Role of Ketamine in the Treatment of Psychiatric Disorders
Purpose of review
This is a comprehensive review of the literature regarding the use of ketamine as a treatment for treatment-resistant depression (TRD). It covers the epidemiology, risk factors, pathophysiology, and current treatment modalities regarding Major Depressive Disorder (MDD) and TRD. It provides background on the mechanism of action of ketamine, its history, current approved and off-label indications in the field of psychiatry, and then provides an overview of the existing evidence for the use of ketamine in the treatment of TRD.
Recent findings
MDD is a mental illness that puts an enormous strain on the affected and a high socio-economic burden on society. The illness is complex and combines genetic, pathophysiologic, and environmental factors that combine to negatively affect neurotransmitter balance in the brain. Additional evidence suggests dysregulation of the hypothalamic-pituitary (HPA) axis, brain-derived neurotrophic factor (BDNF), vitamin D levels, and involvement of pro-inflammatory markers. Core symptoms include depressed mood or anhedonia, combined with neurovegetative symptoms such as sleep impairment, changes in appetite, feelings of worthlessness and guilt, and psychomotor retardation. Current first-line treatment options are antidepressants of the selective serotonin reuptake inhibitor (SSRI) and serotonin-norepinephrine reuptake inhibitor (SNRI) class. Failure to respond to two adequate trials of treatment meets the criteria for TRD. Esketamine (Spravato) is an NMDA-receptor antagonist with additional AMPA-receptor agonist properties, which the FDA approved in 2019 to treat adult TRD in conjunction with an oral antidepressant. It can be administered intranasally, providing a rapid response and proven effective and safe. Additional research suggests that oral ketamine might be effective for PTSD and anxiety disorders. Intravenous administration of ketamine has also shown benefits for acute suicidal ideation and depression and substance use to reduce relapse rates.
Summary
TRD is associated with huge costs on individual and societal levels. Underlying disease processes are multifactorial and not well understood. Adjunctive therapies for TRD with proven benefits exist, but acutely depressed and suicidal patients often require prolonged inpatient stabilization. Intranasal esketamine is a new FDA-approved alternative with rapid benefit for TRD, which has also shown a rapid reduction in suicidal ideation while maintaining a favorable side-effect profile. Additional potential off-label uses for ketamine in psychiatric disorders have been studied, including PTSD, anxiety disorders, bipolar depression, and substance use disorders.
1. Sussman M, O'sullivan AK, Shah A, Olfson M, Menzin J. Economic Burden of Treatment-Resistant Depression on the U.S. Health Care System. J Manag care Spec Pharm.2019;25(7):823-835.doi:10.18553/jmcp.2019.25.7.823
2. Jaffe DH, Rive B, Denee TR. The humanistic and economic burden of treatment-resistant depression in Europe: a cross-sectional study. BMC Psychiatry.2019;19(1):247. doi:10.1186/s12888-019-2222-4
3. Mion G. History of anaesthesia: The ketamine story-past, present and future. Eur JAnaestheiol.2017;34(9):571-575. doi:10.1097/EJA.0000000000000638
4. Hashimoto K. Rapid-acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective. Psychiatry Clin Neurosci.2019;73(10):613-627. doi:10.1111/pcn.12902
