European Journal of Clinical Pharmacology

, Volume 75, Issue 3, pp 289–301 | Cite as

RETRACTED ARTICLE: Effect of N-acetyl cysteine (NAC) supplementation on positive and negative syndrome scale in schizophrenia: a systematic review and meta-analysis of randomised controlled trials

  • Amir Ghaderi
  • Anna Bussu
  • Catherine Tsang
  • Sadegh JafarnejadEmail author



To conduct a systematic review and meta-analysis of published randomised controlled trials on the efficacy of NAC supplementation on positive and negative syndrome scale in schizophrenia.


A meta-analysis was conducted, and studies were identified by a search of electronic databases from inception to May 2018. Combined and stratified analyses were used.


Seven trials were identified, and data from n = 447 participants were included. Pooled analysis showed improvement of positive and negative syndrome scale following NAC treatment compared with placebo, for total (SMB = − 0.96) [95% CI − 1.69, − 0.24; P = 0.009], general (SMB = − 1.04) [95% CI − 1.80, − 0.27; P = 0.008] and negative (SMB = − 0.73) [95% CI − 1.29, − 0.17; P = 0.01] scores, respectively. Significant heterogeneity was found, and subgroup analysis showed significant reductions in studies with a treatment duration of ≤ 24 weeks, with a considerable effect size on total, general, and negative scores (Total SMD = − 0.83; General SMD = − 0.67; Negative SMD = − 1.09) following NAC.


NAC improved all aspects of positive and negative syndrome scale in schizophrenic populations and may be more efficacious with treatment durations up to 24 weeks.


