Open Access Research article

Maintenance N-acetyl cysteine treatment for bipolar disorder: A double-blind randomized placebo controlled trial

Michael Berk12345*, Olivia M Dean145, Sue M Cotton23, Clarissa S Gama6, Flavio Kapczinski6, Brisa Fernandes78, Kristy Kohlmann4, Susan Jeavons4, Karen Hewitt4, Kirsteen Moss109, Christine Allwang10119, Ian Schapkaitz4, Heidi Cobb9, Ashley I Bush4, Seetal Dodd15 and Gin S Malhi89

Author Affiliations

1 Deakin University, School of Medicine, Barwon Health, P.O. Box 291, Geelong, 3220, Australia

2 Orygen Youth Health Research Centre, 35 Poplar Rd, Parkville, 3052, Australia

3 Centre of Youth Mental Health, University of Melbourne, 35 Poplar Rd, Parkville, 3052, Australia

4 Mental Health Research Institute, University of Melbourne, Kenneth Myer Building, 30 Royal Parade, 3052, Parkville, Australia

5 University of Melbourne, Department of Psychiatry, Level 1 North, Main Block, Royal Melbourne Hospital, Parkville, 3052, Australia

6 Laboratory of Molecular Psychiatry, INCT for Translational Medicine, CNPq. Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, 90010-000, Brazil

7 Post-graduate Program in Biological Sciences: Biochemistry, Federal University of Rio Grande do Sul - UFRGS -, Porto Alegre, 90035-000, Brazil

8 Laboratory of Calcium Binding Proteins in the Central Nervous System, Department of Biochemistry, Federal University of Rio Grande do Sul - UFRGS -, Porto Alegre, 90035-000, Brazil

9 Discipline of Psychiatry, Sydney Medical School, University of Sydney, Sydney, 2006, Australia

10 CADE Clinic, Department of Psychiatry, Level 5 Building 36 Royal North Shore Hospital, St. Leonards, 2065, Australia

11 Department of Psychosomatic Medicine and Psychotherapy, Klinikum rechts der Isar der TU, München, Ismaninger Str. 22, 81675, Münich, Germany

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BMC Medicine 2012, 10:91  doi:10.1186/1741-7015-10-91

Published: 14 August 2012



N-acetyl cysteine (NAC) is a glutathione precursor that has been shown to have antidepressant efficacy in a placebo-controlled trial. The current study aimed to investigate the maintenance effects of NAC following eight weeks of open-label treatment for bipolar disorder.


The efficacy of a double blind randomized placebo controlled trial of 2 g/day NAC as adjunct maintenance treatment for bipolar disorder was examined. Participants (n = 149) had a Montgomery Asberg Depression Rating Score of ≥12 at trial entry and, after eight weeks of open-label NAC treatment, were randomized to adjunctive NAC or placebo, in addition to treatment as usual. Participants (primarily outpatients) were recruited through public and private services and through newspaper advertisements. Time to intervention for a mood episode was the primary endpoint of the study, and changes in mood symptoms, functionality and quality of life measures were secondary outcomes.


There was a substantial decrease in symptoms during the eight-week open-label NAC treatment phase. During the subsequent double-blind phase, there was minimal further change in outcome measures with scores remaining low. Consequently, from this low plateau, between-group differences did not emerge on recurrence, clinical functioning or quality of life measures.


There were no significant between-group differences in recurrence or symptomatic outcomes during the maintenance phase of the trial; however, these findings may be confounded by limitations.

Trial Registration

The trial was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12607000074493).

N-acetyl cysteine; depression; bipolar disorder; maintenance; mania; oxidative