N-Acetylcysteine (NAC) in Schizophrenia Resistant to Clozapine: A Double-Blind, Randomized, Placebo-Controlled Trial Targeting Negative Symptoms

Erica Neill; Susan L Rossell; Caitlin Yolland; Denny Meyer; Cherrie Galletly; Anthony Harris; Dan Siskind; Michael Berk; Kiymet Bozaoglu; Frances Dark; Olivia M Dean; Paul S Francis; Dennis Liu; Andrea Phillipou; Jerome Sarris; David J Castle

doi:10.1093/schbul/sbac065

N-Acetylcysteine (NAC) in Schizophrenia Resistant to Clozapine: A Double-Blind, Randomized, Placebo-Controlled Trial Targeting Negative Symptoms

Schizophr Bull. 2022 Nov 18;48(6):1263-1272. doi: 10.1093/schbul/sbac065.

Authors

Erica Neill^{1

2

3}, Susan L Rossell^{1

2}, Caitlin Yolland^{1

2}, Denny Meyer¹, Cherrie Galletly^{4

5

6}, Anthony Harris^{7

8}, Dan Siskind^{9

10}, Michael Berk^{11

12

13}, Kiymet Bozaoglu^{14

15}, Frances Dark^{9

10}, Olivia M Dean^{11

12}, Paul S Francis¹⁶, Dennis Liu^{4

6}, Andrea Phillipou¹, Jerome Sarris^{12

17

18}, David J Castle^{1

2

3}

Affiliations

¹ Centre for Mental Health, Faculty of Health, Arts & Design, Swinburne University of Technology, Melbourne, Australia.
² Department of Mental Health, St Vincent's Hospital, Melbourne, Australia.
³ Department of Psychiatry, University of Melbourne, Melbourne, Australia.
⁴ Department of Psychiatry, Adelaide Medical School, University of Adelaide, Adelaide, Australia.
⁵ Ramsay Health Care (SA) Mental Health, Adelaide, Australia.
⁶ Northern Adelaide Local Health Network, Adelaide, Australia.
⁷ Specialty of Psychiatry, Sydney Medical School, University of Sydney, Sydney, Australia.
⁸ Westmead Institute for Medical Research, Westmead, NSW 2145, Australia.
⁹ Metro South Addiction and Mental Health Service, Brisbane, Australia.
¹⁰ UQ School of Clinical Medicine, Brisbane, Australia.
¹¹ Deakin University, IMPACT-the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia.
¹² Orygen, The National Centre of Excellence in Youth Mental Health, Centre for Youth Mental Health, Melbourne, Australia.
¹³ Florey Institute for Neuroscience and Mental Health and the Department of Psychiatry, The University of Melbourne, Melbourne, Australia.
¹⁴ Department of Paediatrics, The University of Melbourne, Melbourne, Australia.
¹⁵ Bruce Lefroy Centre for Genetic Health Research, Murdoch Children's Research Institute, Melbourne, Australia.
¹⁶ School of Life and Environmental Sciences, Faculty of Science, Engineering and Built Environment, Deakin University, Waurn Ponds, VIC, Australia.
¹⁷ NICM Health Research Institute, Western Sydney University, Westmead, NSW, Australia.
¹⁸ Professional Unit, The Melbourne Clinic, Department of Psychiatry, University of Melbourne, Melbourne, VIC, Australia.

Abstract

Background and hypothesis: Clozapine is the most effective antipsychotic for treatment-resistant schizophrenia, yet a significant proportion of individuals on clozapine continue to experience disabling symptoms, despite being treated with an adequate dose. There is a need for adjunct treatments to augment clozapine, notably for negative and cognitive symptoms. One such potential agent is the glutathione precursor N-acetylcysteine (NAC).

Study design: A randomized double-blind, multi-center, placebo-controlled trial for clozapine patients with enduring psychotic symptoms (n = 84) was undertaken to investigate the efficacy of adjunctive NAC (2 g daily) for negative symptoms, cognition and quality of life (QoL). Efficacy was assessed at 8, 24, and 52 weeks.

Study results: NAC did not significantly improve negative symptoms (P = .62), overall cognition (P = .71) or quality of life (Manchester quality of life: P = .11; Assessment of quality of life: P = .57) at any time point over a 1-year period of treatment. There were no differences in reported side effects between the groups (P = .26).

Conclusions: NAC did not significantly improve schizophrenia symptoms, cognition, or quality of life in treatment-resistant patients taking clozapine. This trial was registered with "Australian and New Zealand Clinical Trials" on the 30 May, 2016 (Registration Number: ACTRN12615001273572).

Keywords: cognition; depression; mental disorders; mental illness; neuroscience; psychiatry; quality of life.

Publication types

Randomized Controlled Trial
Multicenter Study
Research Support, Non-U.S. Gov't

MeSH terms

Acetylcysteine / pharmacology
Antipsychotic Agents* / adverse effects
Australia
Clozapine* / adverse effects
Double-Blind Method
Humans
Quality of Life / psychology
Schizophrenia* / chemically induced
Schizophrenia* / drug therapy
Treatment Outcome

Substances

Clozapine
Acetylcysteine
Antipsychotic Agents

Associated data

ANZCTR/ACTRN12615001273572