Using Oral and Intranasal Dosage Forms of Ketamine for Managing Treatment-Resistant Depression: A Review of the Literature


  • Patrick Arthur Twohig Saba University School of Medicine, Caribbean Netherlands.
  • Vaughn Huckfeldt Saba University School of Medicine, Caribbean Netherlands.



Ketamine, Depressive Disorder, Treatment-Resistant, Administration, Oral, Administration, Intranasal, Intravenous


A lack of effective treatment for patients with treatment-resistant depression (TRD) has led to the evaluation of ketamine, an N-methyl- D-aspartate receptor antagonist. Despite the demonstrated short-term benefits of using intravenous (IV) ketamine, side effects and the difficulty in administering ketamine outside the health-care setting has raised interest in alternative dosage forms. Research articles evaluating oral or intranasal (IN) ketamine were retrieved from the PubMed database. Patients who received oral or IN ketamine experienced a similar reduction in depressive symptoms within 24 hours of treatment and fewer side effects compared to patients who received IV ketamine. Novel administration forms of ketamine provide an opportunity for patients with TRD to achieve remission with fewer adverse side effects. Future studies should continue to evaluate these administration strategies in the hope of promoting ketamine’s use outside health-care settings and for longer time periods.


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Author Biography

Patrick Arthur Twohig, Saba University School of Medicine, Caribbean Netherlands.

Patrick Twohig is currently a fourth- year medical student at Saba University School of Medicine, graduating in 2017. He completed his undergraduate studies and MPH in Canada.


