N-acetylcysteine for major mental disorders: a systematic review and meta-analysis of randomized controlled trials

Acta Psychiatrica Scandinavica

Volumn 137, Issue 5, 2018, Pages 391-400

  Zheng, W ^a   Zhang, Q E ^b   Cai, D B ^c   Yang, X H ^a   Qiu, Y ^a   Ungvari, G S ^d   Ng, C H ^e   Berk, M ^e,f   Ning, Y P ^a   Xiang, Y T ^g  

^a GUANGZHOU MEDICAL UNIVERSITY   (China)

^b CAPITAL MEDICAL UNIVERSITY   (China)

^c GUANGZHOU UNIVERSITY OF CHINESE MEDICINE   (China)

^d UNIVERSITY OF NOTRE DAME   (Australia)

^e UNIVERSITY OF MELBOURNE   (Australia)

^f DEAKIN UNIVERSITY   (Australia)

^g University of Macau   (Macao)

Author keywords

bipolar disorder; major depressive disorder; N acetylcysteine; oxidative stress; schizophrenia

Indexed keywords

ACETYLCYSTEINE; ANTIOXIDANT;

ADJUVANT THERAPY; ARTICLE; BIPOLAR DISORDER; CONSTIPATION; DIARRHEA; DROWSINESS; DRUG EFFECT; DRUG EFFICACY; DRUG SAFETY; DRUG WITHDRAWAL; HEADACHE; HUMAN; MAJOR DEPRESSION; MENTAL DISEASE; META ANALYSIS; NAUSEA; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); SCHIZOPHRENIA; SYMPTOM ASSESSMENT; SYSTEMATIC REVIEW; TREATMENT OUTCOME; YOUNG MANIA RATING SCALE;

ACETYLCYSTEINE; ANTIOXIDANTS; BIPOLAR DISORDER; DEPRESSIVE DISORDER, MAJOR; HUMANS; RANDOMIZED CONTROLLED TRIALS AS TOPIC; SCHIZOPHRENIA;

EID: 85045148315     PISSN: 0001690X     EISSN: 16000447     Source Type: Journal    
DOI: 10.1111/acps.12862     Document Type: Article

References (60)

