Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms

Pharmacological Reviews - Tập 70 Số 3 - Trang 621-660 - 2018
Panos Zanos1,2,3,4, Ruin Moaddel1,2,3,4, Patrick J. Morris1,2,3,4, Lace M. Riggs1,2,3,4, Jaclyn N. Highland1,2,3,4, Polymnia Georgiou1,2,3,4, Edna F. R. Pereira1,2,3,4, Edson X. Albuquerque1,2,3,4, Craig J. Thomas1,2,3,4, Carlos A. Zarate1,2,3,4, Todd D. Gould1,2,3,4
1Biomedical Research Center, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, Maryland (R.M.)
2Departments of Psychiatry (P.Z., L.M.R., J.N.H., P.G., T.D.G.), Pharmacology (E.F.R.P., E.X.A., T.D.G.), Anatomy and Neurobiology (T.D.G.), Epidemiology and Public Health, Division of Translational Toxicology (E.F.R.P., E.X.A.), Medicine (E.X.A.), and Program in Neuroscience (L.M.R.) and Toxicology (J.N.H.), University of Maryland School of Medicine, Baltimore, Maryland
3Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Intramural Research Program, National Institutes of Health, Rockville, Maryland (P.J.M., C.J.T.)
4Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (C.A.Z.)

Tóm tắt

Từ khóa


Tài liệu tham khảo

10.1007/s00213-002-1236-6

10.1016/S0028-3908(03)00073-X

10.1093/jat/29.5.376

10.1002/bms.1200081103

Adams, 1978, Quantitative analysis of ketamine enantiomers, Proc West Pharmacol Soc, 21, 471

10.1007/s00246-004-0707-4

10.1152/physrev.00015.2008

10.1016/0014-2999(89)90202-1

10.1126/science.2403696

10.1001/archpsyc.57.3.270

Andrade, 2017, Ketamine for depression, 3: does chirality matter?, J Clin Psychiatry, 78, e674, 10.4088/JCP.17f11681

Andrade, 2017, Ketamine for depression, 4: in what dose, at what rate, by what route, for how long, and at what frequency?, J Clin Psychiatry, 78, e852

10.1111/j.1476-5381.1983.tb11031.x

10.1093/bja/76.2.271

Arditti, 2002, Ketamine–dreams and realities, Acta Clin Belg, 57, 31, 10.1179/acb.2002.073

10.1016/S0003-9861(02)00214-X

10.1161/01.STR.27.4.743

10.1007/s004010100423

10.1038/nature10130

Azevedo, 2000, Transdermal ketamine as an adjuvant for postoperative analgesia after abdominal gynecological surgery using lidocaine epidural blockade, Anesth Analg, 91, 1479, 10.1097/00000539-200012000-00034

Azzaro, 1977, The inhibitory action of ketamine HC1 on [3H]5-hydroxytryptamine accumulation by rat brain synaptosomal-rich fractions: comparison with [3H]catecholamine and [3H]γ-aminobutyric acid uptake, Neuropharmacology, 16, 349, 10.1016/0028-3908(77)90072-7

10.1016/0304-3959(94)90149-X

10.1016/j.jpsychires.2014.07.027

Ballard, 2017, Anhedonia as a clinical correlate of suicidal thoughts in clinical ketamine trials, J Affect Disord, 218, 195, 10.1016/j.jad.2017.04.057

10.2344/0003-3006-59.2.90

10.1093/bja/aem218

Benoit, 1995, Effects of intravenous anaesthetics on nerve axons, Eur J Anaesthesiol, 12, 59

10.1016/S0006-3223(99)00230-9

10.1016/j.pneurobio.2012.06.001

Bion, 1984, Intrathecal ketamine for war surgery: a preliminary study under field conditions, Anaesthesia, 39, 1023, 10.1111/j.1365-2044.1984.tb08895.x

10.1016/j.biopsych.2012.02.039

10.1080/10550490290088126

10.1177/0897190014525754

Bolze, 1998, HPLC determination of ketamine, norketamine, and dehydronorketamine in plasma with a high-purity reversed-phase sorbent, Clin Chem, 44, 560, 10.1093/clinchem/44.3.560

10.1016/S0020-1383(01)00209-1

Bonifazi, 2015, Novel potent N-methyl-d-aspartate (NMDA) receptor antagonists or σ1 receptor ligands based on properly substituted 1,4-dioxane ring, J Med Chem, 58, 8601, 10.1021/acs.jmedchem.5b01214

10.1097/00000542-198702000-00008

10.1097/00000542-199801000-00015

10.1016/0014-2999(89)90200-8

Bree, 1967, Safety and tolerance of repeated anesthesia with CI 581 (ketamine) in monkeys, Anesth Analg, 46, 596

10.1002/(SICI)1098-2396(199806)29:2<142::AID-SYN5>3.0.CO;2-7

10.1016/0028-3908(95)00017-Z

10.1124/jpet.116.235838

Canuso CM Singh JB Fedgchin M Alphs L Lane R Lim P Pinter C Hough D Sanacora G Manji H (2018) 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 DOI: 10.1176/appi.ajp.2018.17060720.

