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FAST FACTS AND CONCEPTS #384THE ROLE OF KETAMINE IN DEPRESSIONApril Christensen MD1, Jennifer Pruskowski PharmD2Background Depression is common among seriously ill patients. While the mainstay of pharmacotherapy has been psychostimulants for those with a shorter prognosis (days to weeks) and selective serotonin reuptake inhibitors (SSRIs) for those with a longer prognosis (weeks to months), the efficacy of these medications has been mixed in palliative care populations (1-2). See Fast Facts #61 and #309. Ketamine has received attention from clinician experts for its potential to offer rapid relief in treatment-resistant depression (TRD), meaning depression which has not responded to at least two adequate trials of antidepressants (3-5). This Fast Fact aims to provide a concise review of the role of ketamine to treat TRD in adults for experienced palliative care clinicians.Pharmacology Ketamine’s mechanisms of action are discussed in Fast Fact #132. It can be given off-label for depression intravenously (IV) or orally (usually the IV solution mixed into a palatable liquid) (6). However, oral ketamine undergoes extensive first-pass metabolism resulting in poor bioavailability (only 20%) (6-7). Intranasal ketamine or esketamine was recently approved for TRD and has a bioavailability of 45%. Ketamine has not been well studied in seriously ill adults with depression, except for an open label study and a few case reports (3,8-9). There is even less evidence to support its use for TRD in children. Dose adjustments in renal and liver impairment are not felt to be necessary.Intravenous The majority of randomized controlled trials (RCTs) of ketamine for TRD have examined otherwise healthy patients receiving one-time IV infusions of 0.5 mg/kg over 40 minutes as an adjuvant therapy with a follow-up of less than two weeks. In two meta-analyses, a single administration of IV ketamine significantly reduced depressive symptoms and suicidal thinking within one week (4,10). Response rates for a single infusion have been reported to be as high as 50-70%, which appears to be better than traditional antidepressants (11-13). However, the time to relapse is 1-3 weeks, necessitating repeat infusions (10,14). Most studies on single IV ketamine infusions have not reported any serious adverse events (10). Reported side effects generally resolve within four hours and include perceptual disturbances, confusion, blood pressure elevation, dizziness, and euphoria (13).Intranasal Esketamine (an S-isomer) has been approved as a nasal spray for TRD in conjunction with oral antidepressants. A double-blind RCT in 18 subjects showed a 44% response rate to a single dose of 50 mg intranasal ketamine compared to 6% for a placebo saline nasal spray (15). Onset was 40 minutes and lasted less than 3 days. Common side effects are “feeling unreal,” fatigue, and poor memory for up to four hours. Maintenance intranasal ketamine has been examined only in case reports (16).Oral A small, open-label study of oral ketamine in hospice patients demonstrated some improvement in a validated, patient-reported depression scale when dosed at 0.5 mg/kg for 28 days (3,17-18). The time to response was 1-2 weeks. However, four of the 14 patients withdrew before the completion of the study due to lack of response (3,17-18). Maintenance oral regimens have not been systematically studied in palliative care patients (19). Dizziness, delirium, hallucinations, nausea, vomiting, and headache are commonly reported side effects (6).Other Considerations Data on the long-term effects of ketamine are limited. However, there is concern for its potential to elicit urinary, hepatobiliary, and neuropsychiatric side effects if used greater than two weeks consecutively (6, 20-23). Its risk of misuse or addiction is relatively unknown (6, 20). Across methods of administration, ketamine’s effect on depression outlasts the side effect of euphoria. As needed benzodiazepines such as midazolam 1-5 mg IV or lorazepam 0.5 mg-2 mg IV