The Efficacy of Ketamine Augmentation on Treatment-Refractory Obsessive-Compulsive Disorder: A Double-Blind Placebo-Controlled Clinical Trial

Document Type : Original Article


1 Department of Psychiatry, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran

2 Psychiatry and Behavioral Sciences Research Center, Addiction Institute, Mazandaran University of Medical Sciences, Sari, Iran

3 Department of Biostatistics, School of Health, Mazandaran University of Medical Sciences, Sari, Iran


Introduction: Abnormalities occurring in the glutamatergic system during obsessive-compulsive disorder, as a debilitating mental health condition, have been thus far illustrated. However, open-label and clinical trials of ketamine augmentation in limited subjects with treatment-refractory Obsessive-Compulsive Disorder (OCD) have not documented very persistent anti-OCD effects. Therefore, this controlled trial was conducted on patients with treatment-refractory OCD to evaluate the therapeutic efficacy of ketamine augmentation, as a non-competitive N-methyl-D-aspartate receptor antagonist.
Method: In this prospective, double-blind, placebo-controlled clinical trial, a total number of 30 subjects with treatment-refractory OCD were randomly assigned to either the group with the intravenous infusion of ketamine 0.5 mg/kg or the one receiving a dose of midazolam 0.045 mg/kg as an active placebo over 40 min. The OCD Visual Analog Scale (OCD-VAS) and the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) were also performed at mid-infusion, 1 h later, and on the 1st, 3rd, 5th, 7th, 14th, 21st, and 28th days following it.
Results: The mean OCD-VAS score in the group taking ketamine was lower than the value in the group receiving midazolam during the treatment. Even though these differences were not significant, the trend of changes in each study group was considerable (P=0.001). Response to treatment in the ketamine group was significantly higher than the midazolam group on the third day of treatment (P=0.042).
Conclusion: According to the findings of the present study, it can be stated that the adjuvant therapy with ketamine could bring significant positive effects on the third day of the treatment.


