Brain glutamate level after treatment with N-acetylcysteine in obsessive-compulsive disorder patients: A randomized trial

Abstract

Selective serotonin reuptake inhibitors (SSRIs) are routinely used to treat patients with obsessive-compulsive disorder (OCD); however, 40 - 60% of patients with OCD do not respond to SSRIs. Glutamate dysfunction may play a key role in OCD pathogenesis. N-acetylcysteine (NAC), a glutamate-modulating drug, targets the glutamatergic system. This study aimed to assess whether the addition of NAC reduces the severity of OCD symptoms in patients with SSRI-treated moderate-to-severe OCD. A total of 60 patients with OCD were diagnosed according to the DSM-5 criteria, and severity of the symptoms was assessed using the Yale-Brown obsessive-compulsive scale (Y-BOCS). Patients were administered 2,400 mg/day of SSRIs plus placebo (placebo arm) or 2,400 mg/day (NAC arm) of SSRIs plus NAC for 10 weeks. Serum alanine aminotransferase, aspartate aminotransferase, creatinine, and electrocardiogram were monitored to evaluate the safety of NAC. The Y-BOCS score was not significantly different between the two arms at baseline; however, it was significantly different between the two arms after 4 (P = 0.03) and 10 (P = 0.00) weeks. The NAC arm had a reduction of 8.4 (25.51 - 17.15) points compared with 1.42 (25.07 - 23.65) points for the placebo arm from baseline to 10 weeks. NAC was well-tolerated and caused mild gastrointestinal adverse events. Thus, NAC is an effective glutamate-modulating drug as and can be used as an augmentation therapy with standard treatment in patients with moderate-to-severe OCD.

Keywords

Glutamate / N-acetylcysteine / Obsessive-compulsive disorder / Yale-Brown obsessive-compulsive scale

Funding

None.

Conflict of interest

The authors declared that they have no competing interests.

References

[1] American Psychiatric Association (APA). What is Obsessive- Compulsive Disorder? American Psychiatric Association; 2013. Available from: https://www.psychiatry.org/patients-families/ocd/what-is-obsessive-compulsivedisorder[2023 Nov 20]

[2] Adam Y, Meinlschmidt G, Gloster AT, Lieb R. Obsessive-compulsive disorder in the community: 12-month prevalence, comorbidity and impairment. Soc Psychiatry Psychiatr Epidemiol. 2012; 47(3):339-349. doi: 10.1007/s00127-010-0337-5

[3] Solish AJ. Parents’ Involvement in Behavioural Intervention for their Children with Autism. Vol. 73. Canada: York University; 2010. p. 632.

[4] Algin S, Sajib MW, Arafat SY. Demography and symptom severity of obsessive compulsive disorder in Bangladesh: A cross-sectional observation. Bangladesh J Psychiatry. 2016; 30(2):23-26. doi: 10.3329/bjpsy.v30i2.45360

[5] World Health Organization (WHO). The Global Burden of Disease. World Health Organization; 2018. Available from: https://www.ocduk.org/ocd/world-health-organisation[2023 Nov 26]

[6] Meier SM, Mattheisen M, Mors O, Schendel DE, Mortensen PB, Plessen KJ. Mortality among persons with obsessive-compulsive disorder in denmark. JAMA Psychiatry. 2016; 73(3):268-274. doi: 10.1001/jamapsychiatry.2015.3105

[7] Norberg MM, Calamari JE, Cohen RJ, Riemann BC. Quality of life in obsessive-compulsive disorder: An evaluation of impairment and a preliminary analysis of the ameliorating effects of treatment. Depress Anxiety. 2008; 25(3):248-259. doi: 10.1002/da.20298

[8] American Psychiatric Association:Washington, DC. Diagnostic and Statistical Manual of Mental Disorders (DSM-5). 5^th ed. Washington, DC: American Psychiatric Association; 2013. Available from: https://www.ocduk.org/ocd/clinical-classification-of/ocd/dsm-and/ocd[2021 Nov 25]

[9] Zhang H, Wang B, Li K, et al. Altered functional connectivity between the cerebellum and the cortico-striato-thalamo-cortical circuit in obsessive-compulsive disorder. Front Psychiatry. 2019;10:522. doi: 10.3389/fpsyt.2019.00522