are recommended for ketamine-induced delirium and hallucinations, the most common adverse drug reactions (24).Clinical Use Ketamine should only be used for severe TRD in adults after a thorough palliative-case assessment in which other potential diagnoses such as grief or adjustment disorder have been considered. Close collaboration with interdisciplinary team members is essential along with consideration and implementation of standard depression therapies including psychological counseling and first-line antidepressants (ex: SSRIs) as appropriate. Its use for TRD in the palliative care setting should be reserved for specialized palliative care or psychiatry clinicians with significant expertise with the medication who can closely collaborate with a clinical pharmacist (25).At this time, available evidence has not established standard induction and maintenance protocols. Therefore, conservative doses should be utilized with a plan to titrate as tolerated (see table below). Clinicians should closely during any IV administration, any initial administration, and at any dose increase.Route DosingFrequencyIntravenous0.5 mg/kg over 40 minutesInduction: q3 days for 6 infusionsMaintenance: q3 weeks or at time of relapseIntranasal10-50 mgQ 3-7 daysOral10-100 mgQday to 3 times per dayCost IV or oral ketamine is typically not covered by insurance, resulting in out-of-pocket costs to the patient or hospice. The cost of ketamine solution varies from $1 to $3 per mL depending on concentration and negotiated price. Therefore, costs of $400-$800 for single administrations of IV ketamine have been reported. Intranasal ketamine (esketamine) typically costs around $350 per administration.References1.Wilson KG, Chochinov HM, Skirko MG, Allard P, et. al. Depression and anxiety disorders in palliative cancer care. J Pain Symptom Manage. 2007 Feb;33(2):118-29.2.Ostuzzi G, Matcham F, Dauchy S, Barbui C, Hotopf M. Antidepressants for the treatment of depression in people with cancer. Cochrane Database Syst Rev. 2015 Jun 1;(6):CD011006.3.Irwin SA, Iglewicz A, Nelesen RA, Lo JY, 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):958-65.4.Lee EE, Della Selva MP, Liu A, Himelhoch S. Ketamine as a novel treatment for major depressive disorder and bipolar depression: a systematic review and quantitative meta-analysis. Gen Hosp Psychiatry. 2015 Mar-Apr;37(2):178-84.5.Schoevers RA, Chaves TV, Balukova SM, Rot MA, Kortekaas R. Oral ketamine for the treatment of pain and treatment-resistant depression. Br J Psychiatry. 2016 Feb;208(2):108-13. doi: 10.1192/bjp.bp.115.165498.6.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 Jul;25(7):823-835. doi: 10.18553/jmcp.2019.25.7.823.7.Yanagihara Y, Ohtani M, Kariya S, Uchino K, et. al. Plasma concentration profiles of ketamine and norketamine after administration of various ketamine preparations to healthy Japanese volunteers. Biopharm Drug Dispos. 2003 Jan;24(1):37-43.8.Stefanczyk-Sapieha L, Oneschuk D, Demas M. Intravenous ketamine "burst" for refractory depression in a patient with advanced cancer. J Palliat Med. 2008 Nov;11(9):1268-71. doi: 10.1089/jpm.2008.9828.9.Sexton J, Atayee RS, Bruner HC. Case Report: Ketamine for Pain and Depression in Advanced Cancer. J Palliat Med. 2018 Nov;21(11):1670-1673. doi: 10.1089/jpm.2017.0551.10.McGirr A, Berlim MT, Bond DJ, Fleck MP, et. al. A systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials of ketamine in the rapid treatment of major depressive episodes. Psychol Med. 2015 Mar;45(4):693-704.11.Berman RM, Cappiello A, Anand A, Oren DA, et. al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000 Feb 15;47(4):351-4.12.Naughton M, Clarke G, O’Leary OF, Cryan JF, Dinan TG. A review of ketamine in affective disorders: Current evidence on clinical efficacy, limitations of use and pre-clinical evidence on proposed mechanisms of action. J Affect Disord. 2014 Mar;156:24-35.13.Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, et. al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006 Aug;68(8):856-64.14.Murrow JW, Perez AM, Pillemer S, Stern J, et. al. Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biol Psychiatry. 2013 Aug;74(4):250-6.15.Lapidus KA, Levitch CF, Perez AM, Brallier JW, Parides MK, et al. A randomized controlled trial of intranasal ketamine in major depressive disorder. Biol Psychiatry. 2014 Dec 15;76(12):970-6. doi: 10.1016/j.biopsych.2014.03.026. Epub 2014 Apr 3.16.Andrade C. Intranasal drug delivery in neuropsychiatry: focus on intranasal ketamine for refractory depression. J Clin Psychiatry. 2015 May;76(5):e628-31. doi: 10.4088/JCP.15f10026.17.Irwin SA, Iglewicz A. Oral Ketamine for the Rapid Treatment of Depression and Anxiety in Patients Receiving Hospice Care. J Palliat Med. 2010 Jul;13(7):903-8.18.Iglewicz A, Morrison K, Nelesen RA, Zhan T, Iglewicz B, et al. Ketamine for the treatment of depression in patients receiving hospice care: a retrospective medical record review of thirty-one cases. Psychosomatics. 2015 Jul-Aug;56(4):329-39. doi: 10.1016/j.psym.2014.05.005. Epub 2014 Jun 5.19.McNulty JP, Hahn K. Compounded oral ketamine. Int J Pharm Compd. 2012 Sep-Oct;16(5):364-8.20.Jones JL, Mateus CF, Malcom RJ, Brady KT, Back SE. Efficacy of Ketamine in the Treatment of Substance Use Disorders: A Systematic Review. Front Psychiatry. 2018 Jul 24;9:277. doi: 10.3389/fpsyt.2018.00277. eCollection 2018.21.Kim M, Cho S, Lee JH. The Effects of Long-Term Ketamine Treatment on Cognitive Function in Complex Regional Pain Syndrome: A Preliminary Study. Pain Med. 2016 Aug;17(8):1447-51. doi: 10.1093/pm/pnv112. Epub 2016 Feb 27.22.Zhu W, Ding Z, Zhang Y, Shi J, Hashimoto K, Lu L. Risks Associated with Misuse of Ketamine as a Rapid-Acting Antidepressant. Neurosci Bull. 2016 Dec;32(6):557-564. Epub 2016 Nov 22.23.Gutkin E, Hussain SA, Kim SH. Ketamine-induced biliary dilatation: from Hong Kong to New York. J Addict Med. 2012 Mar;6(1):89-91. doi: 10.1097/ADM.0b013e3182399216.24.Trivedi S, Kumar R, Tripathi AK, Mehta RK. A Comparative Study of Dexmedetomidine and Midazolam in Reducing Delirium Caused by Ketamine. J Clin Diagn Res. 2016 Aug;10(8):UC01-4. doi: 10.7860/JCDR/2016/18397.8225. Epub 2016 Aug 1.25.Jamkumar J, Fam J, Yeo EY, Gawe GS. Ketamine and suicidal ideation in depression: jumping the gun? Pharmacol Res. 2015 Sep;99:23-35.Conflicts of Interest: None reportedAuthors’ Affiliations: 1Mayo Clinic, Rochester, Minnesota; 2University of Pittsburgh Medical Center, Pittsburgh, PennsylvaniaVersion History: originally edited by Christopher Lawton MD; first electronically published in September 2019.Fast Facts and Concepts are edited by Sean Marks MD (Medical College of Wisconsin) and associate editor Drew A Rosielle MD (University of Minnesota Medical School), with the generous support of a volunteer peer-review editorial board, and are made available online by the Palliative Care Network of Wisconsin (PCNOW); the authors of each individual Fast Fact are solely responsible for that Fast Fact’s content. The full set of Fast Facts are available at Palliative Care Network of Wisconsin with contact information, and how to reference Fast Facts.Copyright: All Fast Facts and Concepts are published under a Creative Commons Attribution-NonCommercial 4.0 International Copyright (). Fast Facts can only be copied and distributed for non-commercial, educational purposes. If you adapt or distribute a Fast Fact, let us know!Disclaimer: Fast Facts and Concepts provide educational information for health care professionals. This information is not medical advice. Fast Facts are not continually updated, and new safety information may emerge after a Fast Fact is published. Health care providers should always exercise their own independent clinical judgment and consult other relevant and up-to-date experts and resources. Some Fast Facts cite the use of a product in a dosage, for an indication, or in a manner other than that recommended in the product labeling. Accordingly, the official prescribing information should be consulted before any such product is used. ................
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