1. Whiteford HA, Degenhardt L, Rehm J et al. Global burden of disease attributable to mental and substance use disorders: findings from the Global Burden of Disease Study 2010. Lancet 2013;382:1575–1586.
2. Mathers C, Boerma JT, Fat DM, World Health Organization. The global burden of disease: 2004 update. Published by the Harvard School of Public Health on behalf of the World Health Organization and the World Bank, 2008.
3. Chesney E, Goodwin GM, Fazel S. Risks of all-cause and suicide mortality in mental disorders: a meta-review. World Psychiatry 2014;13:153–160.
4. Correll CU, Ng-Mak DS, Stafkey-Mailey D, Farrelly E, Rajagopalan K, Loebel A. Cardiometabolic comorbidities, readmission, and costs in schizophrenia and bipolar disorder: a real-world analysis. Ann Gen Psychiatry 2017;16:9.
5. Correll CU, Solmi M, Veronese N et al. Prevalence, incidence and mortality from cardiovascular disease in patients with pooled and specific severe mental illness: a large-scale meta-analysis of 3,211,768 patients and 113,383,368 controls. World Psychiatry 2017;16:163–180.
6. Torrey EF, Davis JM. Adjunct treatments for schizophrenia and bipolar disorder: what to try when you are out of ideas. Clin Schizophr Relat Psychoses 2012;5:208–216.
7. Pawelczyk T, Grancow-Grabka M, Trafalska E, Szemraj J, Pawelczyk A. Oxidative stress reduction related to the efficacy of n-3 polyunsaturated fatty acids in first episode schizophrenia: secondary outcome analysis of the OFFER randomized trial. Prostaglandins Leukot Essent Fatty Acids 2017;121:7–13.
8. Flatow J, Buckley P, Miller BJ. Meta-analysis of oxidative stress in schizophrenia. Biol Psychiat 2013;74:400–409.
9. Bailey GP, Wood DM, Archer JR, Rab E, Flanagan RJ, Dargan PI. An assessment of the variation in the concentration of acetylcysteine in infusions for the treatment of paracetamol overdose. Br J Clin Pharmacol 2017;83:393–399.
10. Cumurcu BE, Ozyurt H, Etikan I, Demir S, Karlidag R. Total antioxidant capacity and total oxidant status in patients with major depression: impact of antidepressant treatment. Psychiatry Clin Neurosci 2009;63:639–645.
11. Wong A, Landersdorfer C, Graudins A. Pharmacokinetic modelling of modified acetylcysteine infusion regimens used in the treatment of paracetamol poisoning. Eur J Clin Pharmacol 2017;73:1103–1110.
12. Zhang XY, Tan YL, Cao LY et al. Antioxidant enzymes and lipid peroxidation in different forms of schizophrenia treated with typical and atypical antipsychotics. Schizophr Res 2006;81:291.
13. Frey BN, Valvassori SS, Reus GZ et al. Effects of lithium and valproate on amphetamine-induced oxidative stress generation in an animal model of mania. J Psychiatry Neurosci 2006;31:326–332.
14. Shao L, Young LT, Wang J. The effect of the mood stabilizer valproate on the major brain antioxidant glutathione and functionally related enzymes in human neuroblastoma SH-SY5Y cells, in Convention of the Society-Of-Biological-Psychiatry, 2005, pp. 19S.
15. Zheng W, Cai DB, Yang XH et al. Adjunctive celecoxib for schizophrenia: a meta-analysis of randomized, double-blind, placebo-controlled trials. J Psychiatr Res 2017;92:139–146.
16. Magalhaes PV, Dean O, Andreazza AC, Berk M, Kapczinski F. Antioxidant treatments for schizophrenia. Cochrane Database Syst Rev 2016;(2):CD008919.
17. Dringen R, Hirrlinger J. Glutathione pathways in the brain. Biol Chem 2003;384:505–516.
18. Berk M, Malhi GS, Gray LJ, Dean OM. The promise of N-acetylcysteine in neuropsychiatry. Trends Pharmacol Sci 2013;34:167–177.
19. Dean O, Giorlando F, Berk M. N-acetylcysteine in psychiatry: current therapeutic evidence and potential mechanisms of action. J Psychiatry Neurosci 2011;36:78–86.
20. Holdiness MR. Clinical pharmacokinetics of N-acetylcysteine. Clin Pharmacokinet 1991;20:123–134.
21. Wang CC, Fang KM, Yang CS, Tzeng SF. Reactive oxygen species-induced cell death of rat primary astrocytes through mitochondria-mediated mechanism. J Cell Biochem 2009;107:933–943.
22. Otte DM, Sommersberg B, Kudin A et al. N-acetyl cysteine treatment rescues cognitive deficits induced by mitochondrial dysfunction in G72/G30 transgenic mice. Neuropsychopharmacology 2011;36:2233–2243.
23. Iyer SS, Jones DP, Brigham KL, Rojas M. Oxidation of plasma cysteine/cystine redox state in endotoxin-induced lung injury. Am J Respir Cell Mol Biol 2009;40:90–98.
24. Banjac A, Perisic T, Sato H et al. The cystine/cysteine cycle: a redox cycle regulating susceptibility versus resistance to cell death. Oncogene 2008;27:1618–1628.
25. Ciobica A, Padurariu M, Dobrin I, Stefanescu C, Dobrin R. Oxidative stress in schizophrenia – focusing on the main markers. Psychiatr Danub 2011;23:237–245.
26. Scola G, Andreazza AC. Oxidative stress in bipolar disorder. New York, NY: Springer, 2015.
27. Stefanescu C, Ciobica A. The relevance of oxidative stress status in first episode and recurrent depression. J Affect Disord 2012;143:34–38.
28. Berk M, Copolov D, Dean O et al. N-acetyl cysteine as a glutathione precursor for schizophrenia–a double-blind, randomized, placebo-controlled trial. Biol Psychiatry 2008;64:361–368.