5. Esketamine nasal spray(Spravato) for treatment-resistant depression. Med Lett Drugs Ther.2019;61(1569):54-57.
6. Ivan Ezquerra-Romano I, Lawn W, Krupitsky E, Morgan CJA. Ketamine for the treatment of addiction: Evidence and potential mechanisms. Neuropharmacology.2018;142:72-82.doi:10.1016/j.neuropharm.2018.01.017
7. Pribish A, Wood N, Kalava A. A Review of Nonanesthetic Uses of Ketamine. Anesthesiol Res Pract.2020;2020:5798285. doi:10.1155/2020/5798285
8. Fond G, Loundou A, Rabu C, et al. Ketamine administration in depressive disorders: a systematic review and meta-analysis. Psychopharmacology(Berl).2014;231(18):3663-3676. doi:10.1007/s00213-014-3664-5
9. Hartberg J, Garrett-Walcott S, De Gioannis A. Impact of oral ketamine augmentation on hospital admissions in treatment-resistant depression and PTSD: a retrospective study. Psychopharmacology(Berl).2018;235(2):393-398. doi:10.1007/s00213-017-4786-3
10. Fortress AM, Smith IM, Pang KCH. Ketamine facilitates extinction of avoidance behavior and enhances synaptic plasticity in a rat model of anxiety vulnerability: Implications for the pathophysiology and treatment of anxiety disorders. Neuropharmacology.2018;137:372-381. doi:10.1016/j.neuropharm.2018.05.009
11. Glue P, Neehoff S, Sabadel A, et al. Effects of ketamine in patients with treatment-refractory generalized anxiety and social anxiety disorders: Exploratory double-blind psychoactive-controlled replication study. J Psychopharmacol.2020;34(3):267-272. doi:10.1177/0269881119874457
12. Silote GP, de Oliveira SFS, Ribeiro DE, et al. Ketamine effects on anxiety and fear-related behaviors: Current literature evidence and new findings. Prog Neuropsychopharmacol Biol Psychiatry.2020;100:109878. doi:10.1016/j.pnpbp.2020.109878
13. Dakwar E, Nunes EV, Hart CL, et al. A Single Ketamine Infusion Combined With Mindfulness-Based Behavioral Modification to Treat Cocaine Dependence: A Randomized Clinical Trial. Am J Psychiatry.2019;176(11):923-930. doi:10.1176/appi.ajp.2019.18101123
14. Jones JL, Mateus CF, Malcolm RJ, Brady KT, Back SE. Efficacy of Ketamine in the Treatment of Substance Use Disorders: A Systematic Review. Front psychiatry.2018;9:277. doi:10.3389/fpsyt.2018.00277
15. Das RK, Gale G, Walsh K, et al. Ketamine can reduce harmful drinking by pharmacologically rewriting drinking memories. Nat Commun.2019;10(1):5187. doi:10.1038/s41467-019-13162-w
16. Niciu MJ, Luckenbaugh DA, Ionescu DF, et al. Ketamine's antidepressant efficacy is extended for at least four weeks in subjects with a family history of an alcohol use disorder. Int J Neuropsychopharmacol.2014;18(1). doi:10.1093/ijnp/pyu039
17. Gaynes BN, Lux L, Gartlehner G, et al. Defining treatment-resistant depression. Depression and anxiety.2020;37(2):134-145. doi:10.1002/da.22968
18. Reutfors J, Andersson TML, Brenner P, et al. Mortality in treatment-resistant unipolar depression: A register-based cohort study in Sweden. JAffect Disord.2018;238:674-679. doi:10.1016/j.jad.2018.06.030
19. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th Edition.;2013.
20. Verduijn J, Milaneschi Y, Schoevers RA, van Hemert AM, Beekman ATF, Penninx BWJH. Pathophysiology of major depressive disorder: mechanisms involved in etiology are not associated with clinical progression. Transl Psychiatry.2015;5(9):e649. doi:10.1038/tp.2015.137
21. Akil H, Gordon J, Hen R, et al. Treatment resistant depression: A multi-scale, systems biology approach. Neurosci Biobehav Rev.2018;84:272-288. doi:10.1016/j.neubiorev.2017.08.019
22. Moshe H, Gal R, Barnea-Ygael N, Gulevsky T, Alyagon U, Zangen A. Prelimbic Stimulation Ameliorates Depressive-Like Behaviors and Increases Regional BDNF Expression in a Novel Drug-Resistant Animal Model of Depression. Brain Stimul.2016;9(2):243-250. doi:10.1016/j.brs.2015.10.009
23. Wilson S, Vaidyanathan U, Miller MB, McGue M, Iacono WG. Premorbid risk factors for major depressive disorder: are they associated with early onset and recurrent course? Dev Psychopathol.2014;26(4Pt 2):1477-1493. doi:10.1017/S0954579414001151
24. Kautzky A, Dold M, Bartova L, et al. Clinical factors predicting treatment resistant depression: affirmative results from the European multicenter study. Acta Psychiatr Scand. 2019;139(1):78-88. doi:10.1111/acps.12959
25. Mullen S. Major depressive disorder in children and adolescents. Ment Heal Clin.2018;8(6):275-283. doi:10.9740/mhc.2018.11.275
26. Bennabi D, Charpeaud T, Yrondi A, et al. Clinical guidelines for the management of treatment-resistant depression: French recommendations from experts, the French Association for Biological Psychiatry and Neuropsychopharmacology and the fondation FondaMental. BMC psychiatry. 2019;19(1):262. doi:10.1186/s12888-019-2237-x
27. Caldarone BJ, Zachariou V, King SL. Rodent models of treatment-resistant depression. Eur J Pharmacol.2015;753:51-65. doi:10.1016/j.ejphar.2014.10.063
28. Edwards SJ, Hamilton V, Nherera L, Trevor N. Lithium or an atypical antipsychotic drug in the management of treatment-resistant depression: a systematic review and economic evaluation. Health Technol Assess.2013;17(54):1-190. doi:10.3310/hta17540
29. De Berardis D, Fornaro M, Anastasia A, et al. Adjunctive vortioxetine for SSRI-resistant major depressive disorder: a “real-world” chart review study. Rev Bras Psiquiatr.2020;42(3):317-321. doi:10.1590/1516-4446-2019-0690
30. Gall Z, Farkas S, Albert A, et al. Effects of Chronic Cannabidiol Treatment in the Rat Chronic Unpredictable Mild Stress Model of Depression. Biomolecules.2020;10(5). doi:10.3390/biom10050801
31. Zanos P, Gould TD. Mechanisms of ketamine action as an antidepressant. Mol Psychiatry.2018;23(4):801-811. doi:10.1038/mp.2017.255
32. FDA. FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor's office or clinic. https://www.fda.gov/news-events/press-announcements/fda-approves-new-nasal-spray-medication-treatment-resistant-depression-available-only-certified. Published 2019.
