title: N-acetylcysteine (NAC) in schizophrenia resistant to clozapine: a double blind randomised placebo controlled trial targeting negative symptoms.
abstract: Clozapine is an effective treatment for a proportion of people with schizophrenia (SZ) who are resistant to the beneficial effects of other antipsychotic drugs. However, anything from 40-60 % of people on clozapine experience residual symptoms even on adequate doses of the medication, and thus could be considered 'clozapine resistant'. Agents that could work alongside clozapine to improve efficacy whilst not increasing the adverse effect burden are both desired and necessary to improve the lives of individuals with clozapine-resistant SZ. N-Acetylcysteine (NAC) is one such possible agent. Previous research from our research group provided promising pilot data suggesting the efficacy of NAC in this patient population. The aim of the study reported here is to expand this work by conducting a large scale clinical trial of NAC in the treatment of clozapine-resistant SZ.
  
  
  
  This study is an investigator initiated, multi-site, randomised, placebo-controlled trial. It aims to include 168 patients with clozapine-resistant SZ, divided into an intervention group (NAC) and a control group (placebo). Participants in the intervention group will receive 2 g daily of NAC. The primary outcome measures will be the negative symptom scores of the Positive and Negative Syndrome Scale (PANSS). Secondary outcome measures will include: changes in quality of life (QoL) as measured by the Lancashire Quality of Life Profile (LQoLP) and cognitive functioning as measured by the total score on the MATRICS. Additionally we will examine peripheral and cortical glutathione (GSH) concentrations as process outcomes.
  
  
  
  This large scale clinical trial will investigate the efficacy of NAC as an adjunctive medication to clozapine. This trial, if successful, will establish a cheap, safe and easy-to-use agent (NAC) as a 'go to' adjunct in patients that are only partly responsive to clozapine.
  
  
  
  Australian and New Zealand Clinical Trials Registration Number: Current Randomised Controlled Trial ACTRN12615001273572 . The date of registration 23 November 2015.
authors.affiliation: Centre for Mental Health, Faculty of Health, Arts and Design, Swinburne University of Technology, Melbourne, VIC, Australia. srossell@swin.edu.au.|St Vincent's Mental Health Service, St Vincent's Hospital, Melbourne, VIC, Australia. srossell@swin.edu.au.|Monash Alfred Psychiatry Research Centre and The Voices Clinic, The Alfred, Melbourne, VIC, Australia. srossell@swin.edu.au.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Rossell
authors.affiliation: Centre for Chemistry and Biotechnology, School of Life & Environmental Sciences, Deakin University, Geelong, VIC, Australia.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Francis
authors.affiliation: Psychiatry Department, University of Adelaide, Adelaide, South Australia, Australia.|Northern Adelaide Health Local Network, Adelaide, South Australia, Australia.
authors.forename: Cherrie
authors.initials: C
authors.lastname: Galletly
authors.affiliation: Discipline of Psychiatry, Sydney Medical School, University of Sydney, Sydney, NSW, Australia.|Brain Dynamics Centre, The Westmead Institute for Medical Research, University of Sydney, Sydney, NSW, Australia.
authors.forename: Anthony
authors.initials: A
authors.lastname: Harris
authors.affiliation: School of Medicine, University of Queensland, Brisbane, QLD, Australia.
authors.forename: Dan
authors.initials: D
authors.lastname: Siskind
authors.affiliation: IMPACT Strategic Research Centre, Barwon Health, Deakin University, Geelong, VIC, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Berk
authors.affiliation: Baker IDI Heart & Diabetes Institute, Melbourne, VIC, Australia.
authors.forename: Kiymet
authors.initials: K
authors.lastname: Bozaoglu
authors.affiliation: Metro South Addiction and Mental Health Service, Brisbane, QLD, Australia.
authors.forename: Frances
authors.initials: F
authors.lastname: Dark
authors.affiliation: IMPACT Strategic Research Centre, Barwon Health, Deakin University, Geelong, VIC, Australia.
authors.forename: Olivia
authors.initials: O
authors.lastname: Dean
authors.affiliation: Psychiatry Department, University of Adelaide, Adelaide, South Australia, Australia.|Northern Adelaide Health Local Network, Adelaide, South Australia, Australia.
authors.forename: Dennis
authors.initials: D
authors.lastname: Liu
authors.affiliation: Centre for Mental Health, Faculty of Health, Arts and Design, Swinburne University of Technology, Melbourne, VIC, Australia.|Department of Statistics, Data Science and Epidemiology, Swinburne University of Technology, Melbourne, VIC, Australia.
authors.forename: Denny
authors.initials: D
authors.lastname: Meyer
authors.affiliation: St Vincent's Mental Health Service, St Vincent's Hospital, Melbourne, VIC, Australia.
authors.forename: Erica
authors.initials: E
authors.lastname: Neill
authors.affiliation: St Vincent's Mental Health Service, St Vincent's Hospital, Melbourne, VIC, Australia.
authors.forename: Andrea
authors.initials: A
authors.lastname: Phillipou
authors.affiliation: ARCADIA Mental Health Research Group, Professorial Unit, The Melbourne Clinic, Department of Psychiatry, The University of Melbourne, Melbourne, VIC, Australia.|Centre for Human Psychopharmacology, Swinburne University of Technology, Melbourne, VIC, Australia.
authors.forename: Jerome
authors.initials: J
authors.lastname: Sarris
authors.affiliation: St Vincent's Mental Health Service, St Vincent's Hospital, Melbourne, VIC, Australia. david.castle@svha.org.au.|Department of Psychiatry, University of Melbourne, Melbourne, VIC, Australia. david.castle@svha.org.au.
authors.forename: David J
authors.initials: DJ
authors.lastname: Castle
mesh_terms: D000111:Acetylcysteine / Q000627:therapeutic use*; D000293:Adolescent; D000328:Adult; D000368:Aged; D014150:Antipsychotic Agents / Q000627:therapeutic use; D001315:Australia; D003024:Clozapine; D004311:Double-Blind Method; D004351:Drug Resistance; D005260:Female; D005500:Follow-Up Studies; D016166:Free Radical Scavengers / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008875:Middle Aged; D009520:New Zealand; D011788:Quality of Life / Q000523:psychology; D012559:Schizophrenia / Q000188:drug therapy*; D012565:Schizophrenic Psychology; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; D016166:Free Radical Scavengers; D003024:Clozapine; D000111:Acetylcysteine
keywords: Biomarkers; Clozapine; Cognition; N-Acetylcysteine; Negative Symptoms; Schizophrenia