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Ketamine: Clinical Studies in Treatment-Resistant Depressive Disorders

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Ketamine for Treatment-Resistant Depression

Abstract

Since the first report of a robust antidepressant effect of a sub-anesthetic dose of ketamine in 2000, studies have repeatedly confirmed its therapeutic benefits in major depressive disorder (MDD) as well as in depressive episodes in patients with bipolar disorder (BD). Two features of the antidepressant response to ketamine make it striking: first, it can manifest itself within minutes or hours after the transient and generally mild dissociation has disappeared and, second, it has mostly been shown to take place in treatment-resistant patients. The response rate—which is an improvement of 50 % or more—has generally been around 50 % in placebo-controlled studies. Due to the obvious mild dissociative effects of ketamine, low doses of the benzodiazepine midazolam have been used in an attempt to preserve the blind; under such conditions the antidepressant action of ketamine has been confirmed. The main drawback of ketamine is that its antidepressant effects generally do not last more than one week. Several studies have, however, shown that repeated administration can maintain and prolong the response. Finally, clinical experience using repeated administration of ketamine has thus far revealed no significant adverse events; in addition, no tachyphylaxis to the benefits of ketamine in MDD is apparent.

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References

  • aan het Rot M, Collins KA, Murrough JW et al (2010) Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression. Biol Psychiat 67:139–145

    Article  CAS  PubMed  Google Scholar 

  • Anisman H (2009) Cascading effects of stressors and inflammatory immune system activation: implications for major depressive disorders. J Psychiat Neurosci 34:4–20

    Google Scholar 

  • Berman RM, Cappiello A, Anand A et al (2000) Antidepressant effect of ketamine in depressed patients. Biol Psychiat 47:35–354

    Google Scholar 

  • Blier P (2013) Exploiting N-methyl-d-aspartate channel blockade for a rapid antidepressant response in major depressive disorder. Biol Psychiat 74:238–239

    Article  CAS  PubMed  Google Scholar 

  • Blier P, Zigman D, Blier J (2012) On the safety and benefits of repeated intravenous injections of ketamine for depression. Biol Psychiat 72:e11–e12

    Article  CAS  PubMed  Google Scholar 

  • Cusin C, Ionescu DF, Pavone KJ et al (2016) Ketamine augmentation for outpatients with treatment-resistant depression: preliminary evidence for two-step intravenous dose escalation. Aust N Z J Psychiat. pii:0004867416631828

    Google Scholar 

  • Daly E, Singh J, Fedgchin M et al (2015) Intranasal esketamine in treatment-resistant depression, a dose response study-double blind and open label extension data. Neuropsychopharmacol 40(issue1):S340–S341

    Google Scholar 

  • Diamond PR, Farmery AD, Atkinson S et al (2014) Ketamine infusions for treatment-resistant depression: a series of 28 patients treated weekly or twice weekly in an ECT clinic. J Psychopharmacol 28:536–544

    Article  PubMed  Google Scholar 

  • Diazgranados N, Ibrahim I, Brutsche NE et al (2010) A randomized add on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiat 67:793–802

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dunlop BW, Thase ME, Wun CC et al (2012) A meta-analysis of factors impacting detection of antidepressant efficacy in clinical trials: the importance of academic sites. Neuropsychopharmacology 37:2830–2836

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ford N, Ludbrook G, Galletly C (2015) Benzodiazepines may reduce the effectiveness of ketamine in the treatment of depression. Aust N Z J Psychiatry 49:1227

    Google Scholar 

  • Frye MA, Blier P, Tye SJ (2015) Concomitant benzodiazepine use attenuates ketamine response: implications for large scale study design and clinical development. J Clin Psychopharmacol 35:334–336

    Article  PubMed  Google Scholar 

  • Hu YD, Xiang YT, Fang JX et al (2016) Single i.v. ketamine augmentation of newly initiated escitalopram for major depression: results from a randomized, placebo-controlled 4-week study. Psychol Med 46:632–635

    Google Scholar 

  • Ibrahim L, Diazgranados N, Luckenbaugh DA et al (2011) Rapid decrease in depressive symptoms with an N-methyl-D-aspartate antagonist in ECT-resistant major depression. Prog Neuropsychopharmacol Biol Psychiat 35:1155–1159

    Article  CAS  Google Scholar 

  • Keller MB, Lavori PW, Mueller TI et al (1992) Time to recovery, chronicity, and levels of psychopathology in major depression. A 5-year prospective follow-up of 431 subjects. Arch Gen Psychiat 49:809–816

    Article  CAS  PubMed  Google Scholar 

  • Kishimoto T, Chawla JM, Hagi K et al (2016) Single-dose infusion ketamine and non-ketamine N-methyl-D-aspartate receptor antagonists for unipolar and bipolar depression: a meta-analysis of efficacy, safety and time trajectories. Psychol Med 46:1459–1472

    Google Scholar 

  • Lapidus KB, Levitch CF, Prerez AM et al (2014) A randomized controlled trial of intranasal ketamine in major depressive disorder. Biol Psychiat 76:970–976

