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.
Conclusions
NAC appears a safe and effective augmentation strategy for depressive symptoms in
bipolar disorder.
Key Words
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References
- Oxidative stress in psychiatric disorders: Evidence base and therapeutic implications.Int J Neuropsychopharmacol. 2008; ([published online ahead of print January 21])
- gamma-Glutamylglutamine and taurine concentrations are decreased in the cerebrospinal fluid of drug-naive patients with schizophrenic disorders.J Neurochem. 1995; 65: 2652-2662
- Schizophrenia: Glutathione deficit in cerebrospinal fluid and prefrontal cortex in vivo.Eur J Neurosci. 2000; 12: 3721-3728
- Carbohydrate metabolism in brain disease.AMA Arch Intern Med. 1957; 99: 22-27
- Serum S100B and antioxidant enzymes in bipolar patients.J Psychiatr Res. 2007; 41: 523-529
- Activities of superoxide dismutase and glutathione peroxidase in schizophrenic and manic-depressive patients.Clin Chem. 1986; 32: 805-807
- Lipid peroxidation and antioxidant enzyme levels in patients with schizophrenia and bipolar disorder.Cell Biochem Funct. 2002; 20: 171-175
- Antioxidant enzyme activities and oxidative stress in affective disorders.Int Clin Psychopharmacol. 2004; 19: 89-95
- Immediate effects of shock therapies, epinephrine and ACTH on blood glutathione level of psychotic patients.J Appl Physiol. 1951; 3: 411-416
- Blood glutathione level in mental disease before and after treatment.AMA Arch Neurol Psychiatry. 1952; 67: 64-68
- Antioxidative enzyme activities and lipid peroxidation in major depression: Alterations by antidepressant treatments.J Affect Disord. 2001; 64: 43-51
- Hypericum perforatum extract demonstrates antioxidant properties against elevated rat brain oxidative status induced by amnestic dose of scopolamine.Pharmacol Biochem Behav. 2003; 76: 525-533
- Venlafaxine modulates depression-induced oxidative stress in brain and medulla of rat.Neurochem Res. 2007; 32: 495-505
- Standardized hypericum perforatum reduces oxidative stress and increases gene expression of antioxidant enzymes on rotenone-exposed rats.Neuropharmacology. 2007; 52: 606-616
- Valproate inhibits oxidative damage to lipid and protein in primary cultured rat cerebrocortical cells.Neuroscience. 2003; 116: 485-489
- Glutathione S-transferase is a novel target for mood stabilizing drugs in primary cultured neurons.J Neurochem. 2004; 88: 1477-1484
- Gene expression differences in bipolar disorder revealed by cDNA array analysis of post-mortem frontal cortex.J Neurochem. 2001; 79: 826-834
- Schizophrenia and oxidative stress: Glutamate cysteine ligase modifier as a susceptibility gene.Am J Hum Genet. 2006; 79: 586-592
- Effect of N-acetylcysteine on plasma cysteine and glutathione following paracetamol administration.Eur J Clin Pharmacol. 1989; 36: 127-131
- Clinical pharmokinetics of N-acetylcysteine.Clin Pharmokinet. 1991; 20: 123-134
- Chronic inhibition of superoxide dismutase produces apoptotic death of spinal neurons.Proc Natl Acad Sci U S A. 1994; 91: 4155-4159
- In vivo modulation of rodent glutathione and its role in peroxynitrite-induced neocortical synaptosomal membrane protein damage.Biochimica et Biophysica Acta. 1999; 1453: 407-411
- N-acetyl-L-cysteine improves survival and preserves motor performance in an animal model of familial amyotrophic lateral sclerosis.Neuroreport. 2000; 11: 2491-2493
- N-acetyl cysteine as a glutathione precursor for schizophrenia: A double-blind, randomized, placebo-controlled trial.Biol Psychiatry. 2008; ([published online ahead of print April 22])
- Glutathione precursor, N-acetyl-cysteine, improves mismatch negativity in schizophrenia patients.Neuropsychopharmacology. 2007; ([published online ahead of print November 14])
- Effectiveness of adjunctive antidepressant treatment for bipolar depression.N Engl J Med. 2007; 356: 1711-1722
- Randomisation in clinical trials.Med J Aust. 2002; 177: 565-567
- Controlled trial of N-acetylcysteine for patients with probable Alzheimer's disease.Neurology. 2001; 57: 1515-1517
- Effects of oral administration of N-acetyl-L-cysteine: A multi-biomarker study in smokers.Cancer Epidemiol Biomarkers Prev. 2002; 11: 167-175
- Intracellular glutathione and bronchoalveolar cells in fibrosing alveolitis: Effects of N-acetylcysteine.Eur Respir J. 2002; 19: 906-911
- High-dose acetylcysteine in idiopathic pulmonary fibrosis.N Engl J Med. 2005; 353: 2229-2242
- The Bipolar Depression Rating Scale (BDRS): Its development, validation and utility.Bipolar Disord. 2007; 9: 571-579
- International conference on harmonisation; guidance on statistical principles for clinical trials; availability—FDA.Fed Regist. 1998; 63: 49583-49598
- Choice of the primary analysis in longitudinal clinical trials.Pharm Stat. 2004; 3: 161-169
- Statistical Power Analysis for the Behavioral Sciences.2nd ed. Lawrence Earlbaum Associates, Hillsdale, NJ1988
- A sharper Bonferroni procedure for multiple tests of significance.Biometrika. 1988; 75: 800-802
- Synaptic plasticity impairment and hypofunction of NMDA receptors induced by glutathione deficit: Relevance to schizophrenia.Neuroscience. 2006; 137: 807-819
- Systemic administration of N-acetylcysteine protects dopaminergic neurons against 6-hydroxydopamine-induced degeneration.J Neurosci Res. 2004; 76: 551-562
- N-acetylcysteine—a safe antidote for cysteine/glutathione deficiency.Curr Opin Pharmacol. 2006; 7: 355-359
- Treatment of bipolar depression.N Engl J Med. 2007; 356: 1771-1773
Article Info
Publication History
Published online: June 06, 2008
Accepted:
April 11,
2008
Received in revised form:
April 11,
2008
Received:
December 31,
2007
Identification
Copyright
© 2008 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
ScienceDirect
Access this article on ScienceDirectLinked Article
- Regarding “N-Acetyl Cysteine as a Glutathione Precursor for Schizophrenia—A Double-Blind, Randomized, Placebo-Controlled Trial”Biological PsychiatryVol. 64Issue 9
- PreviewI read with great interest the recent article by Berk et al. (1) about the efficacy of N-acetyl cysteine (NAC), a precursor of the antioxidant glutathione (GSH), in patients with chronic schizophrenia. That was a randomized, multicenter (four private and public general psychiatry inpatient and outpatient facilities in Victoria, Australia, and one public clinic in Lausanne, Switzerland), double-blind, placebo-controlled study. Subjects (n = 69) treated with NAC (1 g orally twice daily [b.i.d.] for 24 weeks) improved more than placebo-treated subjects (n = 71) over the study period in Positive and Negative Syndrome Scale (PANSS) total (p = .009), PANSS negative (p = .018), and PANNS general (p = .035) scores as well as in Clinical Global Impression (CGI)-Severity (CGI-S) (p = .004) and CGI-Improvement (CGI-I) (p = .025) scores (1).
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