N-acetyl cysteine Schizophrenia PANSS Meta-analysis 


  1. 1.
    Mitra S, Natarajan R, Ziedonis D, Fan X (2017) Antioxidant and anti-inflammatory nutrient status, supplementation, and mechanisms in patients with schizophrenia. Prog Neuro-Psychopharmacol Biol Psychiatry 78:1–11CrossRefGoogle Scholar
  2. 2.
    Seeman MV (2007) Symptoms of schizophrenia: normal adaptations to inability. Med Hypotheses 69(2):253–257CrossRefGoogle Scholar
  3. 3.
    Chowdari KV, Bamne MN, Nimgaonkar VL (2011) Genetic association studies of antioxidant pathway genes and schizophrenia. Antioxid Redox Signal 15(7):2037–2045CrossRefGoogle Scholar
  4. 4.
    Rabinowitz J, Levine SZ, Garibaldi G, Bugarski-Kirola D, Berardo CG, Kapur S (2012) Negative symptoms have greater impact on functioning than positive symptoms in schizophrenia: analysis of CATIE data. Schizophr Res 137(1–3):147–150CrossRefGoogle Scholar
  5. 5.
    Rossell SL, Francis PS, Galletly C, Harris A, Siskind D, Berk M, Bozaoglu K, Dark F, Dean O, Liu D, Meyer D, Neill E, Phillipou A, Sarris J, Castle DJ (2016) N-acetylcysteine (NAC) in schizophrenia resistant to clozapine: a double blind randomised placebo controlled trial targeting negative symptoms. BMC Psychiatry 16(1):320CrossRefGoogle Scholar
  6. 6.
    Yao JK, Keshavan MS (2011) Antioxidants, redox signaling, and pathophysiology in schizophrenia: an integrative view. Antioxid Redox Signal 15(7):2011–2035CrossRefGoogle Scholar
  7. 7.
    Bloch MH (2009) Trichotillomania across the life span. J Am Acad Child Adolesc Psychiatry 48(9):879–883CrossRefGoogle Scholar
  8. 8.
    Marek GJ, Behl B, Bespalov AY, Gross G, Lee Y, Schoemaker H (2010) Glutamatergic (N-methyl-D-aspartate receptor) hypofrontality in schizophrenia: too little juice or a miswired brain? Mol Pharmacol 77(3):317–326CrossRefGoogle Scholar
  9. 9.
    Pavlović D et al (2002) Oxidative stress as marker of positive symptoms in schizophrenia. Facta Univ 9:157–161Google Scholar
  10. 10.
    Gawryluk JW, Wang JF, Andreazza AC, Shao L, Young LT (2011) Decreased levels of glutathione, the major brain antioxidant, in post-mortem prefrontal cortex from patients with psychiatric disorders. Int J Neuropsychopharmacol 14(1):123–130CrossRefGoogle Scholar
  11. 11.
    Raffa M, Atig F, Mhalla A, Kerkeni A, Mechri A (2011) Decreased glutathione levels and impaired antioxidant enzyme activities in drug-naive first-episode schizophrenic patients. BMC Psychiatry 11:124CrossRefGoogle Scholar
  12. 12.
    Dickinson D, Harvey PD (2009) Systemic hypotheses for generalized cognitive deficits in schizophrenia: a new take on an old problem. Schizophr Bull 35(2):403–414CrossRefGoogle Scholar
  13. 13.
    Lewis R (2004) Should cognitive deficit be a diagnostic criterion for schizophrenia? J Psychiatry Neurosci 29(2):102–113Google Scholar
  14. 14.
    Hamer S, Haddad PM (2007) Adverse effects of antipsychotics as outcome measures. Br J Psychiatry Suppl 50:s64–s70CrossRefGoogle Scholar
  15. 15.
    Harrison G, Hopper K, Craig T, Laska E, Siegel C, Wanderling J, Dube KC, Ganev K, Giel R, der Heiden WA, Holmberg SK, Janca A, Lee PWH, León CA, Malhotra S, Marsella AJ, Nakane Y, Sartorius N, Shen Y, Skoda C, Thara R, Tsirkin SJ, Varma VK, Walsh D, Wiersma D (2001) Recovery from psychotic illness: a 15- and 25-year international follow-up study. Br J Psychiatry 178:506–517CrossRefGoogle Scholar
  16. 16.
    Reddy R, Reddy R (2011) Antioxidant therapeutics for schizophrenia. Antioxid Redox Signal 15(7):2047–2055CrossRefGoogle Scholar
  17. 17.
    Bitanihirwe BK, Woo TU (2011) Oxidative stress in schizophrenia: an integrated approach. Neurosci Biobehav Rev 35(3):878–893CrossRefGoogle Scholar
  18. 18.
    Arakawa M, Ito Y (2007) N-acetylcysteine and neurodegenerative diseases: basic and clinical pharmacology. Cerebellum 6(4):308–314CrossRefGoogle Scholar
  19. 19.
    Choy KH et al (2010) Effects of N-acetyl-cysteine treatment on glutathione depletion and a short-term spatial memory deficit in 2-cyclohexene-1-one-treated rats. Eur J Pharmacol 649(1–3):224–228CrossRefGoogle Scholar
  20. 20.