1. Marcus M, Yasamy MT, van Ommeren M, Chisholm D, Saxena S. Depression: a global public health concern. Geneva: World Health Organization Depart¬ment of Mental Health and Substance Abuse; 2012.
2. American Psychiatric Association. Diagnostic and statistical manual of men¬tal disorders. 5th ed. Washington, DC: American Psychiatric Association; 2013.
3. Wijeratne C, Sachdev P. Treatment-resistant depression: critique of current approaches. Aust N Z J Psychiatry. 2008 Sep;42(9):751-62.
4. Caddy C, Giaroli G, White TP, Shergill SS, Tracy DK. Ketamine as the prototype glutamatergic antidepressant: pharmacodynamics actions, and a systema¬tic review and meta-analysis of efficacy. Ther Adv Psychopharmacol. 2014 Apr;4(2):75-99.
5. Katalinic N, Lai R, Somogyi A, Mitchell PB, Glue P, Loo CK. Ketamine as a new treatment for depression: a review of its efficacy and adverse effects. Aust N Z J Psychiatry. 2013 Aug;47(8):710-27.
6. Naughton M, Clarke G, O’Leary OF, Cryan JF, Dinan TG. A review of ketamine in affective disorders: current evidence of clinical efficacy, limitations of use, and pre-clinical evidence on proposed mechanisms of action. J Affect Disord. 2014 Mar;156:24-35.
7. 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. 2013 Nov;38(12):2475- 83.
8. Mathew SJ, Shah A, Lapidus K, Clark C, Jarun N, Ostermeyer B, et al. Ketami¬ne for treatment-resistant unipolar depression: current evidence. CNS Drugs. 2012 Mar 1;26(3):189-204.
9. Krishnan V, Nestler EJ. Linking molecules to mood: new insight into the biology of depression. Am J Psychiatry. 2010 Nov;167(11):1305-20.
10. Price JL, Drevets WC. Neurocircuitry of mood disorders. Neuropsychophar¬macology. 2010 Jan;35(1):192-216.
11. Opler LA, Opler MG, Arnsten AF. Ameliorating treatment-refractory depres¬sion with intranasal ketamine: potential NMDA receptor actions in the pain circuitry representing mental anguish. CNS Spectr. 2016 Feb;21(1):12-22.
12. Abel KM, Allin MP, Kucharska-Pietura K, David A, Andrew C, Williams S, et al. Ketamine alters neural processing of facial emotion recognition in healthy men: an fMRI study. Neuroreport. 2003 Mar 3;14(3):387-91.
13. Breier A, Adler CM, Weisenfeld N, Su TP, Elman I, Picken L, et al. Effects of NMDA antagonism on striatal dopamine release in healthy subjects: applica¬tion of a novel PET approach. Synapse. 1998 Jun;29(2):142-7.
14. Salvadore G, Cornwell BR, Sambataro F, Latov D, Colon-Rosario V, Carver F, et al. Anterior cingulate desynchronization and functional connectivity with the amygdala during a working memory task predict rapid antidepressant response to ketamine. Neuropsychopharmacology. 2010 Jun;35(7):1415-22.
15. Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000 Feb 15;47(4):351-4.
16. Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-re¬sistant major depression. Arch Gen Psychiatry, 2006 Aug;63(8):856-64.
17. Warden D, Rush AJ, Trivedi MH, Fava M, Wisniewsk SR. The STAR*D Pro¬ject results: a comprehensive review of findings. Curr Psychiatry Rep 2007 Dec;9(6):449-59.
18. Lapidus KA, Levitch CF, Perez AM, Brallier JW, Parides MK, Soleimani L, et al. A randomized controlled trial of intranasal ketamine in major depressive disorder. Biol Psychiatry. 2014 Dec;76(12):970-6.
19. Irwin SA, Iglewicz A, Nelesen RA, Lo JY, Carr CH, Romero SD, et al. Daily oral ketamine for the treatment of depression and anxiety in patients receiving hospice care: a 28-day open-label proof-of-concept trial. J Palliat Med. 2013 Aug;16(8):958-65.
20. Ionescu DF, Luckenbaugh DA, Niciu MJ, Richards EM, Slonena EE, Vande Voort JL, et al. Effect of baseline anxious depression on initial and sustained antidepressant response to ketamine. J Clin Psychiatry. 2014 Sep;75(9):e932-8.
21. Curran HV, Morgan C. Cognitive, dissociative and psychogenetic effects of ketamine on recreational users on the night of drug use and 3 days later. Addiction. 2000 Apr;95(4):575-90.
22. Papolos DF, Teicher MH, Faedda GL, Murphy P, Mattis S. Clinical experience using intranasal ketamine in the treatment of pediatric bipolar disorder/fear of harm phenotype. J Affect Disord. 2013 May;147(1-3):431-6.
23. Iglewicz A, Morrison K, Nelesen RA, Zhan T, Iglewicz B, Fairman N, et al. Ketamine for the treatment of depression in patients receiving hospice care: a retrospective chart review of thirty-one cases. Psychosomatics. 2015 Jul- Aug;56(4):329-37.
24. Lara DR, Bisol LW, Munari LR. Antidepressant, mood stabilizing and pre¬cognitive effects of very low dose sublingual ketamine in refractory unipolar and bipolar depression. Int J Neuropsychopharmacol. 2013 Oct;16(9):2111-17.
25. Paslakis G, Gilles M, Meyer-Lindenberg A, Deuschle M. Oral administration of the NMDA receptor antagonist S-ketamine as add-on therapy of depression: a case series. Pharmacopsychiatry. 2010 Jan;43(1):33-5.
26. Irwin SA, Iglewicz A. Oral ketamine for the rapid treatment of depres¬sion and anxiety in patients receiving hospice care. J Palliat Med. 2010 Jul;13(7):903-8.
27. Niciu MJ, Luckenbaugh DA, Ionescu DF, Guevara S, Machado-Vieira R, Ri¬chards EM, et al. Clinical predictors of ketamine response in treatment-resis¬tant major depression. J Clin Psychiatry. 2014 May;75(5):e417-23.