10.1016/j.neuro.2007.03.009

10.1016/j.pain.2003.07.001

10.1101/cshperspect.a003947

Cavalleri, 2017, Ketamine enhances structural plasticity in mouse mesencephalic and human iPSC-derived dopaminergic neurons via AMPAR-driven BDNF and mTOR signaling, Molecular Psychiatry, 23, 812, 10.1038/mp.2017.241

10.1097/00000542-197204000-00016

Chang, 1974, Biotransformation and disposition of ketamine, Int Anesthesiol Clin, 12, 157, 10.1097/00004311-197412020-00018

Chen, 1966, The neuropharmacology of 2-(omicron-chlorophenyl)-2-methylaminocyclohexanoe hydrochloride, J Pharmacol Exp Ther, 152, 332

10.1523/JNEUROSCI.3481-08.2009

Cheng, 2007, GC-MS quantification of ketamine, norketamine, and dehydronorketamine in urine specimens and comparative study using ELISA as the preliminary test methodology, J Chromatogr B Analyt Technol Biomed Life Sci, 852, 443, 10.1016/j.jchromb.2007.02.005

10.1093/bja/aen325

10.2165/00044011-200929050-00004

10.1111/j.1464-410X.2008.07920.x

10.1093/bja/53.1.27

10.1002/jps.2600710516

10.1038/sj.bjp.0704315

10.1097/00000542-197310000-00003

10.1111/j.1365-2044.1972.tb08186.x

10.1111/cns.12063

10.1213/00000539-196601000-00007

10.1111/j.1365-2044.2007.05298.x

10.1016/0003-4975(96)00055-0

10.1016/0014-2999(91)90101-U

Cusin, 2017, Ketamine augmentation for outpatients with treatment-resistant depression: preliminary evidence for two-step intravenous dose escalation, Aust N Z J Psychiatry, 51, 55, 10.1177/0004867416631828

10.1016/S0196-0644(97)70321-4

10.1080/02791072.1996.10524391

Daly, 2018, Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression: a randomized clinical trial, JAMA Psychiatry, 75, 139, 10.1001/jamapsychiatry.2017.3739

10.1007/BF00607095

De Felice, 2017, Monoamine transporters as ionotropic receptors, Trends Neurosci, 40, 195, 10.1016/j.tins.2017.02.003

10.1016/S0304-3959(01)00278-0

10.1111/cns.12104

Delini-Stula A (1980) Drug-induced alterations in animal behavior as a tool for the evaluation of antidepressants: correlation with biochemical effects, in Psychotropic Agents: Part I: Antipsychotics and Antidepressants ( Hoffmeister F Stille G eds) pp 505–526, Springer, Berlin.

10.3109/00498254.2012.685777

10.1001/archgenpsychiatry.2010.90

10.4088/JCP.09m05327blu

Dinis-Oliveira, 2017, Metabolism and metabolomics of ketamine: a toxicological approach, Forensic Sci Res, 2, 2, 10.1080/20961790.2017.1285219

Domino, 2010, Taming the ketamine tiger: 1965, Anesthesiology, 113, 678, 10.1097/ALN.0b013e3181ed09a2

10.1002/cpt196563279

Downey, 2016, Comparing the actions of lanicemine and ketamine in depression: key role of the anterior cingulate, Eur Neuropsychopharmacol, 26, 994, 10.1016/j.euroneuro.2016.03.006

10.1113/jphysiol.2006.124958

10.1038/npp.2013.170

du Jardin, 2016, Differential interaction with the serotonin system by S-ketamine, vortioxetine, and fluoxetine in a genetic rat model of depression, Psychopharmacology (Berl), 233, 2813, 10.1007/s00213-016-4327-5

Dundee, 1970, Ketamine as an induction agent in anaesthetics, Lancet, 1, 1370, 10.1016/S0140-6736(70)91273-0

Dundee, 1978, Ketamine-iorazepam: attenuation of psychic sequelae of ketamine by lorazepam, Anaesthesia, 33, 312, 10.1111/j.1365-2044.1978.tb12413.x

10.1097/00000539-199507000-00012

10.1016/S0014-2999(97)01116-3

10.2165/00003088-200645070-00004

10.1016/S0079-6468(05)43004-0

10.1016/0304-3959(94)00182-E

10.1016/0304-3959(94)90129-5

Emnett, 2016, A clickable analogue of ketamine retains NMDA receptor activity, psychoactivity, and accumulates in neurons, Sci Rep, 6, 38808, 10.1038/srep38808

Erdemir, 1970, Dissociative anesthesia with ketamine: a suitable adjunct to epidural anesthesia, Anesth Analg, 49, 623, 10.1213/00000539-197007000-00025

Fanta, 2015, Population pharmacokinetics of S-ketamine and norketamine in healthy volunteers after intravenous and oral dosing, Eur J Clin Pharmacol, 71, 441, 10.1007/s00228-015-1826-y

10.1016/S0079-6123(08)60453-7

10.1016/S0196-0644(82)80263-1

10.1097/00000542-198204000-00011

10.1097/00000542-198803000-00013

10.1016/j.pharmthera.2010.04.003

10.1006/exnr.1993.1153

Flood, 2000, Intravenous anesthetics differentially modulate ligand-gated ion channels, Anesthesiology, 92, 1418, 10.1097/00000542-200005000-00033

10.1038/367607a0

10.1093/bja/69.3.292

10.1073/pnas.1414728112

Fukumoto, 2014, Serotonin-1A receptor stimulation mediates effects of a metabotropic glutamate 2/3 receptor antagonist, 2S-2-amino-2-(1S,2S-2-carboxycycloprop-1-yl)-3-(xanth-9-yl)propanoic acid (LY341495), and an N-methyl-D-aspartate receptor antagonist, ketamine, in the novelty-suppressed feeding test, Psychopharmacology (Berl), 231, 2291, 10.1007/s00213-013-3378-0

10.1124/jpet.116.239228

Gage, 1985, Prolongation of inhibitory postsynaptic currents by pentobarbitone, halothane and ketamine in CA1 pyramidal cells in rat hippocampus, Br J Pharmacol, 85, 675, 10.1111/j.1476-5381.1985.tb10563.x

