Granted Patent
B2
US 12,514,831 · App. 18/508,826 · Granted Jan 6, 2026
Method of treating major depressive disorder
Assignee:
CLEXIO BIOSCIENCES LTD.
A61K31/135A61K9/0053A61K9/1611A61K9/1623A61K9/1635A61K9/1652A61K9/167A61K31/136A61K31/15A61K31/343A61K31/36A61K31/381A61K31/7034A61P25/24
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Abstract
The present invention provides a method for safe and efficacious administration of esketamine.
Claims (14)
1 . A method of treating major depressive disorder in a human patient in need thereof consisting essentially thereof orally administering once daily to said patient over a treatment regimen of at least 28 days, an oral dosage form consisting of esketamine and a pharmaceutical carrier, wherein the ratio of S-norketamine C max to esketamine C max after the administration of the esketamine is at least 6, and
wherein said oral esketamine dosage form administration provides for
i. an (2S,6S)-OH-norketamine C max of between 15 and 75 ng/ml;
ii. an (2S,6S)-OH-norketamine AUC 0-t of between 105 and 850 ng*h/ml; or
iii. an (2S,6S)-OH-norketamine C max of between 15 and 75 ng/ml and an (2S,6S)-OH-norketamine AUC 0-t of between 105 and 850 ng*h/ml
and optionally administering to the patient a second medication that is an antidepressant, an antimanic agent or an anxiolytic drug that does not alter the metabolism of the esketamine in the patient.
2 . The method of claim 1 , wherein the treatment regimen is between 28 days and about 730 days.
3 . The method of claim 1 , wherein the treatment regimen is between 28 days and about 365 days.
4 . The method of claim 1 , wherein the administration of the oral dosage form is at night before the human patient goes to sleep.
5 . The method of claim 1 , wherein the oral dosage form is self-administered by the human patient.
6 . The method of claim 5 , wherein the self-administration is in the human patient's own home.
7 . The method of claim 1 , wherein following the administration of the oral dosage form, the patient is restricted from driving for no more than eight hours.
8 . The method of claim 1 , wherein following the administration of the oral dosage form, the patient is restricted from driving until the morning following the administration.
9 . The method of claim 1 , wherein the oral dosage form comprises esketamine or a pharmaceutically acceptable salt thereof.
Priority Claims (1)
WO PCT/IB2018/059107
· Nov 19, 2018
· international
Continuity (4)
Provisional Application
62867354
· Jun 27, 2019
Provisional Application
62741562
· Oct 5, 2018
References Cited (261)
US 7955619B2
· Shah et al.
· 2011
[cited by applicant]
US 9468611B2
· Manfredi et al.
· 2016
[cited by applicant]
US 20110160223A1
· Dingledine et al.
· 2011
[cited by applicant]
US 20120225949A1
· Papalos
· 2012
[cited by applicant]
US 20130236573A1
· Singh et al.
· 2013
[cited by applicant]
US 20160067196A1
· Charney
· 2016
[cited by examiner]
US 20160332962A1
· Chen et al.
· 2016
[cited by applicant]
US 20160338977A1
· Singh et al.
· 2016
[cited by applicant]
US 20180256534A1
· Erickson
· 2018
[cited by examiner]
DE 2062620
· 1971
[cited by applicant]
DE 102007009888A1
· 2008
[cited by applicant]
GB 1330878A
· 1973
[cited by applicant]
JP 2018515557A
· 2018
[cited by applicant]
WO 2007111880A2
· 2007
[cited by applicant]
WO 2008023261A1
· 2008
[cited by applicant]
WO 2008033523A1
· 2008
[cited by applicant]
WO 2011020061A2
· 2011
[cited by applicant]
WO 2013138322A1
· 2013
[cited by applicant]
WO 2014006004A1
· 2014
[cited by applicant]
WO 2014020155A1
· 2014
[cited by applicant]
WO 2015031410A1
· 2015
[cited by applicant]
WO 2015051259A1
· 2015
[cited by applicant]
WO 2015066172A1
· 2015
[cited by applicant]
WO 2015158854A1
· 2015
[cited by applicant]
WO 2016044150A1
· 2016
[cited by applicant]
WO 2016073653A1
· 2016
[cited by applicant]
WO 2016094358A1
· 2016
[cited by applicant]
WO 2016187491A1
· 2016
[cited by applicant]
WO 2017041112A1
· 2017
[cited by applicant]
WO 2018079693A1
· 2018
[cited by applicant]
WO 2018102488A1
· 2018
[cited by applicant]
WO 2018234568A2
· 2018
[cited by applicant]
WO 2019073408A1
· 2019
[cited by applicant]
WO 2019126108A1
· 2019
[cited by applicant]
WO 2020003195A1
· 2020
[cited by applicant]
WO 2020225773A1
· 2020
[cited by applicant]
WO 2021026232A1
· 2021
[cited by applicant]
WO 2021116498A1
· 2021
[cited by applicant]
Fanta et al., “Population pharmacokinetics of S-ketamine and norketamine in healthy volunteers after intravenous and oral dosing,” Eur J Clin Pharmacol (2015) 71:441-447. (Year: 2015).