[10] Kariuki-Nyuthe C, Gomez-Mancilla B, Stein DJ. et al. , DJ. Obsessive compulsive disorder and the glutamatergic system. Curr Opin Psychiatry. 2014; 27(1):32-37. doi: 10.1097/YCO.0000000000000017

[11] Berk M, Ng F, Dean O, Dodd S, Bush AI. Glutathione: A novel treatment target in psychiatry. Trends Pharmacol Sci. 2008; 29(7):346-351. doi: 10.1016/j.tips.2008.05.001

[12] Fenske JN, Petersen K. Obsessive-compulsive disorder: Diagnosis and management. Am Fam Physician. 2015; 92(10):896-903.

[13] Katzman MA, Bleau P, Blier P, et al. Canadian clinical practice guidelines for the management of anxiety, posttraumatic stress and obsessive-compulsive disorders. BMC Psychiatry. 2014;14:S1. doi: 10.1186/1471-244X-14-S1-S1

[14] Bandelow B, Zohar J, Hollander E, Kasper S, Möller HJ. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the pharmacological treatment of anxiety, obsessive-compulsive and post-traumatic stress disorders - first revision. World J Biol Psychiatry. 2008; 9(4):248-312. doi: 10.1080/15622970802465807

[15] Swierkosz-Lenart K, Dos Santos JFA, Elowe J, et al. Therapies for obsessive-compulsive disorder: Current state of the art and perspectives for approaching treatment-resistant patients. Front Psychiatry. 2023;14:1065812. doi: 10.3389/fpsyt.2023.1065812

[16] Janardhan Reddy YC, Sundar AS, Narayanaswamy JC, Math SB. Clinical practice guidelines for obsessive-compulsive disorder. Indian J Psychiatry. 2017; 59(Suppl 1):S74-S90. doi: 10.4103/0019-5545.196976

[17] Pittenger C, Bloch MH. harmacological treatment of obsessive-compulsive disorder. Psychiatr Clin North Am. 2014; 37(3):375-391. doi: 10.1016/j.psc.2014.05.006

[18] Pallanti S, Grassi G, Cantisani A. Emerging drugs to treat obsessive-compulsive disorder. Expert Opin Emerg Drugs. 2014; 19(1):67-77. doi: 10.1517/14728214.2014.875157

[19] Hirschtritt ME, Bloch MH, Mathews CA. Obsessive-compulsive disorder: Advances in diagnosis and treatment. JAMA. 2017; 317(13):1358-1367. doi: 10.1001/jama.2017.2200

[20] Bloch MH, McGuire J, Landeros-Weisenberger A, Leckman JF, Pittenger C. Meta-analysis of the dose-response relationship of SSRI in obsessive-compulsive disorder. Mol Psychiatry. 2010; 15(8):850-855. doi: 10.1038/mp.2009.50

[21] Bandelow B. The medical treatment of obsessive-compulsive disorder and anxiety. CNS Spectr. 2008; 13(9Suppl 14): 37-46. doi: 10.1017/s1092852900026924

[22] Bakizadeh F, Mokhtari S, Saeed F, Mokhtari A, Akbari Koli P, Shalbafan M. Cognitive rehabilitation for adult patients with obsessive-compulsive disorder: A systematic review of randomized controlled trials. Basic Clin Neurosci. 2024; 15(3):287-300. doi: 10.32598/bcn.2022.1604.3

[23] Eissazade N, Mosavari H, Eghdami S, Boroon M, Ashrafi F, Shalbafan M. Efficacy and safety of 5-hydroxytryptamine-3 (5-HT3) receptor antagonists in augmentation with selective serotonin reuptake inhibitors (SSRIs) in the treatment of moderate to severe obsessive-compulsive disorder: A systematic review and meta-analysis of randomized clinical trials. Sci Rep. 2023; 13(1):20837. doi: 10.1038/s41598-023-47931-x

[24] Askari S, Mokhtari S, Shariat SV, Shariati B, Yarahmadi M, Shalbafan M. Memantine augmentation of sertraline in the treatment of symptoms and executive function among patients with obsessive-compulsive disorder: A double-blind placebo-controlled, randomized clinical trial. BMC Psychiatry. 2022; 22(1):34. doi: 10.1186/s12888-021-03642-z