Gao, 2016, Ketamine use in current clinical practice, Acta Pharmacol Sin, 37, 865, 10.1038/aps.2016.5

10.1097/00000542-197204000-00006

10.1093/bja/70.6.666

Georg, 1991, Identification and characterization of two sigma-like binding sites in the mouse neuroblastoma × rat glioma hybrid cell line NG108-15, J Pharmacol Exp Ther, 259, 479

George, 2017, Pilot randomized controlled trial of titrated subcutaneous ketamine in older patients with treatment-resistant depression, Am J Geriatr Psychiatry, 25, 1199, 10.1016/j.jagp.2017.06.007

10.1016/j.drudis.2016.01.016

Ghoneim, 1985, Ketamine: behavioral effects of subanesthetic doses, J Clin Psychopharmacol, 5, 70, 10.1097/00004714-198504000-00003

Gill, 2000, Ketamine in non-hospital and hospital deaths in New York city, J Forensic Sci, 45, 655, 10.1520/JFS14742J

10.1016/j.neuropharm.2009.01.012

Goldberg, 2010, Pharmacodynamic profiles of ketamine (R)- and (S)- with 5-day inpatient infusion for the treatment of complex regional pain syndrome, Pain Physician, 13, 379, 10.36076/ppj.2010/13/379

Gómez de Segura, 1998, Epidural injection of ketamine for perineal analgesia in the horse, Vet Surg, 27, 384, 10.1111/j.1532-950X.1998.tb00145.x

10.1016/j.biopsych.2015.03.010

Gorlin, 2016, Intravenous sub-anesthetic ketamine for perioperative analgesia, J Anaesthesiol Clin Pharmacol, 32, 160, 10.4103/0970-9185.182085

Gould, 2017, Animal models to improve our understanding and treatment of suicidal behavior, Transl Psychiatry, 7, e1092, 10.1038/tp.2017.50

10.1093/bja/53.8.805

10.1093/bja/55.11.1107

10.1258/002367781780959107

10.1016/j.annemergmed.2010.11.030

Grott Zanicotti, 2013, Case report: long-term mood response to repeat dose intramuscular ketamine in a depressed patient with advanced cancer, J Palliat Med, 16, 719, 10.1089/jpm.2013.0057

10.1111/j.1471-4159.2011.07361.x

Haas, 1992, Ketamine: a review of its pharmacologic properties and use in ambulatory anesthesia, Anesth Prog, 39, 61

10.1213/01.ANE.0000052513.91900.D5

10.1016/j.ejpain.2009.10.003

10.1038/mp.2016.99

Hance, 1989, Catalepsy induced by combinations of ketamine and morphine: potentiation, antagonism, tolerance and cross-tolerance in the rat, Neuropharmacology, 28, 109, 10.1016/0028-3908(89)90045-2

10.1080/02791072.1988.10472511

10.1007/PL00005261

10.1292/jvms.60.479

Hare BD Ghosal S Duman RS (2017) Rapid acting antidepressants in chronic stress models: molecular and cellular mechanisms. Chronic Stress (Thousand Oaks) 1: DOI: 10.1177/2470547017697317.

Hargreaves, 1994, Neuroprotective NMDA antagonists: the controversy over their potential for adverse effects on cortical neuronal morphology, Acta Neurochir Suppl (Wien), 60, 15

Harris, 1975, Attention, learning, and personality during ketamine emergence: a pilot study, Anesth Analg, 54, 169, 10.1213/00000539-197503000-00001

10.1111/j.1476-5381.1985.tb12922.x

Hashimoto, 2014, Blood D-serine levels as a predictive biomarker for the rapid antidepressant effects of the NMDA receptor antagonist ketamine, Psychopharmacology (Berl), 231, 4081, 10.1007/s00213-014-3735-7

10.1007/s005400170017

Hawksworth, 1998, Intrathecal anesthesia with ketamine, Reg Anesth Pain Med, 23, 283

10.1038/nature08673

Hennein, 1994, Relationship of the proinflammatory cytokines to myocardial ischemia and dysfunction after uncomplicated coronary revascularization, J Thorac Cardiovasc Surg, 108, 626, 10.1016/S0022-5223(94)70286-1

10.1007/s002130000511

10.1124/dmd.30.7.853

10.1055/s-2007-994851

Hirlinger, 1984, Intramuscular ketamine analgesia in emergency patients. II. Clinical study of traumatized patients, Anaesthesist, 33, 272

10.1097/00000539-200212000-00025

10.1093/bja/aer221

10.1097/00000542-199901000-00023

Hirsiger, 2012, Danger signals activating the immune response after trauma, Mediators Inflamm, 2012, 315941, 10.1155/2012/315941

Ho, 2004, Single amino acid residue in the extracellular portion of transmembrane segment 2 in the nicotinic alpha7 acetylcholine receptor modulates sensitivity to ketamine, Anesthesiology, 100, 657, 10.1097/00000542-200403000-00028

10.1113/jphysiol.1952.sp004717

10.1523/JNEUROSCI.2213-07.2007

10.1007/s00213-005-0001-z

Hornik CP Gonzalez D van den Anker J Atz AM Yogev R Poindexter BB Ng KC Delmore P Harper BL Melloni C (2018) Population pharmacokinetics of intramuscular and intravenous ketamine in children. J Clin Pharmacol 54: DOI: 10.1002/jcph.1116.