[cited by examiner]
Giorgetti et al., “Effects of ketamine on psychomotor, sensory and cognitive functions relevant to driving ability,” Forensic Science International 252 (2015) 127-142. (Year: 2015).
[cited by examiner]
Nemeroff CB, DeVane CL, Pollock BG. Newer antidepressants and the cytochrome P450 system. Am J Psychiatry. Mar. 1996;153(3):311-20. doi: 10.1176/ajp.153.3.311. PMID: 8610817. (Year: 1996).
[cited by examiner]
“Cortef® brand of hydrocortisone tablets, USP,” The Upjohn Company, Nov. 1993, pp. 1-2.
[cited by applicant]
“OxyContin® (oxycodone hydrochloride controlled-release) Tablets, for oral use, Cll,” Highlights of Prescribing Information, Reference ID: 3155030, Jul. 2012, pp. 1-31.
[cited by applicant]
2019 FDA Esketamine Briefing Document, Esketamine Nasal Spray for Patients with Treatment-resistant Depression, Janssen Research & Development, LLC, Feb. 8, 2019, pp. 1-260.
[cited by applicant]
Adhvaryu et al., “Genotoxic Effects of Ketamine on CHO Cells”, Arch. Toxicology, 1986, vol. 59, pp. 124-125.
[cited by applicant]
Alberich et al ‘Efficacy and safety of ketamine in bipolar depression : A systematic review’ Rev Psiquiatr Salud Ment (Bare.), May 2017; vol. 10(2), pp. 104-112.
[cited by applicant]
Albott et al., “Efficacy, safety and durability of repeated ketamine infusions for comorbid posttraumatic stress disorder and treatment depression”, J. Clin. Psychiatry, 2018, vol. 79(3), 11634, pp. 8.
[cited by applicant]
Allergan Study for NCT03726658, AGN-241751 in the Treatment of Major Depressive Disorder, Last Updated on Oct. 8, 2019.
[cited by applicant]
Angst et al, Differential psychopathology and patterns of cerebral glucose utilisation produced by (S)- and (R)-ketamine in healthy volunteers using positron emission tomography (PE I), European Neuropsychopharmacology …
[cited by applicant]
Anonymous, “Major Depressive Disorder: Developing Drugs for Treatment Guidance for Industry”, Jun. 1, 2018, pp. 1-11, XP055956263.
[cited by applicant]
Anonymous: “Trial NL6030 (NTR6161) Ketaminestudie”, Netherlands Trial register Oct. 21, 2016 (Oct. 21, 2016), pp. 1-6, XP002796356, Retrieved from the Internet: URL:https://www.trialregister.nl/trial/6030.
[cited by applicant]
APA Annual Meeting Poster P7-065, Mar. 18, 2018.
[cited by applicant]
APA Annual Meeting Poster P8-054, Mar. 18, 2018.
[cited by applicant]
Arabzadeh, et al., Journal of Affective Disorders, Does oral administration of ketamine accelerate response to treatment in major depressive disorder? Results of a double-blind controlled trial, Journal of Affective Dis…
[cited by applicant]
ASCP Annual Meeting Poster T67, May 29, 2018.
[cited by applicant]
ASCP Annual Meeting Poster W68, May 29, 2018.
[cited by applicant]
Averill et al., “Glutamate dysregulation and glutamatergic therapeutics for PTSD: Evidence from human studies”, Neuroscience Letters, 2017, vol. 649, pp. 147-155.
[cited by applicant]
Avinza® (morphine sulfate) extended-release capsules, for oral use, CII, Highlights of Prescribing Information, Reference ID: 3155722, Jul. 2012, pp. 1-18.
[cited by applicant]
Banwani et al., “Ketamine-induced affective switch in a patient with treatment-resistant depression”, Indian J Pharmacol., Jul.-Aug. 2015; vol. 47(4): pp. 454-455.
[cited by applicant]
Barbee et al, “A Double-Blind Placebo-Controlled Trialof Lamotrigine as an AntidepressantAugmentation Agent in Treatment-Refractory Unipolar Depression”, J Clin Psy 2023, vol. 84, No. 5:22ml14731, pp. 1-3.