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Larkin GL, Beauclair AL (2011) A preliminary naturalistic study of low-dose ketamine for depression and suicide ideation in the emergency department. Int J Neuropsychopharmacol 14:1127–1131

    Article  CAS  PubMed  Google Scholar 

  • Lenze EJ, Farber NB, Kharasch E et al (2016) Ninety-six hour ketamine infusion with co-administered clonidine for treatment-resistant depression: a pilot randomized controlled trial. World J Biol Psychiat 17:230–238

    Google Scholar 

  • Li CT, Chen MH, Lin WC et al (2016) The effects of low-dose ketamine on the prefrontal cortex and amygdala in treatment-resistant depression: a randomized controlled study. Hum Brain Mapp 37:1080–1090

    Article  PubMed  Google Scholar 

  • Luckenbaugh DA, Niciu MJ, Ionescu DF et al (2014) Do the dissociative side effects of ketamine mediate its antidepressant effects? J Affect Disord 159:56–61

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moskal JR, Burgdorf JS, Stanton PK et al (2016) The development of Rapastinel (Formerly GLYX-13); a rapid acting and long lasting antidepressant. Curr Neuropharmacol. March 21, Epub ahead of print. PMID: 26997507

    Google Scholar 

  • Murrough JW, Iosifescu DV, Chang LC et al (2013a) Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiat 170:1134–1142

    Article  PubMed  PubMed Central  Google Scholar 

  • Murrough JW, Perez AM, Pillemer S et al (2013b) Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biol Psychiat 74:250–256

    Article  CAS  PubMed  Google Scholar 

  • Newport DJ, Carpenter LL, McDonald WM et al (2015) Ketamine and other NMDA antagonists: early clinical trials and possible mechanisms in depression. Am J Psychiat 172:950–966

    Article  PubMed  Google Scholar 

  • Phillips JL, Norris S, Talbot et al (2016) Ketamine exerts a prolonged reduction in suicidal ideation independent of its antidepressant effects. Int J Neuropsychopharmacol 19(suppl 1):128

    Google Scholar 

  • Rasmussen KG, Lineberry TW, Galardy CW et al (2013) Serial infusions of low-dose ketamine for major depression. J Psychopharmacol 27:444–450

    Google Scholar 

  • Rush AJ, Trivedi MH, Wisnlewski SR et al (2006) Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiat 163:1905–1917

    Article  PubMed  Google Scholar 

  • Shiroma PR, Johns B, Kuskowski M et al (2014) Augmentation of response and remission to serial intravenous subanesthetic ketamine in treatment-resistant depression. J Affect Disord 155:123–129

    Article  CAS  PubMed  Google Scholar 

  • Singh JB, Fedgchin M, Daly E et al (2015) Intravenous esketamine in adult treatment-resistant depression: a double-blind, double-randomization, placebo-controlled study. Biol Psychiatry80:424–431

    Google Scholar 

  • Sos P, Klivora M, Nowak T et al (2013) Relationship of ketamine’s antidepressant and psychotomimetic effects in unipolar depression. Neuro Endocrinol Lett 34:287–293

    Google Scholar 

  • Vollenweider FX, Leenders KL, Oye I et al (1999) Differential psychopathology and patterns of cerebral glucose utilization produced by (S)- and (R)-ketamine in healthy volunteers using positron emission tomography (PET). Eur Neuropsychopharmacol 7:25–38

    Google Scholar 

  • Xu Y, Hackett M, Carter G et al (2015) Effects of low-dose and very low-dose ketamine among patients with major depression: a systematic review and meta-analysis. Int J Neuropsychopharmacol 19:pii:pyv124

    Google Scholar 

  • Yee CH, Lai PT, Lee WM et al (2015) Clinical outcome of a prospective case series of patients with ketamine cystitis who underwent standardized treatment protocol. Urology 86:236–243

    Article  PubMed  Google Scholar 

  • Zarate CA Jr, Niciu MJ (2015) Ketamine for depression: evidence, challenges and promise. World Psychiatry 14:348–350

    Google Scholar 

  • Zarate CA Jr, Singh JB, Carlson PJ et al (2006) A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiat 63:856–864

    Article  CAS  PubMed  Google Scholar 

  • Zarate CA Jr, Brutsche NE, Ibrahim I et al (2012) Replication of ketamine’s antidepressant efficacy in bipolar depression: a randomized controlled add-on trial. Biol Psychiat 71:939–946

    Google Scholar 

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Correspondence to Pierre Blier .

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Blier, P., Blier, J. (2016). Ketamine: Clinical Studies in Treatment-Resistant Depressive Disorders. In: Mathew, S., Zarate, Jr., C. (eds) Ketamine for Treatment-Resistant Depression. Adis, Cham. https://doi.org/10.1007/978-3-319-42925-0_3

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  • DOI: https://doi.org/10.1007/978-3-319-42925-0_3

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  • Publisher Name: Adis, Cham

  • Print ISBN: 978-3-319-42923-6

  • Online ISBN: 978-3-319-42925-0

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