29. Berk M, Copolov DL, Dean O et al. N-acetyl cysteine for depressive symptoms in bipolar disorder–a double-blind randomized placebo-controlled trial. Biol Psychiatry 2008;64:468–475.
30. Berk M, Dean OM, Cotton SM et al. The efficacy of adjunctive N-acetylcysteine in major depressive disorder: a double-blind, randomized, placebo-controlled trial. J Clin Psychiatry 2014;75:628–636.
31. Farokhnia M, Azarkolah A, Adinehfar F et al. N-acetylcysteine as an adjunct to risperidone for treatment of negative symptoms in patients with chronic schizophrenia: a randomized, double-blind, placebo-controlled study. Clin Neuropharmacol 2013;36:185–192.
32. Hu CC, Xie J. N-acetylcysteine add on treatment for depressive symptoms in bipolar disorder: a comparative trial (in Chinese). Clin Educ Gen Pract 2012;10:515–517.
33. Zhang JH, Chen B, Lu JR. Treatment effect of risperidone alone and combined with N-acetyl-cysteine for first-episode schizophrenic patients (in Chinese). J Clin Psychiatry 2015;25:394–396.
34. Chen AT, Chibnall JT, Nasrallah HA. Placebo-controlled augmentation trials of the antioxidant NAC in schizophrenia: a review. Ann Clin Psychiatry 2016;28:190–196.
35. Fernandes BS, Dean OM, Dodd S, Malhi GS, Berk M. N-Acetylcysteine in depressive symptoms and functionality: a systematic review and meta-analysis. J Clin Psychiatry 2016;77:e457–e466.
36. Higgins J, Higgins J. Cochrane handbook for systematic reviews of interventions. Chichester, UK: John Wiley & Sons Ltd; 2008.
37. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med 2009;151:264–269. w264.
38. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7:177–188.
39. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002;21:1539–1558.
40. Jadad AR, Moore RA, Carroll D et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17:1–12.
41. Balshem H, Helfand M, Schunemann HJ et al. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol 2011;64:401–406.
42. Atkins D, Best D, Briss PA et al. Grading quality of evidence and strength of recommendations. BMJ 2004;328:1490.
43. Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 1987;13:261–276.
44. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315:629–634.
45. Bulut M, Savas HA, Altindag A, Virit O, Dalkilic A. Beneficial effects of N-acetylcysteine in treatment resistant schizophrenia. World J Biol Psychiatry 2009;10:626–628.
46. Carvalho AF, Macedo DS, Goulia P, Hyphantis TN. N-acetylcysteine augmentation to tranylcypromine in treatment-resistant major depression. J Clin Psychopharmacol 2013;33:719–720.
47. Berk M, Dean O, Cotton SM et al. The efficacy of N-acetylcysteine as an adjunctive treatment in bipolar depression: an open label trial. J Affect Disord 2011;135:389–394.
48. Wang JF, Shao L, Sun X, Young LT. Increased oxidative stress in the anterior cingulate cortex of subjects with bipolar disorder and schizophrenia. Bipolar Disord 2009;11:523–529.
49. Kunz M, Gama CS, Andreazza AC et al. Elevated serum superoxide dismutase and thiobarbituric acid reactive substances in different phases of bipolar disorder and in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2008;32:1677–1681.
50. Liu T, Zhong S, Liao X et al. A meta-analysis of oxidative stress markers in depression. PLoS ONE 2015;10:e0138904.
51. Konradi C, Eaton M, MacDonald ML, Walsh J, Benes FM, Heckers S. Molecular evidence for mitochondrial dysfunction in bipolar disorder. Arch Gen Psychiatry 2004;61:300–308.
52. Anglin RE, Garside SL, Tarnopolsky MA, Mazurek MF, Rosebush PI. The psychiatric manifestations of mitochondrial disorders: a case and review of the literature. J Clin Psychiatry 2012;73:506–512.
53. Amrouche-Mekkioui I, Djerdjouri B. N-acetylcysteine improves redox status, mitochondrial dysfunction, mucin-depleted crypts and epithelial hyperplasia in dextran sulfate sodium-induced oxidative colitis in mice. Eur J Pharmacol 2012;691:209–217.
54. Goldsmith DR, Rapaport MH, Miller BJ. A meta-analysis of blood cytokine network alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder and depression. Mol Psychiatry 2016;21:1696–1709.
55. Palacio JR, Markert UR, Martinez P. Anti-inflammatory properties of N-acetylcysteine on lipopolysaccharide-activated macrophages. Inflamm Res 2011;60:695–704.
56. Palmer LA, Doctor A, Chhabra P et al. S-nitrosothiols signal hypoxia-mimetic vascular pathology. J Clin Investig 2007;117:2592–2601.
57. Duailibi MS, Cordeiro Q, Brietzke E et al. N-acetylcysteine in the treatment of craving in substance use disorders: systematic review and meta-analysisAm J Addict 2017;26:660–666.
58. Oliver G, Dean O, Camfield D et al. N-acetyl cysteine in the treatment of obsessive compulsive and related disorders: a systematic review. Clin Psychopharmacol Neurosci 2015;13:12–24.
59. Prado E, Maes M, Piccoli LG et al. N-acetylcysteine for therapy-resistant tobacco use disorder: a pilot study. Redox Rep 2015;20:215–222.
60. Grant JE, Odlaug BL, Kim SW. N-acetylcysteine, a glutamate modulator, in the treatment of trichotillomania: a double-blind, placebo-controlled study. Arch Gen Psychiatry 2009;66:756–763.