[25] Shalbafan M, Malekpour F, et al.Tadayon Najafabadi B, Fluvoxamine combination therapy with tropisetron for obsessive-compulsive disorder patients: A placebo-controlled, randomized clinical trial. J Psychopharmacol. 2019; 33(11):1407-1414. doi: 10.1177/0269881119878177

[26] Van Noppen BL, Pato MT, Marsland R, Rasmussen SA. A time-limited behavioral group for treatment of obsessive-compulsive disorder. J Psychother Pract Res. 1998; 7(4):272-280.

[27] Figueroa Y, Rosenberg DR, Birmaher B, Keshavan MS. Combination treatment with clomipramine and selective serotonin reuptake inhibitors for obsessive-compulsive disorder in children and adolescents. J Child Adolesc Psychopharmacol. 1998; 8(1):61-67. doi: 10.1089/cap.1998.8.61

[28] Treatment of obsessive-compulsive disorder. The expert consensus panel for obsessive-compulsive disorder. J Clin Psychiatry. 1997; 58(Suppl 4):2-72.

[29] Decloedt EH, Stein DJ. Current trends in drug treatment of obsessive-compulsive disorder. Neuropsychiatr Dis Treat. 2010; 6:233-242. doi: 10.2147/ndt.s3149

[30] Marinova Z, Chuang DM, Fineberg N. Glutamate-modulating drugs as a potential therapeutic strategy in obsessive-compulsive disorder. Curr Neuropharmacol. 2017; 15(7):977-995. doi: 10.2174/1570159X15666170320104237

[31] Zhu Y, Fan Q, Han X, et al. Decreased thalamic glutamate level in unmedicated adult obsessive-compulsive disorder patients detected by proton magnetic resonance spectroscopy. J Affect Disord. 2015; 178:193-200. doi: 10.1016/j.jad.2015.03.008

[32] Ting JT, Feng G. Neurobiology of obsessive-compulsive disorder: Insights into neural circuitry dysfunction through mouse genetics. Curr Opin Neurobiol. 2011; 21(6):842-848. doi: 10.1016/j.conb.2011.04.010

[33] Hadi F, Kashefinejad S, Kamalzadeh L, Hoobehfekr S, Shalbafan M. Glutamatergic medications as adjunctive therapy for moderate to severe obsessive-compulsive disorder in adults: A systematic review and meta-analysis. BMC Pharmacol Toxicol. 2021; 22(1):69. doi: 10.1186/s40360-021-00534-6

[34] Wu K, Hanna GL, Rosenberg DR, Arnold PD. The role of glutamate signaling in the pathogenesis and treatment of obsessive-compulsive disorder. Pharmacol Biochem Behav. 2012; 100(4):726-735. doi: 10.1016/j.pbb.2011.10.007

[35] Pittenger C, Bloch MH, Williams K. Glutamate abnormalities in obsessive compulsive disorder: Neurobiology, pathophysiology, and treatment. Pharmacol Ther. 2011; 132(3):314-332. doi: 10.1016/j.pharmthera.2011.09.006

[36] Ting JT, Feng G. Glutamatergic synaptic dysfunction and obsessive-compulsive disorder. Curr Chem Genomics. 2008;2:62-75. doi: 10.2174/1875397300802010062

[37] Chakrabarty K, Bhattacharyya S, Christopher R, Khanna S. Glutamatergic dysfunction in OCD. Neuropsychopharmacology. 2005; 30(9):1735-1740. doi: 10.1038/sj.npp.1300733

[38] Rosenberg DR, MacMaster FP, Keshavan MS, Fitzgerald KD, Stewart CM, Moore GJ. Decrease in caudate glutamatergic concentrations in pediatric obsessive-compulsive disorder patients taking paroxetine. J Am Acad Child Adolesc Psychiatry. 2000; 39(9):1096-1103. doi: 10.1097/00004583-200009000-00008

[39] Bhattacharyya S, Khanna S, Chakrabarty K, Mahadevan A, Christopher R, Shankar SK. Anti-brain autoantibodies and altered excitatory neurotransmitters in obsessive-compulsive disorder. Neuropsychopharmacology. 2009; 34(12):2489-2496. doi: 10.1038/npp.2009.77