[cited by applicant]
Berman et al., “Antidepressant Effects of Ketamine in Depressed Patients”, Biol. Psychiatry, 2000, pp. 351-354.
[cited by applicant]
Bioequivalence Studies with Pharmacokinetic Endpoints for Drugs Submitted Under and ANDA Guidance for Industry, Aug. 2021.
[cited by applicant]
Blonk et al., “Use of Oral Ketamine in Chronic Pain Management: A Review”, European Journal of Pain, 2010, pp. 466-472.
[cited by applicant]
Bobo et al ‘Ketamine for treatment-resistant unipolar and bipolar major depression: critical review and implications for clinical practice’ Depression and Anxiety, vol. 33, Jan. 2016, pp. 698-710.
[cited by applicant]
Body Weight at www.cnn.com/2018/12/20/health/us-average-height-weight-report/index.html (retrieved from the internet Aug. 25, 2021) (Year: 2018).
[cited by applicant]
Bot et al., “Eicosapentaenoic acid as an add-on to antidepressant medication for co-morbid major depression in patients with diabetes mellitus: A randomized, double-blind placebo-controlled study” Journal of Affective D…
[cited by applicant]
Branerjee et al, “AGN-241751, an Orally Bioavailable Positive NMDA Receptor Modulator, Exhibits Rapid and Sustained Antidepressant-Like Effects in Rodents”, Biological Psychiatry, May 15, 2019, vol. 85, p. S348.
[cited by applicant]
Brennan et al., “The comparative pharmacokinetics of physical manipulation by crushing of XtampzaR ER compared with OxyContin”, Future Medicine Ltd., Sep. 18, 2017, 12 pages.
[cited by applicant]
Calabrese et al ‘A Randomized, Double-Blind, Placebo-Controlled Trial of Quetiapine in the Treatment of Bipolar 1 or II Depression’ Am J Psychiatry 2005, vol. 162, pp. 1351-1360.
[cited by applicant]
Canuso 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-Con…
[cited by applicant]
Celon Pharma Press Release, Celon Pharma S.A. begins a clinical programme for Esketamine in the treatment of drug-resistant depression, Nov. 28, 2017.
[cited by applicant]
Celon Pharma Press Release, Completed administration of the Esketamine-based drug to all subjects of the first part of the phase 1 trial; Jan. 5, 2018.
[cited by applicant]
Chedekel, Yale, “Magic Antidepressant May Hold promise for PTSD”, Harvard Courant, Jun. 3, 2012.
[cited by applicant]
Chen et al, “Therapeutic effects of add-on low-dose dextromethorphan plus valproic acid in bipolar disorder”, European Neuropsychopharmacology, Sep. 2014, vol. 24, pp. 1753-1759.
[cited by applicant]
Chong et al., “Development of a Sublingual/Oral Formulation of Ketamine for Use in Neuropathic Pain”, Clin Drug Invest 2009, vol. 29, No. 5, pp. 317-324.
[cited by applicant]
Clements et al., “Bioavailability, Pharmacokinetics and Analgesic Activity of Ketamine in Humans”, Journal of Pharmaceutical Sciences, May 1982, pp. 539-542.
[cited by applicant]
Correia-Melo et al., “Rapid infusion of esketamine for unipolar and bipolar depression: a retrospective chart review”, Neuropsychiatric Disease and Treatment, 2017, vol. 13, pp. 1627-1632.
[cited by applicant]
Currie, “Pharmacology, Part 1: Introduction to Pharmacology and Pharmacodynamics,” Journal of Nuclear Medicine Technology, vol. 46, No. 2, Jun. 2018, pp. 81-86.
[cited by applicant]
Cusin et al. Rating Scales for Depression, Handbook of Clinical Rating Scales and Assessment in Psychiatry and Mental Health, L. Baer, M.A. Blais (Eds.), Humana Press, 2010, Chapter 2, pp. 7-35.
[cited by applicant]
D'Andrea et al., “Transient Resolution of Treatment-Resistant Posttraumatic Stress Disorder Following Ketamine Infusion”, Biol Psy, 2013, vol. 74, pp. e-13-e14.
[cited by applicant]
Dahan et al., “Population pharmacokinetic-pharmacodynamic modeling of ketamine-induced pain relief of chronic pain”, European Journal of Pain, vol. 15, 2011, pp. 258-267.
[cited by applicant]
Daly et al., “A Randomized Withdrawal, Double-Blind, Multicenter Study of Esketamine Nasal Spray Plus an Oral Antidepressant for Relapse Prevention in Treatment-Resistant Depression”, Presented at the 2018 Annual Meetin…
[cited by applicant]
Daly et al., “Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression: A Randomized Clinical Trial,” JAMA Psychiatry, 2018, vol. 75, No. 2, pp. 139-148.
