although I know it wasn’t always easy! Words cannot express how grateful I am to you. To Plucky, from Peanut: I don’t think we would have gotten through these past two years without each other. You’ve helped me through the toughest times, and I hope you can say the same about me. There are too many moments to reminisce about here, but maybe we can blog about it some time. Rachel Rabin, you were the first friend I made here at CAMH, and I know our friendship will continue outside of these walls. Thank you for being a constant source of emotional and academic support for me, and I look forward to doing the same for you in the upcoming years! A special thank you to all my lab mates over the years: Michelle Goodman, Rachel Rabin, Karolina Kozak, Emily Simpkin, Maryam Sharif-Razi, Marya Morozova, Matt Tracey, Kristen Mackowick, Anushka Talpur, Caroline Wass, and Vicky Wing. It’s been a blast, and I can’t believe it’s already over! Thank you to my sister, Kayla Bridgman, for being absolutely hilarious and a pleasure to be around. You are truly my best friend. Also, thank you to my father, Alan Bridgman, who unintentionally pointed me down my career path. Thank you to the rest of my family for being your loud, boisterous, amazingly fun selves and giving me refuge from my own seriousness. And last but certainly not least, thank you to my dear mother, Tracy Mullin. I would not have even made it to university without you. Your patience, advice, and love have molded me into the person that I am today. I am especially grateful that you have never told me what path to follow, but have simply allowed me to bounce my wild ideas off you and see where I end up (including that time I wanted to be an archaeologist and go to school in Hawaii). Thanks for being the best mom ever. iii Contributions The study protocol from which this thesis was derived was developed by Dr. Tony George (PI), Dr. Jeff Daskalakis, Dr. Mera Barr, and Dr. Tarek Rajji, and was entitled “The Effects of Varenicline on Cortical Neuroplasticity in Patients with Schizophrenia Compared to Non- Psychiatric Controls”. The candidate, Alanna C. Bridgman, was responsible for recruitment, retention, and conduct of all study sessions. Emily Simpkin and Matthew Tracey were responsible for conducting the structured clinical interviews and physical examinations performed during the screening session. Dr. Mera Barr trained the candidate on all neurophysiological and neurocognitive measures, including working memory and paired associative stimulation. The candidate, Alanna C. Bridgman, conducted all data analysis, interpretation of research data, and drafting of the thesis. Dr. Mera Barr and Dr. Tony George assisted with analysis and interpretation of data. The Program Advisory Committee (PAC) members, Dr. Bernard Le Foll and Dr. Robert Chen, assisted with the interpretation of the data. This study was funded by a contract from Pfizer, and by the BACDRL lab at CAMH. iv Table of Contents Page Abstract……………………………………………………………………………… ii Acknowledgments………………………………………………………….….……. iii Contributions………………………………………………………………….…..… iv Table of Contents………………………………………………………………….… v List of Abbreviations…………………………………………………………….….. viii List of Tables………………………………………………………………………… x List of Figures……………………………………………………………………….. xi List of Appendices…………………………………………………………………... xiii Chapter 1: Literature Review…………………………………………….. 1 1.1 Schizophrenia………………………………………………….…………... 1 1.1.1 Schizophrenia: Phenomenology, Epidemiology, and Etiology…………….. 1 1.1.2 Pathophysiology of Schizophrenia…………………………………………. 3 1.2 Tobacco Use in Schizophrenia………………….………………………… 9 1.3 Nicotinic Acetylcholine Receptor System………………………………… 9 1.3.1 Nicotinic Acetylcholine Receptor Dysfunction in Schizophrenia………….. 11 1.4 Varenicline………………………………………………………………… 12 1.4.1 Pharmacology………………………………………………………………. 12 1.4.2 Preclinical Studies………………………………………………………….. 13 1.4.3 Clinical Studies……………………………………………………………... 14 1.4.3.1 Phase II Clinical Trials…………………………………………………... 14 1.4.3.2 Phase III Clinical Trials…………………………………………………. 15 1.4.3.3 Phase IV Clinical Trials…………………………………………………. 17 1.4.4 Safety and Efficacy of Varenicline in Non-Psychiatric Individuals and Patients with Schizophrenia……...…………………………………………. 17 1.4.4.1 Safety and Efficacy of Varenicline……………………………………… 17 1.4.4.2 Safety and Efficacy of Varenicline in Schizophrenia…………………… 18 1.5 Working Memory………...................................….………..……………… 20 1.5.1 Working Memory Deficits in Schizophrenia……………………………….. 21 1.5.2 Nicotinic Modulation of Working Memory in Non-Psychiatric Individuals and Patients with Schizophrenia……………………………………………. 23 1.5.2.1 Nicotinic Modulation of Working Memory……………………………... 23 1.5.2.2 Nicotinic Modulation of Working Memory in Schizophrenia………....... 24 1.5.3 Effects of Varenicline on Working Memory in Non-Psychiatric Individuals and Patients with Schizophrenia……………………………………………. 26 1.5.3.1 Effects of Varenicline on Working Memory……………………………. 26 v 1.5.3.2 Effects of Varenicline on Working Memory in Schizophrenia…………. 26 1.6 Neuroplasticity……………………………………………………………... 27 1.6.1 Long-Term Potentiation and Long-Term Depression………………………. 28 1.6.2 Induction of Neuroplasticity Using Brain Stimulation…………...………… 32 1.6.2.1 Transcranial Direct Current Stimulation………………………………… 32 1.6.2.2 Repetitive Transcranial Magnetic Stimulation…………………………... 34 1.6.2.3 Paired Associative Stimulation………………………………………….. 36 1.6.3 Neuroplasticity Deficits in Schizophrenia……………………………….…. 39 1.6.4 Nicotinic Modulation of Neuroplasticity in Non-Psychiatric Individuals and Patients with Schizophrenia………………………………...………….. 41 1.6.4.1 Nicotinic Modulation of Neuroplasticity………………………………... 41 1.6.4.2 Nicotinic Modulation of Neuroplasticity in Schizophrenia……………... 45 1.6.5 Effects of Varenicline on Neuroplasticity…………………………………... 47 1.7 Overall Summary………………………………………………………….. 47 1.8 Study Objectives and Hypotheses………………………….……………... 48 Chapter 2: Methods……………………………………………………….. 50 2.1 Study Design……………………………………………………………….. 50 2.2 Participants………………………………………………………………… 50 2.2.1 Total Sample………………………………………………………………... 50 2.3 Measures…………………………………………………………………… 52 2.3.1 Clinical Interview Measures………………………………………………... 52 2.3.2 Extrapyramidal Side Effects.……………………………………………..… 53 2.3.3 Physical Examination………………………………………………………. 54 2.3.4 Working Memory……………………………………………………..……. 55 2.3.5 Paired Associative Stimulation……………………………………………... 56 2.4 Study Medication…………………………………………………..……… 59 2.5 Study Procedure…………………………………...…….………………… 59 2.5.1 Screening……………………………………………………………………. 60 2.5.2 Randomization……………………………………………………………… 61 2.5.3 Varenicline Administration…………………………………………………. 62 2.5.4 Assessment of Compliance…………...…………………………………….. 62 2.5.5 Testing Sessions……………………………………………………..…....… 62 2.6 Data Analysis…………………………………...…………………………. 63 2.6.1 Working Memory Analysis………………………………………………… 64 2.6.2 Long-Term Potentiation Analysis………………………………………….