Hu, 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, 623, 10.1017/S0033291715002159

Huang, 2009, Accumulated amyloid-beta peptide and hyperphosphorylated tau protein: relationship and links in Alzheimer’s disease, J Alzheimers Dis, 16, 15, 10.3233/JAD-2009-0960

10.1073/pnas.85.4.1307

10.1016/j.ejpain.2009.08.002

10.1111/j.1600-0773.1995.tb01041.x

10.1038/npp.2011.338

10.1093/bja/51.12.1167

10.1111/j.1365-2044.1983.tb10376.x

Ihmsen, 2001, Stereoselective pharmacokinetics of ketamine: R(-)-ketamine inhibits the elimination of S(+)-ketamine, Clin Pharmacol Ther, 70, 431, 10.1067/mcp.2001.119722

Ionescu, 2015, A single infusion of ketamine improves depression scores in patients with anxious bipolar depression, Bipolar Disord, 17, 438, 10.1111/bdi.12277

10.1097/00000539-200007000-00043

10.1016/j.neuropharm.2014.08.002

10.1038/nrn2370

10.1126/science.1346477

10.1136/bmj.298.6689.1708

10.1080/02791072.2000.10400244

10.1080/02791072.2001.10400480

10.1016/S0006-8993(01)02079-0

10.1186/1757-7241-21-38

10.1523/JNEUROSCI.6078-08.2009

Jozwiak, 2002, Displacement and nonlinear chromatographic techniques in the investigation of interaction of noncompetitive inhibitors with an immobilized alpha3beta4 nicotinic acetylcholine receptor liquid chromatographic stationary phase, Anal Chem, 74, 4618, 10.1021/ac0202029

Kadriu B Gold PW Luckenbaugh DA Lener MS Ballard ED Niciu MJ Henter ID Park LT De Sousa RT Yuan P (2017) Acute ketamine administration corrects abnormal inflammatory bone markers in major depressive disorder. Mol Psychiatry [published ahead of print].

Kang, 2017, Ephenidine: a new psychoactive agent with ketamine-like NMDA receptor antagonist properties, Neuropharmacology, 112, 144, 10.1016/j.neuropharm.2016.08.004

10.1016/S0006-3223(01)01110-6

10.1038/sj.mp.4001093

Karch SB Drummer OH (2015) Dissociative anesthetics, in Karch’s Pathology of Drug Abuse, 5th ed, pp 697–754, CRS Press, Boca Raton, FL.

Kathirvel, 2000, Effects of intrathecal ketamine added to bupivacaine for spinal anaesthesia, Anaesthesia, 55, 899, 10.1046/j.1365-2044.2000.01472.x

10.1176/appi.ajp.2012.12040531

10.1007/BF03016701

10.1097/00000539-199909000-00024

Ke, 2018, The profile of cognitive impairments in chronic ketamine users, Psychiatry Res, 266, 124, 10.1016/j.psychres.2018.05.050

10.1002/syn.10010

10.1093/bja/77.2.254

10.1542/peds.102.4.956

10.1097/00000542-199209001-01201

10.1176/appi.psy.14.6.344

10.1016/S0301-0082(02)00008-4

10.1016/j.neuron.2012.05.027

10.1017/S0033291716000064

10.1016/0014-2999(90)90379-K

10.1097/00000539-199811000-00039

10.1016/j.bbr.2014.05.065

10.1016/j.bbr.2011.05.035

Kokkinou, 2018, The effects of ketamine on dopaminergic function: meta-analysis and review of the implications for neuropsychiatric disorders, Mol Psychiatry, 23, 59, 10.1038/mp.2017.190

10.1016/0014-2999(89)90339-7

Kortekaas, 2008, Despite irreversible binding, PET tracer [11C]-SA5845 is suitable for imaging of drug competition at sigma receptors: the cases of ketamine and haloperidol, Neurochem Int, 53, 45, 10.1016/j.neuint.2008.04.010

10.1523/JNEUROSCI.3703-08.2009

10.1113/jphysiol.2009.176297

Krystal, 2001, Comment on “ketamine has equal affinity for NMDA receptors and the high-affinity state of the dopamine D(2) receptor.”, Biol Psychiatry, 50, 555, 10.1016/S0006-3223(01)01258-6

10.1001/archpsyc.1994.03950030035004

10.1038/sj.npp.1300994

10.1093/toxsci/kfv100

10.1016/S0893-133X(01)00243-3

Lai, 2014, Pilot dose-response trial of i.v. ketamine in treatment-resistant depression, World J Biol Psychiatry, 15, 579, 10.3109/15622975.2014.922697

10.1038/tp.2014.105

10.1177/0269881114568041

10.1051/vetres:2004061

10.1016/j.biopsych.2014.03.026

10.1097/00000542-199811000-00023

10.1007/s12630-011-9560-0

10.1097/00000542-199906000-00005

Lepack AE Fuchikami M Dwyer JM Banasr M Duman RS (2014) BDNF release is required for the behavioral actions of ketamine. Int J Neuropsychopharmacol 18: DOI: 10.1093/ijnp/pyu033.

