N-Acetyl Cysteine for Depressive Symptoms in Bipolar Disorder—A Double-Blind Randomized Placebo-Controlled Trial

Berk, Michael; Copolov, David L.; Dean, Olivia; Lu, Kristy; Jeavons, Sue; Schapkaitz, Ian; Anderson-Hunt, Murray; Bush, Ashley I.

doi:10.1016/j.biopsych.2008.04.022

« Previous Next »Biological Psychiatry
Volume 64, Issue 6 , Pages 468-475, 15 September 2008

N-Acetyl Cysteine for Depressive Symptoms in Bipolar Disorder—A Double-Blind Randomized Placebo-Controlled Trial

Michael Berk
- The Mental Health Research Institute of Victoria, Victoria, Australia
- Department of Clinical and Biomedical Sciences, The University of Melbourne, Geelong, Australia
- Orygen Youth Health, Melbourne, Australia
David L. Copolov
- The Mental Health Research Institute of Victoria, Victoria, Australia
- Monash University, Clayton, Australia
Olivia Dean
- The Mental Health Research Institute of Victoria, Victoria, Australia
Kristy Lu
- Department of Clinical and Biomedical Sciences, The University of Melbourne, Geelong, Australia
Sue Jeavons
- Bendigo Health, Bendigo, Australia
Ian Schapkaitz
- Department of Clinical and Biomedical Sciences, The University of Melbourne, Geelong, Australia
Murray Anderson-Hunt
- Department of Clinical and Biomedical Sciences, The University of Melbourne, Geelong, Australia
Ashley I. Bush
- The Mental Health Research Institute of Victoria, Victoria, Australia
- Department of Pathology, University of Melbourne, Geelong, Australia
- Department of Psychiatry, Massachusetts General Hospital, Charlestown, Massachusetts
- Address reprint requests to Ashley I. Bush, M.D., Ph.D., The Mental Health Research Institute of Victoria, 155 Oak Street, Parkville, Victoria 3052, Australia

Received 31 December 2007; received in revised form 11 April 2008; accepted 11 April 2008. published online 06 June 2008.

Background

Treatment-resistant subthreshold depression is a major problem in bipolar disorder. Both depression and bipolar disorder are complicated by glutathione depletion. We hypothesized that treatment with N-acetyl cysteine (NAC), a safe, orally bioavailable precursor of glutathione, may improve the depressive component of bipolar disorder.

Methods

A randomized, double-blind, multicenter, placebo-controlled study of individuals (n = 75) with bipolar disorder in the maintenance phase treated with NAC (1 g twice daily) adjunctive to usual medication over 24 weeks, with a 4-week washout. The two primary outcomes were the Montgomery Asberg Depression Rating Scale (MADRS) and time to a mood episode. Secondary outcomes included the Bipolar Depression Rating Scale and 11 other ratings of clinical status, quality of life, and functioning.

Results

NAC treatment caused a significant improvement on the MADRS (least squares mean difference [95% confidence interval]: −8.05 [−13.16, −2.95], p = .002) and most secondary scales at end point. Benefit was evident by 8 weeks on the Global Assessment of Functioning Scale and Social and Occupational Functioning Assessment Scale and at 20 weeks on the MADRS. Improvements were lost after washout. There was no effect of NAC on time to a mood episode (log-rank test: p = .968) and no significant between-group differences in adverse events. Effect sizes at end point were medium to high for improvements in MADRS and 9 of the 12 secondary readouts.