[40] Ozdemir E, Cetinkaya S, Ersan S, Kucukosman S, Ersan EE. Serum selenium and plasma malondialdehyde levels and antioxidant enzyme activities in patients with obsessive-compulsive disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2009; 33(1):62-65. doi: 10.1016/j.pnpbp.2008.10.004

[41] Ersan S, Bakir S, Erdal Ersan E, Dogan O. Examination of free radical metabolism and antioxidant defence system elements in patients with obsessive-compulsive disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2006; 30(6):1039-1042. doi: 10.1016/j.pnpbp.2006.03.034

[42] Tenório MCD, Graciliano NG, Moura FA, Goulart MOF. N-Acetylcysteine (NAC): Impacts on human health. Antioxidants (Basel). 2021; 10(6):967. doi: 10.3390/antiox10060967

[43] Raghu G, Berk M, Campochiaro PA, et al. The multifaceted therapeutic role of N-acetylcysteine (NAC) in disorders characterized by oxidative stress. Curr Neuropharmacol. 2021; 19(8):1202-1224. doi: 10.2174/1570159X19666201230144109

[44] Dean O, Giorlando F, Berk M. N-acetylcysteine in psychiatry: Current therapeutic evidence and potential mechanisms of action. J Psychiatry Neurosci. 2011; 36(2):78-86. doi: 10.1503/jpn.100057

[45] Baxter PS, Bell KF, Hasel P, et al. Synaptic NMDA receptor activity is coupled to the transcriptional control of the glutathione system. Nat Commun. 2015;6:6761. doi: 10.1038/ncomms7761

[46] Sarris J, Byrne G, Castle D, et al. N-acetyl cysteine (NAC) augmentation in the treatment of obsessive-compulsive disorder: A phase III, 20-week, double-blind, randomized, placebo-controlled trial. Prog Neuropsychopharmacol Biol Psychiatry. 2022;117:110550. doi: 10.1016/j.pnpbp.2022.110550

[47] Li F, Welling MC, Johnson JA, et al. N-acetylcysteine for pediatric obsessive-compulsive disorder: A small pilot study. J Child Adolesc Psychopharmacol. 2020; 30(1):32-37. doi: 10.1089/cap.2019.0041

[48] Ghanizadeh A, Mohammadi MR, Bahraini S, Keshavarzi Z, Firoozabadi A, Alavi Shoshtari A. Efficacy of N-acetylcysteine augmentation on obsessive compulsive disorder: A multicenter randomized double blind placebo controlled clinical trial. Iran J Psychiatry. 2017; 12(2):134-141.

[49] Costa DLC, Diniz JB, Requena G, et al. Randomized, double-blind, placebo-controlled trial of N-acetylcysteine augmentation for treatment-resistant obsessive-compulsive disorder. J Clin Psychiatry. 2017; 78(7):e766-e773. doi: 10.4088/JCP.16m11101

[50] Paydary K, Akamaloo A, Ahmadipour A, Pishgar F, Emamzadehfard S, Akhondzadeh S. N-acetylcysteine augmentation therapy for moderate-to-severe obsessive-compulsive disorder: Randomized, double-blind, placebo-controlled trial. J Clin Pharm Ther. 2016; 41(2):214-219. doi: 10.1111/jcpt.12370

[51] Sarris J, Oliver G, Camfield DA, et al. N-Acetyl Cysteine (NAC) in the treatment of obsessive-compulsive disorder: A 16-week, double-blind, randomised, placebo-controlled study. CNS Drugs. 2015; 29(9):801-809. doi: 10.1007/s40263-015-0272-9

[52] Afshar H, Roohafza H, Mohammad-Beigi H, et al. N-acetylcysteine add-on treatment in refractory obsessive-compulsive disorder: A randomized, double-blind, placebo-controlled trial. J Clin Psychopharmacol. 2012; 32(6):797-803. doi: 10.1097/JCP.0b013e318272677d

[53] Yazici KU, Percinel I. N-acetylcysteine augmentation in children and adolescents diagnosed with treatment-resistant obsessive-compulsive disorder: Case series. J Clin Psychopharmacol. 2015; 35(4):486-489. doi: 10.1097/JCP.0000000000000362