10.1016/0304-3940(91)90927-L

10.1021/jm00161a043

10.1523/JNEUROSCI.0936-11.2011

Li, 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, 10.1002/hbm.23085

Li, 1997, Ketamine inhibits nitric oxide synthase in lipopolysaccharide-treated rat alveolar macrophages, Can J Anaesth, 44, 989, 10.1007/BF03011971

Li, 2014, Inhibition of HCN1 channels by ketamine accounts for its antidepressant actions, Sichuan Da Xue Xue Bao Yi Xue Ban, 45, 888

10.1126/science.1190287

Li, 2017, Chronic ketamine exposure causes white matter microstructural abnormalities in adolescent cynomolgus monkeys, Front Neurosci, 11, 285, 10.3389/fnins.2017.00285

10.1093/brain/awq131

Lilius, 2018, Ketamine and norketamine attenuate oxycodone tolerance markedly less than that of morphine: from behaviour to drug availability, Br J Anaesth, 120, 818, 10.1016/j.bja.2017.11.081

Lilius, 2018, Interactions of (2S,6S;2R,6R)-Hydroxynorketamine, a Secondary Metabolite of (R,S)-Ketamine, with Morphine, Basic Clin Pharmacol Toxicol, 122, 481, 10.1111/bcpt.12941

Lim, 2003, Ketamine associated psychedelic effects and dependence, Singapore Med J, 44, 31

10.1093/jat/28.3.181

Lin, 1992, General anesthetics potentiate gamma-aminobutyric acid actions on gamma-aminobutyric acidA receptors expressed by Xenopus oocytes: lack of involvement of intracellular calcium, J Pharmacol Exp Ther, 263, 569

Lisek, 2016, Regional brain dysregulation of Ca(2+)-handling systems in ketamine-induced rat model of experimental psychosis, Cell Tissue Res, 363, 609, 10.1007/s00441-015-2332-3

Little, 1972, Study of ketamine as an obstetric anesthetic agent, Am J Obstet Gynecol, 113, 247, 10.1016/0002-9378(72)90774-0

10.1016/j.neuroimage.2006.05.022

Lockhart, 1974, The relationship of ketamine requirement to age in pediatric patients, Anesthesiology, 40, 507, 10.1097/00000542-197405000-00020

10.1016/0304-3940(82)90330-5

10.1523/JNEUROSCI.5419-08.2009

Loix, 2011, The anti-inflammatory effects of ketamine: state of the art, Acta Anaesthesiol Belg, 62, 47

Loo, 2016, Placebo-controlled pilot trial testing dose titration and intravenous, intramuscular and subcutaneous routes for ketamine in depression, Acta Psychiatr Scand, 134, 48, 10.1111/acps.12572

10.1017/S1461145708008547

10.1016/S0896-6273(00)80509-7

Lynch, 1995, Pharmacological characterization of heterodimeric NMDA receptors composed of NR 1a and 2B subunits: differences with receptors formed from NR 1a and 2A, J Neurochem, 64, 1462, 10.1046/j.1471-4159.1995.64041462.x

Ma, 2017, Alterations in amino acid levels in mouse brain regions after adjunctive treatment of brexpiprazole with fluoxetine: comparison with (R)-ketamine, Psychopharmacology (Berl), 234, 3165, 10.1007/s00213-017-4700-z

10.1113/jphysiol.1991.sp018396

MacDonald, 1987, Use-dependent block of excitatory amino acid currents in cultured neurons by ketamine, J Neurophysiol, 58, 251, 10.1152/jn.1987.58.2.251

10.1016/j.biopsych.2007.05.028

Malaquin, 1984, Ketamine via rectal route for the induction of pediatric anesthesia, Cah Anesthesiol, 32, 373

10.1016/S0893-133X(97)00036-5

10.1016/0893-133X(95)00137-3

10.1093/bja/77.2.203

10.1097/00000542-199502000-00020

Marchetti, 2015, Efficacy and safety of oral ketamine for the relief of intractable chronic pain: a retrospective 5-year study of 51 patients, Eur J Pain, 19, 984, 10.1002/ejp.624

Marietta, 1977, On the pharmacology of the ketamine enantiomorphs in the rat, J Pharmacol Exp Ther, 202, 157

Martin, 1988, Inhibition of synaptosomal serotonin uptake by Ketalar, Res Commun Chem Pathol Pharmacol, 62, 129

10.1016/0304-3940(90)90329-8

Martin, 1982, Ketamine inhibits serotonin uptake in vivo, Neuropharmacology, 21, 113, 10.1016/0028-3908(82)90149-6

10.1016/j.crad.2010.05.003

10.1017/S1461145709000169

10.1016/0304-3959(94)00170-J

10.1016/0014-2999(96)00497-9

10.1002/j.1552-4604.1965.tb00219.x

10.1111/j.1526-4637.2011.01220.x

10.1038/sj.bjp.0703918

Meng, 2013, A murderer of young bladders: ketamine-associated cystitis, Urol Sci, 24, 113, 10.1016/j.urols.2013.09.001

10.1097/00000542-199906000-00007

10.7554/eLife.03581

10.1016/j.tips.2010.09.004

10.1111/cns.12099

10.1016/0028-3908(68)90067-1

10.1016/j.ejphar.2012.11.023

Moaddel, 2015, D-serine plasma concentration is a potential biomarker of (R,S)-ketamine antidepressant response in subjects with treatment-resistant depression, Psychopharmacology (Berl), 232, 399, 10.1007/s00213-014-3669-0

Moaddel, 2015, The distribution and clearance of (2S,6S)-hydroxynorketamine, an active ketamine metabolite, in Wistar rats, Pharmacol Res Perspect, 3, e00157, 10.1002/prp2.157

10.1016/j.jpba.2016.03.030

10.1016/j.talanta.2010.08.005

10.1523/JNEUROSCI.17-08-02921.1997

10.1111/j.1360-0443.2011.03576.x

10.1038/sj.npp.1300342

Morgan, 2006, Semantic priming after ketamine acutely in healthy volunteers and following chronic self-administration in substance users, Biol Psychiatry, 59, 265, 10.1016/j.biopsych.2005.06.018

Morris, 2017, Synthesis and N-methyl-d-aspartate (NMDA) receptor activity of ketamine metabolites, Org Lett, 19, 4572, 10.1021/acs.orglett.7b02177

10.2460/ajvr.72.11.1505

10.1016/j.drugalcdep.2008.01.024

10.1176/appi.ajp.2013.13030392

10.1016/j.biopsych.2012.06.022

10.1017/S0033291715001506

10.1021/jm00050a008

10.1007/s00213-010-1834-7

10.1016/S0893-133X(98)00067-0

10.1176/appi.ajp.2015.15040465

Newton K Dixit VM (2012) Signaling in innate immunity and inflammation. Cold Spring Harb Perspect Biol 4: DOI: 10.1101/cshperspect.a006049.