33. Strasburger SE, Bhimani PM, Kaabe JH, et al. What is the mechanism of Ketamine's rapid-onset antidepressant effect? A concise overview of the surprisingly large number of possibilities. J Clin Pharm Ther.2017;42(2):147-154. doi:10.1111/jcpt.12497
34. Williams NR, Schatzberg AF. NMDA antagonist treatment of depression. Curr Opin Neurobiol.2016;36:112-117. doi:10.1016/j.conb.2015.11.001
35. Williams NR, Heifets BD, Blasey C, et al. Attenuation of Antidepressant Effects of Ketamine by Opioid Receptor Antagonism. Am J Psychiatry.2018;175(12):1205-1215. doi:10.1176/appi.ajp.2018.18020138
36. Kornhall D, Nielsen EW. Failure of ketamine anesthesia in a patient with lamotrigine overdose. Case reports Crit care.2014;2014:916360. doi:10.1155/2014/916360
37. Andrashko V, Novak T, Brunovsky M, Klirova M, Sos P, Horacek J. The Antidepressant Effect of Ketamine Is Dampened by Concomitant Benzodiazepine Medication. Front psychiatry.2020;11:844. doi:10.3389/fpsyt.2020.00844
38. Hijazi Y, Boulieu R. Contribution of CYP3A4, CYP2B6, and CYP2C9 isoforms to N-demethylation of ketamine in human liver microsomes. Drug Metab Dispos.2002;30(7):853-858. doi:10.1124/dmd.30.7.853
39. Yanagihara Y, Kariya S, Ohtani M, et al. Involvement of CYP2B6 in n-demethylation of ketamine in human liver microsomes. Drug Metab Dispos.2001;29(6):887-890.
40. Edwards SR, Mather LE. Tissue uptake of ketamine and norketamine enantiomers in the rat: indirect evidence for extrahepatic metabolic inversion. Life Sci.2001;69(17):2051-2066. doi:10.1016/s0024-3205(01)01287-5
41. Pfenninger EG, Durieux ME, Himmelseher S. Cognitive impairment after small-dose ketamine isomers in comparison to equianalgesic racemic ketamine in human volunteers. Anesthesiology.2002;96(2):357-366. doi:10.1097/00000542-200202000-00022
42. Zielmann S, Kazmaier S, Schniill S, Weyland A. [S-(+)-Ketamine and circulation]. Anaesthesist. 1997;46 Suppl 1:S43-6. doi:10.1007/pl00002464
43. White PF, Ham J, Way WL, Trevor AJ. Pharmacology of ketamine isomers in surgical patients. Anesthesiology.1980;52(3):231-239. doi:10.1097/00000542-198003000-00008
44. Kallmünzer B, Volbers B, Karthaus A, Tektas OY, Kornhuber J, Miller HH. Treatment escalation in patients not responding to pharmacotherapy, psychotherapy, and electro-convulsive therapy: experiences from a novel regimen using intravenous S-ketamine as add-on therapy in treatment-resistant depression. J Neural Transm.2016;123(5):549-552. doi:10.1007/s00702-015-1500-7
45. Bartova L, Vogl SE, Stamenkovic M, et al. Combination of intravenous S-ketamine and oral tranylcypromine in treatment-resistant depression: A report of two cases. Eur Neuropsychopharmacol J Eur Coll Neuropsychopharmacol.2015;25(11):2183-2184. doi:10.1016/j.euroneuro.2015.07.021
46. Segmiller F, Rither T, Linhardt A, et al. Repeated S-ketamine infusions in therapy resistant depression: a case series. J Clin Pharmacol.2013;53(9):996-998. doi:10.1002/jcph.122
47. Zhang JC, Li SX, Hashimoto K. R(-)-ketamine shows greater potency and longer lasting antidepressant effects than S(+)-ketamine. Pharmacol Biochem Behav.2014;116:137-141. doi:10.1016/j.pbb.2013.11.033
48. Andrade C. Ketamine for Depression, 3: Does Chirality Matter? J Clin Psychiatry.2017;78(6):e674-e677. doi:10.4088/JCP.17f11681
49. Fedgchin M, Trivedi M, Daly EJ, et al. Efficacy and Safety of Fixed-Dose Esketamine Nasal Spray Combined With a New Oral Antidepressant in Treatment-Resistant Depression: Results of a Randomized, Double-Blind, Active-Controlled Study (TRANSFORM-1). Int J Neuropsychopharmacol.2019;22(10):616-630. doi:10.1093/ijnp/pyz039
