N-Acetyl Cysteine In Schizophrenia Resistant To Clozapine: A Double-Blind Randomised Placebo-Controlled Trial Targeting Negative Symptoms

A proportion of individuals with schizophrenia (SZ) do not respond adequately to clozapine, with anything from 40-60% of individuals having residual symptoms at the completion of an adequate trial of clozapine. Agents that could work synergistically with clozapine to improve efficacy whilst not increasing the side effect burden are both desired and necessary to improve the lives of individuals with clozapine-resistant SZ, such as N-acetyl cysteine (NAC). Our group has extensive experience with NAC with pilot data support from a rigorous RCT exploring the efficacy of NAC in clozapine-resistant SZ. This project grant seeks funding to expand this work by conducting a multi-site randomised placebo-controlled trial of NAC in the treatment of clozapine-resistant schizophrenia, with 8, 24 and 52 week endpoints. We will target negative symptoms as our primary outcome measure, with quality of life and cognition as secondary outcomes. We will examine both peripheral and cortical glutathione concentrations. Additionally, we will measure a number of other biomarkers pertinent to the glutathione hypothesis. Such analyses will further our understanding the role of oxidative stress in SZ. The trial is a randomised controlled double-blinded superiority trial of two parallel patient groups. The study will be conducted across four Australian sites, namely Melbourne (St Vincent’s Mental Health Service), Sydney (Cumberland Hospital), Adelaide (Northern Adelaide Local Health Network), and Brisbane (Metro South Addiction and Mental Health Service). Forty-two patients will be recruited from each of the sites, with a total target of 168 patients aged 18 - 65 years meeting DSM-5 criteria for schizophrenia. Block randomisation will be used. This trial, if successful, will establish a cheap, safe and easy-to-use agent (NAC) as a ‘go to’ adjunct in patients only partly responsive to clozapine.