10.1097/00000542-199803000-00029

10.1016/1043-4666(92)90070-8

10.1126/science.2660263

10.1126/science.1835799

10.1097/00000542-199704000-00021

Oye, 1992, Effects of ketamine on sensory perception: evidence for a role of N-methyl-D-aspartate receptors, J Pharmacol Exp Ther, 260, 1209

Pacheco Dda, 2014, Central antinociception induced by ketamine is mediated by endogenous opioids and μ- and δ-opioid receptors, Brain Res, 1562, 69, 10.1016/j.brainres.2014.03.026

Pal, 2002, Ketamine dependence, Anaesth Intensive Care, 30, 382, 10.1177/0310057X0203000323

Pande, 1999, A placebo-controlled trial of igmesine in the treatment of major depression, Eur Neuropsychopharmacol, 9, 138, 10.1016/S0924-977X(99)80011-X

10.1038/nrn3504

Park, 2017, Change in cytokine levels is not associated with rapid antidepressant response to ketamine in treatment-resistant depression, J Psychiatr Res, 84, 113, 10.1016/j.jpsychires.2016.09.025

10.1111/j.1460-9568.1996.tb01228.x

10.1016/0028-3908(95)00092-K

10.1097/ALN.0000000000000285

Peltoniemi, 2016, Ketamine: a review of clinical pharmacokinetics and pharmacodynamics in anesthesia and pain therapy, Clin Pharmacokinet, 55, 1059, 10.1007/s40262-016-0383-6

Peltoniemi, 2012, Rifampicin has a profound effect on the pharmacokinetics of oral S-ketamine and less on intravenous S-ketamine, Basic Clin Pharmacol Toxicol, 111, 325, 10.1111/j.1742-7843.2012.00908.x

10.1002/neu.10146

10.4103/2279-042X.155758

Petrenko, 2014, Defining the role of NMDA receptors in anesthesia: are we there yet?, Eur J Pharmacol, 723, 29, 10.1016/j.ejphar.2013.11.039

10.1097/00000542-200202000-00022

Pham TH Defaix C Xu X Deng SX Fabresse N Alvarez JC Landry DW Brachman RA Denny CA Gardier AM (2017 a) Common neurotransmission recruited in (R,S)-ketamine and (2R,6R)-hydroxynorketamine-induced sustained antidepressant-like effects. Biol Psychiatry [published ahead of print].

Pham, 2017, Ketamine treatment involves medial prefrontal cortex serotonin to induce a rapid antidepressant-like activity in BALB/cJ mice, Neuropharmacology, 112, 198, 10.1016/j.neuropharm.2016.05.010

10.1016/j.biopsych.2008.09.029

10.1007/s00213-010-1932-6

10.1192/bjp.bp.105.015263

Porter, 1995, Regional variations in the pharmacology of NMDA receptor channel blockers: implications for therapeutic potential, J Neurochem, 64, 614, 10.1046/j.1471-4159.1995.64020614.x

10.1016/j.chroma.2010.06.028

10.1016/j.biopsych.2009.04.029

Rao, 2016, Role of cytochrome P4502B6 polymorphisms in ketamine metabolism and clearance, Anesthesiology, 125, 1103, 10.1097/ALN.0000000000001392

10.1177/0269881113478283

10.1007/BF03011442

10.1136/emj.2010.092825

10.1213/ANE.0b013e3181bdc8a0

Reynolds, 1989, Ifenprodil is a novel type of N-methyl-D-aspartate receptor antagonist: interaction with polyamines, Mol Pharmacol, 36, 758

Riva-Posse P Reiff CM Edwards JA Job GP Galendez GC Garlow SJ Saah TC Dunlop BW McDonald WM (2018) Blood pressure safety of subanesthetic ketamine for depression: a report on 684 infusions. J Affect Disord DOI: 10.1016/j.jad.2018.02.025 [published ahead of print].

10.1016/j.euroneuro.2011.08.002

10.1111/bcp.12264

Rosa, 2016, Antidepressant-like effects of ascorbic acid and ketamine involve modulation of GABAA and GABAB receptors, Pharmacol Rep, 68, 996, 10.1016/j.pharep.2016.05.010

Roytblat, 1993, Postoperative pain: the effect of low-dose ketamine in addition to general anesthesia, Anesth Analg, 77, 1161, 10.1213/00000539-199312000-00014

10.1097/00000539-199808000-00006

10.1176/appi.ajp.163.11.1905

Russabrov, 2008, Effect of ketamine on inflammatory and immune responses after short- duration surgery in obese patients, Open Anesthesiol J, 2, 40, 10.2174/1874321800802010040

10.1016/0014-2999(78)90217-0

10.1136/pgmj.48.557.156

10.1016/j.neuropharm.2015.07.037

10.1213/01.ANE.0000156951.83242.8D

10.1038/sj.bjp.0706385

10.1007/BF00587527

10.1007/BF01066320

10.1002/syn.10221

10.1038/sj.mp.4001682

10.1002/jcph.122

10.1097/00003643-199611000-00011

Selye, 1976, Forty years of stress research: principal remaining problems and misconceptions, Can Med Assoc J, 115, 53

