Assessing the Acute Effects of CDP-Choline on Sensory Gating and Cognitive Deficits in Chronic Schizophrenia by Robert Aidelbaum A thesis submitted to the Faculty of Graduate Studies and Postdoctoral Affairs in partial fulfillment of the requirements for the degree of Master of Arts In Psychology Carleton University Ottawa, Canada ©2015 Robert Aidelbaum ii Abstract Deficient sensory gating (SG) and cognition in schizophrenia are associated with functional outcome and offer therapeutic targets as they are linked to the altered function/expression of the α7 nicotinic acetylcholine receptors (nAChR). This study analyzed the effects of CDP-Choline, an α7 nAChR agonist, on SG and cognition in a sample of chronic schizophrenia patients. Using a randomized, placebo controlled, double-blind design the dose dependent (500 mg, 1000 mg, 2000 mg) and baseline SG dependent (deficient vs. normal suppressors) effects of CDP-Choline were analyzed using the P50 index of SG and a computerized cognition test battery. CDP-Choline improved SG (500 mg) in the deficient suppressor subgroup by increasing suppression of the S2 P50 amplitude. No positive effects of CDP-Choline on cognition were observed. These findings tentatively support α7 nAChR dysfunction in the expression of SG deficits and support further trials with CDP-choline to asses the effects of sustained α7 nAChR activation. iii Acknowledgements I would like to sincerely thank a few people who each contributed tot the completion of this thesis. I would like to extend my thanks to my primary supervisor Dr. Verner Knott for his guidance, assistance, and patience. Thank you for offering me the opportunity to work with you and the experiences that came with it. I would also like to thank Dr. John Logan for his support and advice along the way. Thank you to all of the patients who took the time to complete the sometimes tedious test sessions. Thank you to Etelle Bourassa for all of her kind words, encouragement, and advice. Thank you to my friends and brothers for offering me motivation and distractions exactly when I needed them. Thank you to Shannon for always being there for me, offering kind words of encouragement, making me laugh, and offering her editing expertise. Finally, thank you to my family and most importantly my mom and dad for always being there for me and helping me achieve this. iv Table of Contents Abstract ............................................................................................................................... ii Acknowledgements ............................................................................................................ iii Table of Contents ............................................................................................................... iv List of Tables ..................................................................................................................... vi List of Figures ................................................................................................................... vii List of Appendices ........................................................................................................... viii List of Abbreviations ......................................................................................................... ix Assessing the Acute Effects of CDP-Choline on Sensory Gating and Cognition in Chronic Schizophrenia ........................................................................................................ 1 Schizophrenia: Cognitive Deficits as a Core Clinical Feature ........................................ 1 Schizophrenia Endophenotypes: Sensory Gating Deficits and ERP Biomarkers ........... 3 Efficacy of Antipsychotics in Treating Sensory Gating and Cognitive Deficits .......... 10 Novel Therapeutic Targets: The Nicotinic Acetylcholine Receptor System ................ 17 The Schizophrenic Brain: α7 nAChR Dysfunction and Sensory Gating Deficits ........ 20 Novel Cholinergic Agents: Recent drug development efforts ...................................... 26 Study Objectives ........................................................................................................... 34 Hypotheses .................................................................................................................... 37 Method .............................................................................................................................. 38 Participants .................................................................................................................... 38 Study Design ................................................................................................................. 39 Drug .............................................................................................................................. 40 Study Procedure ............................................................................................................ 41 Task Stimuli .................................................................................................................. 42 ERP Recordings ............................................................................................................ 44 Other Measures ............................................................................................................. 45 Statistical Analysis ........................................................................................................ 45 Results ............................................................................................................................... 47 v Vital Signs and Adverse Events .................................................................................... 47 Demographic and Psychometric Measures ................................................................... 48 CDP-Choline Effects on Sensory Gating ...................................................................... 48 CDP-Choline Effects on Cognition .............................................................................. 56 Discussion ......................................................................................................................... 57 Sensory Gating .............................................................................................................. 58 Cognition ...................................................................................................................... 61 Limitations .................................................................................................................... 64 Conclusions ....................................................................................................................... 66 References ......................................................................................................................... 68 Appendix A ..................................................................................................................... 104 Appendix B ..................................................................................................................... 106 Appendix C ..................................................................................................................... 108 Appendix D ..................................................................................................................... 109 Appendix E ..................................................................................................................... 116 Appendix F...................................................................................................................... 118 vi List of Tables Table 1. Mean (± SE) Demographic and Psychometric Scores for Whole.……………...48 Table 2. Mean (± SE) Suppression Measures and Stimulus Measures at.…………….…50 Table 3. Mean (± SE) CogState Test Scores at Each CDP-Choline Dose……………….57 vii List of Figures Figure 1. Normal and deficient P50 amplitudes in response to S1 and S2………………..8 Figure 2. Grand average waveforms representing P50 responses to S1…………………49 Figure 3. Mean (± SE) P50 ratio (S2/S1) and difference (S1-S2) scores………………..52 Figure 4. A) Grand average waveform representing the P50 amplitude difference……..54 Figure 5. Mean (± SE) stimulus amplitude (S1 and S2) scores recorded at the…………55 viii List of Appendices Appendix A. Positive and Negative Symptom Scale………………………...…………104 Appendix B. Structural Clinical Interview for DSM-IV-TR………………………...…106 Appendix C. Inclusion & Exclusion Form……………………………………………..108 Appendix D. Consent Form ………. …………………………………………………..109 Appendix E. Psychotic Symptoms Rating Scale…………………………...…………. 116 Appendix F. Adverse Event Questionnaire ……………………………………..……..118 ix List of Abbreviations Abbreviation Explanation ANOVA Analysis of Variance CDP-Choline 5ʹ′-Cytidine Diphosphocholine CSB Cogstate Test Battery dP50 P50 Difference Scores DSM-5 Diagnostic and Statistical Manual ERP Event Related Potential GABA γ-Aminobutyric Acid GAF General Assessment of Function nAChRs Nicotinic Acetylcholine Receptors PANSS Positive and Negative Symptom Scale PSYRATS Psychotic Rating Scale rP50 Ratio P50 Scores S1 First Stimuli in Paired Click Paradigm S2 Second Stimuli in Paired Click Paradigm SCID-CV Structured Clinical Interview for DSM-IV SZ Schizophrenia Running Head: CHOLINE AND SENSORY GATING DEFICITS IN SCHIZOPHRENIA Assessing the Acute Effects of CDP-Choline on Sensory Gating and Cognition in Chronic Schizophrenia Schizophrenia: Cognitive Deficits as a