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

      Affiliations

    • 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

      Affiliations

    • The Mental Health Research Institute of Victoria, Victoria, Australia
    • Monash University, Clayton, Australia
  • ,
  • Olivia Dean

      Affiliations

    • The Mental Health Research Institute of Victoria, Victoria, Australia
  • ,
  • Kristy Lu

      Affiliations

    • Department of Clinical and Biomedical Sciences, The University of Melbourne, Geelong, Australia
  • ,
  • Sue Jeavons

      Affiliations

    • Bendigo Health, Bendigo, Australia
  • ,
  • Ian Schapkaitz

      Affiliations

    • Department of Clinical and Biomedical Sciences, The University of Melbourne, Geelong, Australia
  • ,
  • Murray Anderson-Hunt

      Affiliations

    • Department of Clinical and Biomedical Sciences, The University of Melbourne, Geelong, Australia
  • ,
  • Ashley I. Bush

      Affiliations

    • 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
    • Corresponding Author InformationAddress 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 ,Revised 11 April 2008 ,Accepted 11 April 2008.

References 

  1. Ng F, Berk M, Dean O, Bush AI. Oxidative stress in psychiatric disorders: Evidence base and therapeutic implications. [published online ahead of print January 21] Int J Neuropsychopharmacol. 2008;
  2. Do KQ, Lauer CJ, Schreiber W, Zollinger M, Gutteck-Amsler U, Cuenod M, et al. gamma-Glutamylglutamine and taurine concentrations are decreased in the cerebrospinal fluid of drug-naive patients with schizophrenic disorders. J Neurochem. 1995;65:2652–2662
  3. Do KQ, Trabensinger MK, Lauer CJ, Dydak U, Hell D, Holsboer F, et al. Schizophrenia: Glutathione deficit in cerebrospinal fluid and prefrontal cortex in vivo. Eur J Neurosci. 2000;12:3721–3728
  4. Altschule MD, Goncz RM, Henneman DH, Holliday PD. Carbohydrate metabolism in brain disease (VII. The effect of glutathione on carbohydrate intermediary metabolism in schizophrenic and manic-depressive psychoses). AMA Arch Intern Med. 1957;99:22–27
  5. Andreazza AC, Cassini C, Rosa AR, Leite MC, de Almeida LM, Nardin P, et al. Serum S100B and antioxidant enzymes in bipolar patients. J Psychiatr Res. 2007;41:523–529
  6. Abdalla DS, Monteiro HP, Oliveira JA, Bechara EJ. Activities of superoxide dismutase and glutathione peroxidase in schizophrenic and manic-depressive patients. Clin Chem. 1986;32:805–807
  7. Kuloglu M, Ustundag B, Atmaca M, Canatan H, Tezcan AE, Cinkilinc N. Lipid peroxidation and antioxidant enzyme levels in patients with schizophrenia and bipolar disorder. Cell Biochem Funct. 2002;20:171–175
  8. Ozcan ME, Gulec M, Ozerol E, Polat R, Akyol O. Antioxidant enzyme activities and oxidative stress in affective disorders. Int Clin Psychopharmacol. 2004;19:89–95
  9. Henneman DH, Altschule MD. Immediate effects of shock therapies, epinephrine and ACTH on blood glutathione level of psychotic patients. J Appl Physiol. 1951;3:411–416
  10. Altschule MD, Siegel EP, Henneman DH. Blood glutathione level in mental disease before and after treatment. AMA Arch Neurol Psychiatry. 1952;67:64–68
  11. Bilici M, Efe H, Koroglu MA, Uydu HA, Bekaroglu M, Deger O. Antioxidative enzyme activities and lipid peroxidation in major depression: Alterations by antidepressant treatments. J Affect Disord. 2001;64:43–51
  12. El-Sherbiny DA, Khalifa AE, Attia AS, Eldenshary Eel-D. 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
  13. Eren I, Naziroglu M, Demirdas A, Celik O, Uguz AC, Altunbasak A, et al. Venlafaxine modulates depression-induced oxidative stress in brain and medulla of rat. Neurochem Res. 2007;32:495–505
  14. Sanchez-Reus MI, Gomez del Rio MA, Iglesias I, Elorza M, Slowing K, Benedi J. Standardized hypericum perforatum reduces oxidative stress and increases gene expression of antioxidant enzymes on rotenone-exposed rats. Neuropharmacology. 2007;52:606–616
  15. Wang JF, Azzam JE, Young LT. Valproate inhibits oxidative damage to lipid and protein in primary cultured rat cerebrocortical cells. Neuroscience. 2003;116:485–489
  16. Wang JF, Shao L, Sun X, Young LT. Glutathione S-transferase is a novel target for mood stabilizing drugs in primary cultured neurons. J Neurochem. 2004;88:1477–1484