10.1016/j.neuropharm.2014.07.008

10.1113/jphysiol.2013.270058

10.1016/j.urology.2007.01.038

10.1007/BF00974875

Shimada, 1994, Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians, J Pharmacol Exp Ther, 270, 414

10.1093/bja/77.2.238

Shirayama, 2018, Lack of antidepressant effects of (2R,6R)-hydroxynorketamine in a rat learned helplessness model: comparison with (R)-ketamine, Int J Neuropsychopharmacol, 21, 84, 10.1093/ijnp/pyx108

Short, 2018, Side-effects associated with ketamine use in depression: a systematic review, Lancet Psychiatry, 5, 65, 10.1016/S2215-0366(17)30272-9

Siegel, 1978, Phencyclidine and ketamine intoxication: a study of four populations of recreational users, NIDA Res Monogr, 21, 119

10.1016/j.biopsych.2015.10.018

10.1176/appi.ajp.2016.16010037

Singh NS Bernier M Camandola S Khadeer MA Moaddel R Mattson MP Wainer IW (2015) Enantioselective inhibition of d-serine transport by (S)-ketamine. Br J Pharmacol DOI: 10.1111/bph.13239 [published ahead of print].

Singh, 2013, Nicotinic acetylcholine receptor antagonists alter the function and expression of serine racemase in PC-12 and 1321N1 cells, Cell Signal, 25, 2634, 10.1016/j.cellsig.2013.08.025

Singh, 2016, Ketamine metabolites enantioselectively decrease intracellular D-serine concentrations in PC-12 cells, PLoS One, 11, e0149499, 10.1371/journal.pone.0149499

Singh, 2014, What is hydroxynorketamine and what can it bring to neurotherapeutics?, Expert Rev Neurother, 14, 1239, 10.1586/14737175.2014.971760

Sinner, 2008, Ketamine, Handb Exp Pharmacol, 14, 313, 10.1007/978-3-540-74806-9_15

10.1038/nrurol.2014.22

10.1097/00008877-200211000-00003

10.1016/0028-3908(87)90084-0

10.1016/0304-3959(85)90089-2

10.1016/S0893-133X(97)00092-4

Sofia, 1975, Evaluation of ketamine HCl for anti-depressant activity, Arch Int Pharmacodyn Ther, 214, 68

10.1146/annurev-med-062613-093100

Stewart, 2001, Ketamine as a street drug, Emerg Med Serv, 30, 30, 32, 34 passim

10.1016/j.ajem.2007.12.005

10.1111/j.1399-6576.1997.tb04854.x

10.1111/adb.12004

10.1016/j.lfs.2003.11.035

10.1097/00000542-197405000-00012

Suzuki, 2017, Effects of a ketamine metabolite on synaptic NMDAR function, Nature, 546, E1, 10.1038/nature22084

10.1097/00000542-200607000-00020

Szymkowicz, 2013, A 12-month naturalistic observation of three patients receiving repeat intravenous ketamine infusions for their treatment-resistant depression, J Affect Disord, 147, 416, 10.1016/j.jad.2012.10.015

Takeyama, 2006, Ketamine enhances the expression of serine racemase and D-amino acid oxidase mRNAs in rat brain, Eur J Pharmacol, 540, 82, 10.1016/j.ejphar.2006.04.021

Tanaka, 2000, Reevaluation of rectal ketamine premedication in children: comparison with rectal midazolam, Anesthesiology, 93, 1217, 10.1097/00000542-200011000-00014

Temme, 2018, Comparative pharmacological study of common NMDA receptor open channel blockers regarding their affinity and functional activity toward GluN2A and GluN2B NMDA receptors, ChemMedChem, 13, 446, 10.1002/cmdc.201700810

10.1038/313479a0

Traber, 1969, Involvement of the sympathetic nervous system in the pressor response to ketamine, Anesth Analg, 48, 248, 10.1213/00000539-196903000-00020

Traber, 1970, The effect of beta-adrenergic blockade on the cardiopulmonary response to ketamine, Anesth Analg, 49, 604

Trescot, 2008, Opioid pharmacology, Pain Physician, 11, S133, 10.36076/ppj.2008/11/S133

10.1111/j.1442-2042.2009.02361.x

10.1097/PEC.0b013e3182624935

10.1124/dmd.108.026328

10.1016/j.pscychresns.2010.10.009

Vickers, 2017, A case report: subanesthetic ketamine infusion for treatment of cancer-related pain produces urinary urge incontinence, A A Case Rep, 8, 219, 10.1213/XAA.0000000000000472

10.1097/00000542-196709000-00008

10.1016/S0924-977X(96)00042-9

10.1016/S0022-3956(99)00031-X

Vyklicky, 2014, Structure, function, and pharmacology of NMDA receptor channels, Physiol Res, 63, S191, 10.33549/physiolres.932678

10.1097/00000542-200112000-00020

10.1007/s00018-008-8525-0

10.1038/npp.2013.71

Wallach, 2016, Pharmacological investigations of the dissociative ‘legal highs’ diphenidine, methoxphenidine and analogues, PLoS One, 11, e0157021, 10.1371/journal.pone.0157021

Wan, 2015, Ketamine safety and tolerability in clinical trials for treatment-resistant depression, J Clin Psychiatry, 76, 247, 10.4088/JCP.13m08852

Wang, 2013, Brain damages in ketamine addicts as revealed by magnetic resonance imaging, Front Neuroanat, 7, 23, 10.3389/fnana.2013.00023

Wang, 2007, Novel sigma (sigma) receptor agonists produce antidepressant-like effects in mice, Eur Neuropsychopharmacol, 17, 708, 10.1016/j.euroneuro.2007.02.007