    Holmay MJ, Terpstra M, Coles LD, Mishra U, Ahlskog M, Öz G, Cloyd JC, Tuite PJ (2013) N-acetylcysteine boosts brain and blood glutathione in Gaucher and Parkinson diseases. Clin Neuropharmacol 36(4):103–106CrossRefGoogle Scholar
  21. 21.
    Steullet P, Neijt HC, Cuénod M, Do KQ (2006) Synaptic plasticity impairment and hypofunction of NMDA receptors induced by glutathione deficit: relevance to schizophrenia. Neuroscience 137(3):807–819CrossRefGoogle Scholar
  22. 22.
    Gere-Paszti E, Jakus J (2009) The effect of N-acetylcysteine on amphetamine-mediated dopamine release in rat brain striatal slices by ion-pair reversed-phase high performance liquid chromatography. Biomed Chromatogr 23(6):658–664CrossRefGoogle Scholar
  23. 23.
    Otte DM, Sommersberg B, Kudin A, Guerrero C, Albayram Ö, Filiou MD, Frisch P, Yilmaz Ö, Drews E, Turck CW, Bilkei-Gorzó A, Kunz WS, Beck H, Zimmer A (2011) N-acetyl cysteine treatment rescues cognitive deficits induced by mitochondrial dysfunction in G72/G30 transgenic mice. Neuropsychopharmacology 36(11):2233–2243CrossRefGoogle Scholar
  24. 24.
    Csontos C, Rezman B, Foldi V, Bogar L, Drenkovics L, Röth E, Weber G, Lantos J (2012) Effect of N-acetylcysteine treatment on oxidative stress and inflammation after severe burn. Burns 38(3):428–437CrossRefGoogle Scholar
  25. 25.
    Kigerl KA, Ankeny DP, Garg SK, Wei P, Guan Z, Lai W, McTigue DM, Banerjee R, Popovich PG (2012) System x(c)(−) regulates microglia and macrophage glutamate excitotoxicity in vivo. Exp Neurol 233(1):333–341CrossRefGoogle Scholar
  26. 26.
    Bulut M, Savas HA, Altindag A, Virit O, Dalkilic A (2009) Beneficial effects of N-acetylcysteine in treatment resistant schizophrenia. World J Biol Psychiatry 10(4 Pt 2):626–628CrossRefGoogle Scholar
  27. 27.
    Rapado-Castro M, Dodd S, Bush AI, Malhi GS, Skvarc DR, On ZX, Berk M, Dean OM (2017) Cognitive effects of adjunctive N-acetyl cysteine in psychosis. Psychol Med 47(5):866–876CrossRefGoogle Scholar
  28. 28.
    Sansone RA, Sansone LA (2011) Getting a knack for NAC: N-acetyl-cysteine. Innov Clin Neurosci 8(1):10–14Google Scholar
  29. 29.
    Tsai GE, Lin PY (2010) Strategies to enhance N-methyl-D-aspartate receptor-mediated neurotransmission in schizophrenia, a critical review and meta-analysis. Curr Pharm Des 16(5):522–537CrossRefGoogle Scholar
  30. 30.
    Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med 151(4):264–269 w64CrossRefGoogle Scholar
  31. 31.
    Association AP (2013) Diagnostic and statistical manual of mental disorders (DSM-5®). American Psychiatric PubGoogle Scholar
  32. 32.
    Kay SR, Fiszbein A, Opler LA (1987) The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 13(2):261–276CrossRefGoogle Scholar
  33. 33.
    Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJM, Gavaghan DJ, McQuay HJ (1996) Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 17(1):1–12CrossRefGoogle Scholar
  34. 34.
    Jafarnejad S, Tsang C, Taghizadeh M, Asemi Z, Keshavarz SA (2018) A meta-analysis of cumin (Cuminum cyminim L.) consumption on metabolic and anthropometric indices in overweight and type 2 diabetics. J Funct Foods 44:313–321CrossRefGoogle Scholar
  35. 35.
    Jafarnejad S, Keshavarz SA, Mahbubi S, Saremi S, Arab A, Abbasi S, Djafarian K (2017) Effect of ginger (Zingiber officinale) on blood glucose and lipid concentrations in diabetic and hyperlipidemic subjects: a meta-analysis of randomized controlled trials. J Funct Foods 29:127–134CrossRefGoogle Scholar
  36. 36.
    Hosseini B et al (2018) The effect of omega-3 fatty acids, EPA, and/or DHA on male infertility: a systematic review and meta-analysis. J Dietary Suppl:1–12Google Scholar
  37. 37.
    Gopalakrishnan S, Ganeshkumar P (2013) Systematic reviews and meta-analysis: understanding the best evidence in primary healthcare. J Family Med Prim Care 2(1):9–14CrossRefGoogle Scholar
  38. 38.
    Rapado-Castro M, Berk M, Venugopal K, Bush AI, Dodd S, Dean OM (2015) Towards stage specific treatments: effects of duration of illness on therapeutic response to adjunctive treatment with N-acetyl cysteine in schizophrenia. Prog Neuro-Psychopharmacol Biol Psychiatry 57:69–75CrossRefGoogle Scholar
  39. 39.
    Higgins JP et al (2011) The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ 343:d5928CrossRefGoogle Scholar