50. Daly EJ, Singh JB, Fedgchin M, et al. Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral
Antidepressant Therapy in Treatment-Resistant Depression: A Randomized Clinical Trial. JAMA psychiatry. 2018;75(2):139-148. doi:10.1001/jamapsychiatry.2017.3739
51. Singh JB, Fedgchin M, Daly E,et al. Intravenous Esketamine in Adult Treatment-Resistant Depression: A Double-Blind, Double-Randomization,Placebo-Controlled Study. Biol Psychiatry.2016;80(6):424-431. doi:10.1016/j.biopsych.2015.10.018
52. Milak MS, Rashid R, Dong Z,et al. Assessment of Relationship of Ketamine Dose With Magnetic Resonance Spectroscopy of Glx and GABA Responses in Adults With Major Depression: A Randomized Clinical Trial. JAMA Netw Open.2020;3(8):e2013211.doi:10.1001/jamanetworkopen.2020.13211
53. Chen MH, Lin WC, Wu HJ,et al. Antisucidal effect,BDNF Val66Met polymorphism, and low-dose ketamine infusion: Reanalysis of adjunctive ketamine study of Taiwanese patients with treatment-resistant depression(AKSTP-TRD).JAffect Disord.2019;251:162-169.doi:10.1016/j.jad.2019.03.075
54. Chen MH, Li CT, Lin WC,et al. Rapid inflammation modulation and antidepressant efficacy of a low-dose ketamine infusion in treatment-resistant depression: A randomized, double-blind control study. Psychiatry Res.2018;269:207-211. doi:10.1016/j.psychres.2018.08.078
55. Ionescu DF, Bentley KH, Eikermann M,et al.Repeat-dose ketamine augmentation for treatment-resistant depression with chronic suicidal ideation: A randomized, double blind, placebo controlled trial.Psychiatry Res.2019;243:516-524.doi:10.1016/j.jad.2018.09.037
56. Canuso CM, Singh JB, Fedgchin M,et al. Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of Symptoms of Depression and Suicidality in Patients at Imminent Risk for Suicide:Results of a Double-Blind, Randomized, Placebo-Controlled Study. Am J Psychiatry.2018;175(7):620-630.doi:10.1176/appi.ajp.2018.17060720
57. Chang L,Zhang K,Pu Y,et al. Comparison of antidepressant and side effects in mice after intranasal administration of(R,S)-ketamine,(R)-ketamine,and(S)-ketamine.Pharmacol Biochem Behav.2019;181:53-59.doi:10.1016/j.pbb.2019.04.008
58. Muller J, Pentyala S,Dilger J, Pentyala S. Ketamine enantiomers in the rapid and sustained antidepressant effects. Ther Adv Psychopharmacol.2016;6(3):185-192. doi:10.1177/2045125316631267
59. Correia-Melo FS, Leal GC, Carvalho MS,et al.Comparative study of esketamine and racemic ketamine in treatment-resistant depression: Protocol for a non-inferiority clinical trial.Medicine(Baltimore).2018;97(38):e12414. doi:10.1097/MD.0000000000012414
60. Gautam CS, Mahajan SS, Sharma J, Singh H, Singh J. Repurposing Potential of Ketamine: Opportunities and Challenges. Indian J Psychol Med.2020;42(1):22-29. doi:10.4103/IJPSYM.IJPSYM_228_19
61. Carreno FR, Lodge DJ, Frazer A. Ketamine:Leading us into the future for development of antidepressants. Behav Brain Res.2020;383:112532.doi:10.1016/j.bbr.2020.112532
62. Smith-Apeldoorn SY, Veraart JKE, Kamphuis J, et al. Oral esketamine for treatment-resistant depression: rationale and design of a randomized controlled trial. BMC Psychiatry.2019;19(1):375. doi:10.1186/s12888-019-2359-1
63. Pérez-Esparza R,Kobayashi-Romero LF, Garcia-Mendoza AM, Lamas-Aguilar RM, Fonseca-Perezamador A. Promises and concerns regarding the use of ketamine and esketamine in the treatment of depression. Acta Psychiatr Scand.2019;140(2):182-183.doi:10.1111/acps.13063