Watanabe, 2010, Subchronic administration of ketamine decreases the mRNA expression of serine racemase in rat brain, Tokai J Exp Clin Med, 35, 137

10.1111/j.1460-9592.2004.01358.x

Wei, 2017, Acute amino acid d-serine administration, similar to ketamine, produces antidepressant-like effects through identical mechanisms, J Agric Food Chem, 65, 10792, 10.1021/acs.jafc.7b04217

10.1016/S0736-4679(00)00162-1

Weisman, 1971, Anesthesia for pediatric ophthalmology, Ann Ophthalmol, 3, 229

10.1007/BF03011307

10.1097/00000542-198003000-00008

10.1093/bja/57.2.197

10.1097/00000542-198202000-00007

Wieber, 1975, Pharmacokinetics of ketamine in man, Anaesthesist, 24, 260

Wilkins, 2012, Anomalous bodily-self experiences among recreational ketamine users, Cogn Neuropsychiatry, 17, 415, 10.1080/13546805.2012.663162

Wohleb, 2017, Molecular and cellular mechanisms of rapid-acting antidepressants ketamine and scopolamine, Curr Neuropharmacol, 15, 11, 10.2174/1570159X14666160309114549

10.2165/00023210-200620030-00003

10.1111/j.1742-4658.2008.06515.x

10.1073/pnas.83.18.7104

10.1111/j.1471-4159.1988.tb13260.x

10.1016/0028-3908(80)90075-1

Woolf, 1987, Biotransformation of ketamine, (Z)-6-hydroxyketamine, and (E)-6-hydroxyketamine by rat, rabbit, and human liver microsomal preparations, Xenobiotica, 17, 839, 10.3109/00498258709043993

Wray NH Schappi JM Singh H Senese NB Rasenick MM (2018) NMDAR-independent, cAMP-dependent antidepressant actions of ketamine. Mol Psychiatry DOI: 10.1038/s41380-018-0083-8 [published ahead of print].

Wu, 1996, Pharmacological characterization of inward current evoked by N-methyl-D-aspartate in dopamine neurons in the rat brain slice, J Pharmacol Exp Ther, 279, 457

10.1097/00000542-199512000-00018

10.1097/00000542-200004000-00033

10.1097/00001756-199306000-00021

10.1016/S0301-0082(99)00007-6

Yamamoto, 2013, Subanesthetic doses of ketamine transiently decrease serotonin transporter activity: a PET study in conscious monkeys, Neuropsychopharmacology, 38, 2666, 10.1038/npp.2013.176

10.1038/tp.2013.112

Yamazaki, 1992, Effects of ketamine on voltage-dependent Ca2+ currents in single smooth muscle cells from rabbit portal vein, Pharmacology, 45, 162, 10.1159/000138994

Yanagihara, 2001, Involvement of CYP2B6 in n-demethylation of ketamine in human liver microsomes, Drug Metab Dispos, 29, 887

10.1002/bdd.336

Yang, 2016, Loss of parvalbumin-immunoreactivity in mouse brain regions after repeated intermittent administration of esketamine, but not R-ketamine, Psychiatry Res, 239, 281, 10.1016/j.psychres.2016.03.034

Yang, 2017, (R)-Ketamine shows greater potency and longer lasting antidepressant effects than its metabolite (2R,6R)-hydroxynorketamine, Biol Psychiatry, 82, e43, 10.1016/j.biopsych.2016.12.020

10.1038/tp.2015.136

Yang, 2005, Large dose ketamine inhibits lipopolysaccharide-induced acute lung injury in rats, Inflamm Res, 54, 133, 10.1007/s00011-004-1334-5

Yao N Skiteva O Zhang X Svenningsson P Chergui K (2017) Ketamine and its metabolite (2R,6R)-hydroxynorketamine induce lasting alterations in glutamatergic synaptic plasticity in the mesolimbic circuit. Mol Psychiatry DOI: 10.1038/mp.2017.239 [published ahead of print].

10.1016/j.toxlet.2010.01.008

Zanos, 2018, Intracellular signaling pathways involved in (S)- and (R)-ketamine antidepressant actions, Biol Psychiatry, 83, 2, 10.1016/j.biopsych.2017.10.026

Zanos, 2018, Convergent mechanisms underlying rapid antidepressant action, CNS Drugs, 32, 197, 10.1007/s40263-018-0492-x

Zanos, 2018, Mechanisms of ketamine action as an antidepressant, Mol Psychiatry, 23, 801, 10.1038/mp.2017.255

10.1038/nature17998

Zanos P Moaddel R Morris PJ Georgiou P Fischell J Elmer GI Alkondon M Yuan P Pribut HJ Singh NS (2017 a) Zanos et al. reply. Nature DOI: 10.1038/nature22085.

Zanos, 2017, Zanos et al. reply, Nature, 546, E4, 10.1038/nature22085

Zanos, 2017, Reply to: antidepressant actions of ketamine versus hydroxynorketamine, Biol Psychiatry, 81, e69, 10.1016/j.biopsych.2016.08.039

10.1016/j.biopsych.2012.03.004

10.1016/j.biopsych.2011.12.010

10.1001/archpsyc.63.8.856

10.1016/0014-2999(92)90248-3

Zhang, 2018, Other drug use does not impact cognitive impairments in chronic ketamine users, Drug Alcohol Depend, 186, 1, 10.1016/j.drugalcdep.2018.01.007

10.1016/j.pbb.2013.11.033

10.1126/scisignal.aai7884

10.1111/j.1365-2125.2012.04198.x

10.1016/j.jocn.2007.11.007

10.1016/j.eurpsy.2013.10.005

10.1016/S0361-9230(00)00283-5