Contents lists available at ScienceDirect International Journal of Psychophysiology journal homepage: www.elsevier.com/locate/ijpsycho Combining CDP-choline and galantamine, an optimized α7 nicotinic strategy, to ameliorate sensory gating to speech stimuli in schizophrenia Joelle Choueiry a , Crystal M. Blais b , Dhrasti Shah c , Dylan Smith c , Derek Fisher d , Alain Labelle e , Verner Knott a,b,c,d,e,f, ⁎ a Department of Neuroscience, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada b Institute of Cognitive Science, Carleton University, Ottawa, ON, Canada c School of Psychology, Faculty of Social Sciences, University of Ottawa, Ottawa, ON, Canada d Department of Psychology, Faculty of Social Sciences, Mount Saint Vincent University, Halifax, NS, Canada e The Royal Ottawa Mental Health Centre, Ottawa, ON, Canada f University of Ottawa Institute of Mental Health Research, Ottawa, ON, Canada ARTICLE INFO Keywords: CDP-choline α7 nAChR P50 sensory gating Galantamine PAM Schizophrenia ABSTRACT Neural α7 nicotinic acetylcholine receptor (nAChR) expression and functioning deficits have been extensively associated with cognitive and early sensory gating (SG) impairments in schizophrenia (SCZ) patients and their relatives. SG, the suppression of irrelevant and redundant stimuli, is measured in a conditioning-testing (S 1 -S 2 ) paradigm eliciting electroencephalography-derived P50 event-related potentials (ERPs), the S 2 amplitudes of which are typically suppressed relative to S 1 . Despite extensive reports of nicotine-related improvements and several decades of research, an efficient nicotinic treatment has yet to be approved for SCZ. Following reports of SG improvements in low P50 suppressing SCZ patients and healthy participants with the α7 agonist, CDP- choline, this pilot study examined the combined modulatory effect of CDP-choline (500 mg) and galantamine (16 mg), a nAChR positive allosteric modulator and acetylcholinesterase inhibitor, on SG to speech stimuli in twenty-four SCZ patients in a randomized, double-blind and placebo-controlled design. As expected, in low P50 suppressors CDP-choline/galantamine (vs. Placebo) improved rP50 and dP50 scores by increasing inhibitory mechanisms as reflected by S 2 P50 amplitude reductions. Results also suggest a moderating role for auditory verbal hallucinations in treatment response. These preliminary findings provide supportive evidence for the involvement of α7 nAChR activity in speech gating in SCZ and support additional trials, examining different dose combinations and repeated doses of this optimized and personalized targeted α7 cholinergic treatment for SG dysfunction in subgroups of SCZ patients. 1. Introduction 1.1. Nicotinic receptor and sensory cognitive impairments in schizophrenia Nicotine, initially, then followed by a multitude of other nicotinic acetylcholine receptor (nAChR) agonists have been the subject of ex- tensive research in schizophrenia (SCZ). Although cigarette smoking rates in healthy populations (10–15%) are at an all time low, ~60–80% of individuals with SCZ (Cather et al., 2017) are still attempting to al- leviate cognitive impairments one deep and sustained cigarette puff at a time, as hypothesized by the nicotine self-medicating hypothesis (Kumari and Postma, 2005). Although this hypothesis has recently been challenged (Boggs et al., 2014, 2018), nicotinic modulation of cognitive processes has been supported by numerous animal and human research studies (Featherstone and Siegel, 2015). Cholinergic system abnorm- alities have been implicated in substance (i.e. nicotine and cocaine) abuse and dependence and in multiple brain disorders notably SCZ (Grasing, 2016; Nees, 2015). The CHRNA7 gene, responsible for α7 nAChR expression in the brain, has been identified as a risk gene in SCZ (Bertelsen et al., 2015; Sinkus et al., 2015) with lower post-mortem expression of α7 receptors reported in the frontal cortex (Guan et al., 2000), the hippocampus (Freedman et al., 1995; Olincy and Stevens, 2007), and the thalamus (Court et al., 1999). Furthermore, multiple single nucleotide polymorphisms and variants in the core promoter region of the CHRNA7 gene have been associated with deficits in neurophysiological measures of information processing in SCZ (Freedman et al., 2000, 1997, 2003; Leonard et al., 2002; Olincy and Freedman, 2012; Tregellas, 2014; Turetsky et al., 2007). https://doi.org/10.1016/j.ijpsycho.2019.02.005 Received 6 August 2018; Received in revised form 4 January 2019; Accepted 12 February 2019 ⁎ Corresponding author at: Department of Neuroscience, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada. E-mail address: verner.knott@theroyal.ca (V. Knott). International Journal of Psychophysiology xxx (xxxx) xxx–xxx 0167-8760/ © 2019 Elsevier B.V. All rights reserved. Please cite this article as: Joelle Choueiry, et al., International Journal of Psychophysiology, https://doi.org/10.1016/j.ijpsycho.2019.02.005