  40. 40.
    Breier A, Liffick E, Hummer TA, Vohs JL, Yang Z, Mehdiyoun NF, Visco AC, Metzler E, Zhang Y, Francis MM (2018) Effects of 12-month, double-blind N-acetyl cysteine on symptoms, cognition and brain morphology in early phase schizophrenia spectrum disorders. Schizophr Res 199:395–402CrossRefGoogle Scholar
  41. 41.
    Berk M, Copolov D, Dean O, Lu K, Jeavons S, Schapkaitz I, Anderson-Hunt M, Judd F, Katz F, Katz P, Ording-Jespersen S, Little J, Conus P, Cuenod M, Do KQ, Bush AI (2008) N-acetyl cysteine as a glutathione precursor for schizophrenia—a double-blind, randomized, placebo-controlled trial. Biol Psychiatry 64(5):361–368CrossRefGoogle Scholar
  42. 42.
    Farokhnia M, Azarkolah A, Adinehfar F, Khodaie-Ardakani MR, Hosseini SMR, Yekehtaz H, Tabrizi M, Rezaei F, Salehi B, Sadeghi SMH, Moghadam M, Gharibi F, Mirshafiee O, Akhondzadeh S (2013) 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 36(6):185–192CrossRefGoogle Scholar
  43. 43.
    Sepehrmanesh Z, Heidary M, Akasheh N, Akbari H, Heidary M (2018) Therapeutic effect of adjunctive N-acetyl cysteine (NAC) on symptoms of chronic schizophrenia: a double-blind, randomized clinical trial. Prog Neuro-Psychopharmacol Biol Psychiatry 82:289–296CrossRefGoogle Scholar
  44. 44.
    Anzures-Cabrera J, Higgins JP (2010) Graphical displays for meta-analysis: an overview with suggestions for practice. Res Synth Methods 1(1):66–80CrossRefGoogle Scholar
  45. 45.
    Magalhães PV et al (2016) Antioxidant treatments for schizophrenia. Cochrane Database Syst Rev 2Google Scholar
  46. 46.
    Howes O, McCutcheon R, Stone J (2015) Glutamate and dopamine in schizophrenia: an update for the 21st century. J Psychopharmacol 29(2):97–115CrossRefGoogle Scholar
  47. 47.
    Ziment I (1986) Acetylcysteine: a drug with an interesting past and a fascinating future. Respiration 50(Suppl 1):26–30CrossRefGoogle Scholar
  48. 48.
    Dean O, Giorlando F, Berk M (2011) N-acetylcysteine in psychiatry: current therapeutic evidence and potential mechanisms of action. J Psychiatry Neurosci 36(2):78–86CrossRefGoogle Scholar
  49. 49.
    Berk M, Munib A, Dean O, Malhi GS, Kohlmann K, Schapkaitz I, Jeavons S, Katz F, Anderson-Hunt M, Conus P, Hanna B, Otmar R, Ng F, Copolov DL, Bush AI (2011) Qualitative methods in early-phase drug trials: broadening the scope of data and methods from an RCT of N-acetylcysteine in schizophrenia. J Clin Psychiatry 72:909–913CrossRefGoogle Scholar
  50. 50.
    Carmeli C, Knyazeva MG, Cuénod M, Do KQ (2012) Glutathione precursor N-acetyl-cysteine modulates EEG synchronization in schizophrenia patients: a double-blind, randomized, placebo-controlled trial. PLoS One 7(2):e29341CrossRefGoogle Scholar
  51. 51.
    McEvoy JP et al (2006) Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatry 163(4):600–610CrossRefGoogle Scholar
  52. 52.
    Edwards MJ et al (2002) N-acetylcysteine and Unverricht-Lundborg disease: variable response and possible side effects. Neurology 59(9):1447–1449CrossRefGoogle Scholar
  53. 53.
    Farokhnia M, Sabzabadi M, Pourmahmoud H, Khodaie-Ardakani MR, Hosseini SMR, Yekehtaz H, Tabrizi M, Rezaei F, Salehi B, Akhondzadeh S (2014) A double-blind, placebo controlled, randomized trial of riluzole as an adjunct to risperidone for treatment of negative symptoms in patients with chronic schizophrenia. Psychopharmacology 231(3):533–542CrossRefGoogle Scholar
  54. 54.
    Garcia RJ, Francis L, Dawood M, Lai ZW, Faraone SV, Perl A (2013) Brief report: attention deficit and hyperactivity disorder scores are elevated and respond to n-acetylcysteine treatment in patients with systemic lupus erythematosus. Arthritis Rheum 65(5):1313–1318CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Addiction Studies, School of MedicineKashan University of Medical SciencesKashanIran
  2. 2.Department of Psychiatry, School of MedicineKashan University of Medical ScienceKashanIran
  3. 3.Applied Health and Social Care, Faculty of Health and Social CareEdge Hill UniversityOrmskirkUK
  4. 4.Research Center for Biochemistry and Nutrition in Metabolic DiseasesKashan University of Medical SciencesKashanIran

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