28. Diazgranados N, Ibrahim L, Brutsche NE, Newberg A, Kronstein P, Kha¬life S, et al. A randomized add-on trial of an N-methyl-D-aspartate antago¬nist in treatment-resistant bipolar depression. Arch Gen Psychiatry. 2010 Aug;67(8):793-802.
29. Zarate CA Jr, Brutsche NE, Ibrahim L, Franco-Chaves J, Diazgranados N, Cravchik A, et al. Replication of ketamine’s antidepressant efficacy in bipolar depression: a randomized controlled add-on trial. Biol Psychiatry. 2012 Jun 1;71(11):939-46.
30. Mathew SJ, Murrough JW, aan het Rot M, Collins KA, Reich DL, Charney DS. Riluzole for relapse prevention following intravenous ketamine in treat¬ment-resistant depression: a pilot randomized, placebo-controlled continua¬tion trial. Int J Neuropsychopharmacol. 2010 Feb;13(1):71–82.
31. Murrough JW, Iosifescu DV, Chang LC, Al Jurdi RK, Green CE, Perez AM, et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry. 2013 Oct;170(10):1134- 42.
32. aan het Rot M, Collins KA, Murrough JW, Perez AM, Reich DL, Charney DS, et al. Safety and efficacy of repeated-dose intravenous ketamine for treat¬ment-resistant depression. Biol Psychiatry. 2010 Jan;67(2):139-45.
33. Ibrahim L, Diazgranados N, Franco-Chaves J, Brutsche N, Henter ID, Krons¬tein P, et al. Course of improvement in depressive symptoms to a single intravenous infusion of ketamine vs add-on riluzole: results from a 4-week, double-blind, placebo-controlled study. Neuropsychopharmacology. 2012 May;37(6):1526-33.
34. Sanacora G, Zarate CA, Krystal JH, Manji HK. Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders. Nat Rev
Drug Discov. 2008 May;7(5):426-37.
35. Correll GE, Futter GE. Two case studies of patients with major depressive disorder given low-dose (subanesthetic) ketamine infusions. Pain Med. 2006 Jan-Feb;7(1):92-5.
36. Glue P, Gulati A, Le Nedelec M, Duffull S. Dose- and exposure-response to ketamine in depression. Biol Psychiatry. 2011 Aug 15;70(4):e9-10.
37. Goforth HW, Holsinger T. Rapid relief of severe major depressive disorder by use of preoperative ketamine and electroconvulsive therapy. J ECT. 2007 Mar;23(1):23-5.
38. Machado-Vieira R, Manji HK, Zarate CA. The role of the tripartite glutama¬tergic synapse in the pathophysiology and therapeutics of mood disorders. Neuroscientist. 2009 Oct;15(5):525-39.
39. Ibrahim L, Diazgranados N, Luckenbaugh DA, Machado-Vieira R, Baumann J, Mallinger AG, et al. Rapid decrease in depressive symptoms with an N-me¬thyl-d-aspartate antagonist in ECT-resistant major depression. Prog Neuropsy¬chopharmacol Biol Psychiatry. 2011 Jun 1;35 (4):1155-9.
40. Phelps LE, Brutsche N, Moral JR, Luckenbaugh DA, Manji HK, Zarate CA Jr. Family history of alcohol dependence and initial antidepressant response to an N-methyl-D-aspartate antagonist. Biol Psychiatry. 2009 Jan 15;65(2):181-4.
41. Salvadore G, Cornwell BR, Colon-Rosario V, Coppola R, Grillon C, Zarate CA Jr, et al. Increased anterior cingulate cortical activity in response to fearful faces: a neurophysiological biomarker that predicts rapid antidepressant res¬ponse to ketamine. Biol Psychiatry. 2009 Feb 15;65(4):289-95.
42. Salvadore G, van der Veen JW, Zhang Y, Marenco S, Machado-Vieira R, Bau¬mann J, et al. An investigation of amino-acid neurotransmitters as potential predictors of clinical improvement to ketamine in depression. Int J Neuropsy¬chopharmacol 2012 Sep;15(8):1063-72.
43. Krystal JH, Petrakis IL, Krupitsky E, Schutz C, Trevisan L, D’Souza DC. NMDA receptor antagonism and the ethanol intoxication signal: form alcoholism risk to pharmacotherapy. Ann N Y Acad Sci. 2003 Nov;1003:176-84.
44. Aan Het Rot M, Zarate CA Jr, Charney DS, Mathew SJ. Ketamine for de¬pression: Where do we go from here? Biol Psychiatry. 2012 Oct;72(7):537-47.
45. Petrakis IL, Limoncelli D, Gueorguieva R, Jatlow P, Boutros NN, Trevisan L, et al. Altered NMDA glutamate receptor antagonist response in individuals with a family vulnerability to alcoholism. Am J Psychiatry. 2004 Oct;161(10):1776-82.
46. Howland RH. Ketamine for the treatment of depression. J Psychosoc Nurs Ment Health Serv. 2013 Jan;51(1):11-4.
47. Wohleb ES, Gerhard D, Thomas A, Duman RS. Molecular and cellular me¬chanisms of rapid-acting antidepressants ketamine and scopolamine. Curr Neuropharmacol. 2016 Mar 8. [Epub ahead of print]
48. Carreno FR, Donegan JJ, Boley AM, Shah A, DeGuzman M, Frazer A, et al. Activation of a ventral hippocampus-medial prefrontal cortex pathway is both necessary and sufficient for an antidepressant response to ketamine. Mol Psychiatry. 2015 Dec 1. [Epub ahead of print]
49. Harraz MM, Tyagi R, Cortés P, Snyder SH. Antidepressant action of keta¬mine via mTOR is mediated by inhibition of nitrergic Rheb degradation. Mol Psychiatry. 2016 Mar;21(3):313-9.
50. Monreal M, Davant E. Thrombotic complications of central venous cathe¬ters in cancer patients. Acta Haematol. 2001;106(1-2):69-72.
51. Kurul S, Saip P, Aydin T. Totally implantable venous-access ports: local problems and extravasation injury. Lancet Oncol. 2002 Nov;3(11):684-92.



How to Cite

Arthur Twohig, P., & Huckfeldt, V. (2016). Using Oral and Intranasal Dosage Forms of Ketamine for Managing Treatment-Resistant Depression: A Review of the Literature. International Journal of Medical Students, 4(2), 64–71.