  1. Fenske JN, Petersen K. Obsessive-Compulsive Disorder: Diagnosis and Management. American family physician. 2015;92(10):896-903.
  2. Bystritsky A. Treatment-resistant anxiety disorders. Molecular psychiatry. 2006;11(9):805-14. DOI: 10.1038/
  3. Koran LM, Hanna GL, Hollander E, Nestadt G, Simpson HB. Practice guideline for the treatment of patients with obsessive-compulsive disorder. The American journal of psychiatry. 2007;164(7 Suppl):5-53.
  4. Albert U, Marazziti D, Salvo GD, Solia F, Rosso G, Maina G. A Systematic Review of Evidence-based Treatment Strategies for Obsessive- compulsive Disorder Resistant to first-line Pharmacotherapy. Current Medicinal Chemistry. 2018;25(41). DOI: 10.2174/0929867325666171222163645
  5. Del Casale A, Sorice S, Padovano A, Simmaco M, Ferracuti S, Lamis DA, et al. Psychopharmacological treatment of obsessive-compulsive disorder (OCD). Current neuropharmacology. 2019;17(8):710-36. DOI: 10.2174/1570159X16666180813155017
  6. Chakrabarty K, Bhattacharyya S, Christopher R, Khanna S. Glutamatergic dysfunction in OCD. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2005;30(9):1735-40. DOI: 10.1038/sj.npp.1300733
  7. Wu K, Hanna GL, Rosenberg DR, Arnold PD. The role of glutamate signaling in the pathogenesis and treatment of obsessive–compulsive disorder. Pharmacology Biochemistry and Behavior. 2012;100(4):726-35. DOI: 10.1016/j.pbb.2011.10.007
  8. Krystal JH, Davis LL, Neylan TC, Raskind MA, Schnurr PP, Stein MB, et al. It is time to address the crisis in the pharmacotherapy of posttraumatic stress disorder: a consensus statement of the PTSD Psychopharmacology Working Group. Biological psychiatry. 2017;82(7):e51-e9. DOI: 10.1016/j.biopsych.2017.03.007
  9. McGrath MJ, Campbell KM, Parks III CR, Burton FH. Glutamatergic drugs exacerbate symptomatic behavior in a transgenic model of comorbid Tourette’s syndrome and obsessive–compulsive disorder. Brain research. 2000;877(1):23-30. DOI: 10.1016/s0006-8993(00)02646-9
  10. Samuels J, Wang Y, Riddle MA, Greenberg BD, Fyer AJ, McCracken JT, et al. Comprehensive family‐based association study of the glutamate transporter gene SLC1A1 in obsessive‐compulsive disorder. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics. 2011;156(4):472-7. DOI: 10.1002/ajmg.b.31184
  11. Delorme R, Krebs M-O, Chabane N, Roy I, Millet B, Mouren-Simeoni MC, et al. Frequency and transmission of glutamate receptors GRIK2 and GRIK3 polymorphisms in patients with obsessive compulsive disorder. Neuroreport. 2004;15(4):699-702. DOI: 10.1097/00001756-200403220-00025
  12. Albelda N, Joel D. Animal models of obsessive-compulsive disorder: exploring pharmacology and neural substrates. Neuroscience & Biobehavioral Reviews. 2012;36(1):47-63. DOI: 10.1016/j.neubiorev.2011.04.006
  13. Arnold PD, MacMaster FP, Richter MA, Hanna GL, Sicard T, Burroughs E, et al. Glutamate receptor gene (GRIN2B) associated with reduced anterior cingulate glutamatergic concentration in pediatric obsessive–compulsive disorder. Psychiatry Research: Neuroimaging. 2009;172(2):136-9. DOI: 10.1016/j.pscychresns.2009.02.005
  14. Menzies L, Chamberlain SR, Laird AR, Thelen SM, Sahakian BJ, Bullmore ET. Integrating evidence from neuroimaging and neuropsychological studies of obsessive-compulsive disorder: the orbitofronto-striatal model revisited. Neuroscience and biobehavioral reviews. 2008;32(3):525-49. DOI: 10.1016/j.neubiorev.2007.09.005
  15. Brennan BP, Rauch SL, Jensen JE, Pope Jr HG. A critical review of magnetic resonance spectroscopy studies of obsessive-compulsive disorder. Biological psychiatry. 2013;73(1):24-31. DOI: 10.1016/j.biopsych.2012.06.023
  16. Stress, anxiety and depression and the role of glutamate neurotransmission [Internet]. oxford medicine online. 2015.
  17. Salloum NC, Fava M, Freeman MP, Flynn M, Hoeppner B, Hock RS, et al. Efficacy of intravenous ketamine treatment in anxious versus nonanxious unipolar treatment‐resistant depression. Depression and anxiety. 2019;36(3):235-43. DOI: 10.1002/da.22875
  18. McIntyre RS, Rosenblat JD, Nemeroff CB, Sanacora G, Murrough JW, Berk M, et al. Synthesizing the evidence for ketamine and esketamine in treatment-resistant depression: an international expert opinion on the available evidence and implementation. American Journal of Psychiatry. 2021;178(5):383-99. DOI: 10.1176/appi.ajp.2020.20081251
  19. Goodman WK, Price LH, Rasmussen SA, Mazure C, Delgado P, Heninger GR, et al. The Yale-Brown Obsessive Compulsive Scale. II. Validity. Archives of general psychiatry. 1989;46(11):1012-6. DOI: 10.1001/archpsyc.1989.01810110054008
  20. Glue P, Medlicott NJ, Harland S, Neehoff S, Anderson-Fahey B, Le Nedelec M, et al. Ketamine’s dose-related effects on anxiety symptoms in patients with treatment refractory anxiety disorders. Journal of Psychopharmacology. 2017;31(10):1302-5. DOI: 10.1177/0269881117705089
  21. Taylor JH, Landeros-Weisenberger A, Coughlin C, Mulqueen J, Johnson JA, Gabriel D, et al. Ketamine for social anxiety disorder: a randomized, placebo-controlled crossover trial. Neuropsychopharmacology. 2018;43(2):325-33. DOI: 10.1038/npp.2017.194
  22. Glue P, Neehoff S, Sabadel A, Broughton L, Le Nedelec M, Shadli S, et al. Effects of ketamine in patients with treatment-refractory generalized anxiety and social anxiety disorders: exploratory double-blind psychoactive-controlled replication study. Journal of Psychopharmacology. 2020;34(3):267-72. DOI: 10.1177/0269881119874457
  23. Marinova Z, Chuang D-M, Fineberg N. Glutamate-modulating drugs as a potential therapeutic strategy in obsessive-compulsive disorder. Current Neuropharmacology. 2017;15(7):977-95. DOI: 10.2174/1570159X15666170320104237
  24. Rodriguez CI, Kegeles LS, Levinson A, Feng T, Marcus SM, Vermes D, et al. Randomized controlled crossover trial of ketamine in obsessive-compulsive disorder: proof-of-concept. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2013;38(12):2475-83. DOI: 10.1038/npp.2013.150
  25. Bloch MH, Wasylink S, Landeros-Weisenberger A, Panza KE, Billingslea E, Leckman JF, et al. Effects of ketamine in treatment-refractory obsessive-compulsive disorder. Biol Psychiatry. 2012;72(11):964-70. DOI: 10.1016/j.biopsych.2012.05.028
  26. Sharma LP, Thamby A, Balachander S, Janardhanan CN, Jaisoorya T, Arumugham SS, et al. Clinical utility of repeated intravenous ketamine treatment for resistant obsessive-compulsive disorder. Asian journal of psychiatry. 2020;52:102183. DOI: 10.1016/j.ajp.2020.102183
  27. Hamilton M. A rating scale for depression. Journal of neurology, neurosurgery, and psychiatry. 1960;23:56-62. DOI: 10.1136/jnnp.23.1.56
  28. Bremner JD, Krystal JH, Putnam FW, Southwick SM, Marmar C, Charney DS, et al. Measurement of dissociative states with the clinician‐administered dissociative states scale (CADSS). Journal of Traumatic Stress: Official Publication of The International Society for Traumatic Stress Studies. 1998;11(1):125-36. DOI: 10.1023/A:1024465317902
  29. Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, validity and sensitivity. The British journal of psychiatry. 1978;133(5):429-35. DOI: 10.1192/bjp.133.5.429
  30. Overall JE, Gorham DR. The brief psychiatric rating scale. Psychological reports. 1962;10(3):799-812.
  31. Wilkinson ST, Farmer C, Ballard ED, Mathew SJ, Grunebaum MF, Murrough JW, et al. Impact of midazolam vs. saline on effect size estimates in controlled trials of ketamine as a rapid-acting antidepressant. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2019;44(7):1233-8. DOI: 10.1038/s41386-019-0317-8
  32. About this FactMed analysis covering adverse side effect reports of Midazolam hcl patients who developed obsessive-compulsive disorder: FactMed; 2015 [Available from: