The effects of glycine on auditory mismatch negativity in schizophrenia ☆ Lisa-Marie Greenwood a, ⁎, Sumie Leung b , Patricia T. Michie c,d , Amity Green e , Pradeep J. Nathan e,f,g , Paul Fitzgerald e , Patrick Johnston h,i , Nadia Solowij a,d , Jayashri Kulkarni e , Rodney J. Croft a a School of Psychology and Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, Australia b Centre for Human Psychopharmacology, Swinburne University of Technology, Victoria, Australia c School of Psychology and Priority Research Centre for Translational Neuroscience and Mental Health, University of Newcastle, Newcastle, Australia d Schizophrenia Research Institute, Sydney, Australia e Monash Alfred Psychiatry Research Centre, Monash University, Melbourne, Australia f Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom g School of Psychology and Psychiatry, Monash University, Melbourne, Australia h Department of Psychology and York Neuroimaging Centre, University of York, York, United Kingdom i School of Psychology and Counselling, Queensland University of Technology, Kelvin Grove, Australia abstract article info Article history: Received 17 January 2017 Received in revised form 22 May 2017 Accepted 25 May 2017 Available online xxxx Glycine increases N-methyl-D-aspartate receptor (NMDAR) mediated glutamatergic function. Mismatch negativ- ity (MMN) is a proposed biomarker of glutamate-induced improvements in clinical symptoms, however, the ef- fect of glycine-mediated NMDAR activation on MMN in schizophrenia is not well understood. This study aimed to determine the effects of acute and 6-week chronic glycine administration on MMN in schizophrenia patients. MMN amplitude was compared at baseline between 22 patients (schizophrenia or schizoaffective disorder; re- ceiving stable antipsychotic medication; multi-centre recruitment) and 21 age- and gender-matched controls. Patients underwent a randomised, double-blind, placebo-controlled clinical trial with glycine added to their reg- ular antipsychotic medication (placebo, n = 10; glycine, n = 12). MMN was reassessed post-45-minutes of first dose (0.2 g/kg) and post-6-weeks treatment (incremented to 0.6 g/kg/day). Clinical symptoms were assessed at baseline and post-6-weeks treatment. At baseline, duration MMN was smaller in schizophrenia compared to con- trols. Acute glycine increased duration MMN (compared to placebo), whilst this difference was absent post-6- weeks treatment. Six weeks of chronic glycine administration improved PANSS-Total, PANSS-Negative and PANSS-General symptoms compared to placebo. Smaller baseline duration MMN was associated with greater PANSS-Negative symptoms and predicted (at trend level) PANSS-Negative symptom improvement post-6- weeks glycine treatment (not placebo). These findings support the benefits of chronic glycine administration and demonstrate, for the first time, that acute glycine improves duration MMN in schizophrenia. This result, to- gether with smaller baseline duration MMN predicting greater clinical treatment response, suggests the potential for duration MMN as a biomarker of glycine-induced improvements in negative symptoms in schizophrenia. © 2017 Elsevier B.V. All rights reserved. Keywords: Schizophrenia Mismatch negativity Glycine N-methyl-D-aspartate Negative symptoms 1. Introduction Antipsychotic medications aim to normalise neurochemical dys- function within fronto-striatal circuitry in schizophrenia (SCZ). First and second generation antipsychotics primarily attenuate dopamine D 2 receptor function in striatum to reduce positive symptoms, but show modest effects in treating negative symptoms and cognitive defi- cits (Buckley and Stahl, 2007), suggesting the need for an alternative approach to ameliorate the severity of these symptom domains. Phar- macological models increasing dopaminergic function in striatum are associated with increased positive symptoms (Howes et al., 2012), whereas models that block N-methyl-D-aspartate receptor (NMDAR) function increase positive and negative symptoms, and cognitive defi- cits (Krystal et al., 1994; Krystal et al., 2005; Olney and Farber, 1995; Seillier and Giuffrida, 2009). Recent pharmacological trials investigating glycine type-I reuptake inhibitors (GTI-RIs) as an adjunct treatment in schizophrenia, aim to increase glutamatergic function and subsequently decrease negative symptoms (Thomas et al., 2014). Clarifying mecha- nisms of hypofunctional glutamatergic neurotransmission and identify- ing biomarkers that index neurochemical change in NMDAR function, may elucidate the heterogeneous nature of phenotypic expression and treatment response within the disorder. Schizophrenia Research xxx (2017) xxx–xxx ☆ Trial registration: ACTRN12609000184279 (www.anzctr.org.au). Tailoring adjunct glycine therapy to improve cognitive function and clinical symptoms in schizophrenia. ⁎ Corresponding author. E-mail addresses: lmg001@uowmail.edu.au, lisagreewood@live.com.au (L.-M. Greenwood). SCHRES-07321; No of Pages 9 http://dx.doi.org/10.1016/j.schres.2017.05.031 0920-9964/© 2017 Elsevier B.V. All rights reserved. Contents lists available at ScienceDirect Schizophrenia Research journal homepage: www.elsevier.com/locate/schres Please cite this article as: Greenwood, L.-M., et al., The effects of glycine on auditory mismatch negativity in schizophrenia, Schizophr. Res. (2017), http://dx.doi.org/10.1016/j.schres.2017.05.031