  17. Bezchlibnyk YB, Wang JF, McQueen GM, Young LT. Gene expression differences in bipolar disorder revealed by cDNA array analysis of post-mortem frontal cortex. J Neurochem. 2001;79:826–834
  18. Tosic M, Ott J, Barral S, Bovet P, Deppen P, Gheorghita F, et al. Schizophrenia and oxidative stress: Glutamate cysteine ligase modifier as a susceptibility gene. Am J Hum Genet. 2006;79:586–592
  19. Burgunder JM, Varriale A, Lauterburg BH. Effect of N-acetylcysteine on plasma cysteine and glutathione following paracetamol administration. Eur J Clin Pharmacol. 1989;36:127–131
  20. Holdiness MR. Clinical pharmokinetics of N-acetylcysteine. Clin Pharmokinet. 1991;20:123–134
  21. Rothstein JD, Bristol LA, Hosler B, Brown RH, Kuncl RW. Chronic inhibition of superoxide dismutase produces apoptotic death of spinal neurons. Proc Natl Acad Sci U S A. 1994;91:4155–4159
  22. Koppal T, Drake J, Butterfield DA. 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
  23. Andreassen OA, Dedeoglu A, Klivenyi P, Beal MF, Bush AI. N-acetyl-L-cysteine improves survival and preserves motor performance in an animal model of familial amyotrophic lateral sclerosis. Neuroreport. 2000;11:2491–2493
  24. Berk M, Copolov D, Dean O, Lu K, Jeavons S, Schapkaitz I, et al. N-acetyl cysteine as a glutathione precursor for schizophrenia: A double-blind, randomized, placebo-controlled trial. [published online ahead of print April 22] Biol Psychiatry. 2008;
  25. Lavoie S, Murray MM, Deppen P, Knyazeva MG, Berk M, Boulat O, et al. Glutathione precursor, N-acetyl-cysteine, improves mismatch negativity in schizophrenia patients. [published online ahead of print November 14] Neuropsychopharmacology. 2007;
  26. Sachs GS, Nierenberg AA, Calabrese JR, Marangell LB, Wisniewski SR, Gyulai L, et al. Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med. 2007;356:1711–1722
  27. Beller EM, Gebski V, Keech AC. Randomisation in clinical trials. Med J Aust. 2002;177:565–567
  28. Adair JC, Knoefel JE, Morgan N. Controlled trial of N-acetylcysteine for patients with probable Alzheimer's disease. Neurology. 2001;57:1515–1517
  29. Van Schooten FJ, Besaratinia A, De Flora S, D'Agostini F, Izzotti A, Camoirano A, et al. Effects of oral administration of N-acetyl-L-cysteine: A multi-biomarker study in smokers. Cancer Epidemiol Biomarkers Prev. 2002;11:167–175
  30. Behr J, Degenkolb B, Krombach F, Vogelmeier C. Intracellular glutathione and bronchoalveolar cells in fibrosing alveolitis: Effects of N-acetylcysteine. Eur Respir J. 2002;19:906–911
  31. Demedts M, Behr J, Buhl R, Costabel U, Dekhuijzen R, Jansen HM, et al. High-dose acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med. 2005;353:2229–2242
  32. Berk M, Malhi GS, Cahill C, Carman AC, Hadzi-Pavlovic D, Hawkins MT, et al. The Bipolar Depression Rating Scale (BDRS): Its development, validation and utility. Bipolar Disord. 2007;9:571–579
  33. International conference on harmonisation; guidance on statistical principles for clinical trials; availability—FDA (Notice). Fed Regist. 1998;63:49583–49598
  34. Mallinckrodt C, Watkin J, Molenberghs G, Carroll R. Choice of the primary analysis in longitudinal clinical trials. Pharm Stat. 2004;3:161–169
  35. Cohen J. Statistical Power Analysis for the Behavioral Sciences. 2nd ed.. Hillsdale, NJ: Lawrence Earlbaum Associates; 1988;
  36. Hochberg Y. A sharper Bonferroni procedure for multiple tests of significance. Biometrika. 1988;75:800–802
  37. Steullet P, Neijt HC, Cuenod M, Do KQ. Synaptic plasticity impairment and hypofunction of NMDA receptors induced by glutathione deficit: Relevance to schizophrenia. Neuroscience. 2006;137:807–819
  38. Munoz AM, Rey P, Soto-Otero R, Guerra MJ, Labandeira-Garcia JL. Systemic administration of N-acetylcysteine protects dopaminergic neurons against 6-hydroxydopamine-induced degeneration. J Neurosci Res. 2004;76:551–562
  39. Atkuri KR, Mantovani JJ, Herzenberg LA, Herzenberg LA. N-acetylcysteine—a safe antidote for cysteine/glutathione deficiency. Curr Opin Pharmacol. 2006;7:355–359
  40. Belmaker RH. Treatment of bipolar depression. N Engl J Med. 2007;356:1771–1773

PII: S0006-3223(08)00500-3

doi: 10.1016/j.biopsych.2008.04.022

Biological Psychiatry
Volume 64, Issue 6 , Pages 468-475 , 15 September 2008