[54] Lafleur DL, Pittenger C, Kelmendi B, et al. N-acetylcysteine augmentation in serotonin reuptake inhibitor refractory obsessive-compulsive disorder. Psychopharmacology (Berl). 2006; 184(2):254-256. doi: 10.1007/s00213-005-0246-6

[55] Yolland CO, Hanratty D, Neill E, et al. Meta-analysis of randomised controlled trials with N-acetylcysteine in the treatment of schizophrenia. Aust N Z J Psychiatry. 2020; 54(5):453-466. doi: 10.1177/0004867419893439

[56] Bhaskara S. N-Acetylcysteine augmentation in refractory obsessive-compulsive disorder. J Psychiatry Neurosci. 2019; 44(3):215-216. doi: 10.1503/jpn.180179

[57] Goodman WK, Price LH, Rasmussen SA, et al. The yale-brown obsessive compulsive scale. I. Development, use, and reliability. Arch Gen Psychiatry. 1989; 46(11):1006-1011. doi: 10.1001/archpsyc.1989.01810110048007

[58] Saxena S, Bota RG, Brody AL. Brain-behavior relationships in obsessive-compulsive disorder. Semin Clin Neuropsychiatry. 2001; 6(2):82-101. doi: 10.1053/scnp.2001.21833

[59] Moran MM, McFarland K, Melendez RI, Kalivas PW, Seamans JK. Cystine/glutamate exchange regulates metabotropic glutamate receptor presynaptic inhibition of excitatory transmission and vulnerability to cocaine seeking. J Neurosci. 2005; 25(27):6389-6393. doi: 10.1523/JNEUROSCI.1007-05.2005

[60] Ng F, Berk M, Dean O, Bush AI. Oxidative stress in psychiatric disorders: Evidence base and therapeutic implications. Int J Neuropsychopharmacol. 2008; 11(6):851-876. doi: 10.1017/S1461145707008401

[61] 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(6):185-192. doi: 10.1097/WNF.0000000000000001

[62] Nikoo M, Radnia H, Farokhnia M, Mohammadi MR, Akhondzadeh S. N-acetylcysteine as an adjunctive therapy to risperidone for treatment of irritability in autism: A randomized, double-blind, placebo-controlled clinical trial of efficacy and safety. Clin Neuropharmacol. 2015; 38(1):11-17. doi: 10.1097/WNF.0000000000000063

[63] Atkuri KR, Mantovani JJ, Herzenberg LA, Herzenberg LA. N-Acetylcysteine--a safe antidote for cysteine/glutathione deficiency. Curr Opin Pharmacol. 2007; 7(4):355-359. doi: 10.1016/j.coph.2007.04.005

[64] Berk M, Malhi GS, Gray LJ, Dean OM. The promise of N-acetylcysteine in neuropsychiatry. Trends Pharmacol Sci. 2013; 34(3):167-177. doi: 10.1016/j.tips.2013.01.001

[65] Selek S, Herken H, Bulut M, et al. Oxidative imbalance in obsessive compulsive disorder patients: A total evaluation of oxidant-antioxidant status. Prog Neuropsychopharmacol Biol Psychiatry. 2008; 32(2):487-491. doi: 10.1016/j.pnpbp.2007.10.002

[66] Nascimento MM, Suliman ME, Silva M, et al. Effect of oral N-acetylcysteine treatment on plasma inflammatory and oxidative stress markers in peritoneal dialysis patients: A placebo-controlled study. Perit Dial Int. 2010; 30(3):336-342. doi: 10.3747/pdi.2009.00073

[67] Ooi SL, Green R, Pak SC. N-acetylcysteine for the treatment of psychiatric disorders: A review of current evidence. Biomed Res Int. 2018;2018:2469486. doi: 10.1155/2018/2469486

[68] Van Ameringen M, Patterson B, Simpson W, Turna J. N-acetylcysteine augmentation in treatment resistant obsessive compulsive disorder: A case series. J Obsessive Compuls Relat Disord. 2013; 2(1):48-52. doi: 10.1016/j.jocrd.2012.10.003