[cited by applicant]
Daly et al., “Intranasal Esketamine in Treatment-resistant Depression, a Dose Response Study—Double Blind and Open Label Extension Data”, Neuropsychopharmacology, 2015, vol. 40, pp. 5272-5442.
[cited by applicant]
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, American Psychiatric Association, 2013, pp. 160-167.
[cited by applicant]
Diazgranados et al., “A Randomized Add-on Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Bipolar Depression”, Arch Gen Psychiatry. Aug. 2010, vol. 67, No. 8, pp. 793-802.
[cited by applicant]
Domino, “Taming the Ketamine Tiger”, Anesthesiology, 2010, vol. 113, pp. 678-686.
[cited by applicant]
Donoghue et al., “Remission From Behavioral Dysregulation in a Child With PTSD After Receiving Procedural Ketamine”, Pediatrics, 2015, vol. 136, e694.
[cited by applicant]
DSM-V “Major Depressive Disorder”, 2013, at p. 161.
[cited by applicant]
Durgam et al., “An 8-Week Randomized, Double-Blind , Placebo-Controlled Evaluation of the Safety and Efficacy of Cariprazine in Patients With Bipolar 1 Depression”, Am J Psychiatry 2016, vol. 173, pp. 271-281.
[cited by applicant]
Earley et al., “Cariprazine Treatment of Bipolar Depression: A Randomized Double-Blind Placebo-Controlled Phase 3 Study”, Am J Psychiatry, Jun. 2019, vol. 176, No. 6, pp. 439-448.
[cited by applicant]
Atsushi Hakura, “Genotoxicity Testing”, Folia Pharmacol. Jpn., vol. 130, 2007, 57-61.
[cited by applicant]
Rasmussen Feder et al., “Ketamine for Posttraumatic Stress Disorder”, JAMA Psychiatry, Jan. 2015, vol. 72, No. 1, 2015, pp. 94-96.
[cited by applicant]
Rayner et al., “Antidepressants for the treatment of depression in palliative care: systematic review and meta-analysis”, Palliat Med., 2011, vol. 25, No. 1, pp. 36-51.
[cited by applicant]
Reagan-Shaw, et al., Dose translation from animal to human studies revisited, The FASEB Journal, vol. 22, 2007, pp. 659-661.
[cited by applicant]
Rizvi et al., “Predictors of response to adjunctive osmotic-release methylphenidate or placebo in patients with major depressive disorder: Effects of apathy/anhedonia and fatigue”, J Clinical Psychopharmacology, Dec. 20…
[cited by applicant]
Rong et al., “Predictors of Response to Ketamine in Treatment Resistant Major Depressive Disorder and Bipolar Disorder”, Int. J. Environ. Res. Public Health, 2018, vol. 15, No. 771, pp. 1-10.
[cited by applicant]
Rot et al., “Safety and Efficacy of Repeated-Dose Intravenous Ketamine for Treatment-Resistant Depression”, Biol Psychiatry, 2010, vol. 67, pp. 139-145.
[cited by applicant]
Sanacora et al., “Preliminary Evidence of Riluzole Efficacy in Antidepressant-Treated Patients with Residual Depressive Symptoms” Biol Psychiatry. Mar. 2007, vol. 61, No. 6, pp. 822-825.
[cited by applicant]
Sanacora et al., A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders, JAMA Psychiatry, Apr. 2017, vol. 74, No. 4, pp. 399-405.
[cited by applicant]
Schindler et al, “Lithium versus lamotrigine augmentation in treatment resistant unipolar depression: a randomized, open-label study”, International Clinical Psychopharmacology, 2007, vol. 22 No. 3, pp. 179-182.
[cited by applicant]
Schoevers et al., “Oral Ketamine for the Treatment of Pain and Treatment-Resistant Depression”,, British Journal of Psychiatry, 2016, vol. 208, pp. 108-113.
[cited by applicant]
Schonenberg et al., “Effects of peritraumatic ketamine medication on early and sustained posttraumatic stress symptoms in moderately injured accident victims”, Psychopharmacology, 2005, vol. 182, pp. 420-425.
[cited by applicant]
Schonenberg et al., “Ketamine aggravates symptoms of acute stress disorder in a naturalistic sample of accident victims”, Journal of Psychopharmacology, 2008, vol. 22, No. 5, pp. 493-497.
[cited by applicant]
Segmiller, et al, Repeated S-ketamine Infusions in Therapy Resistant Depression: A Case Series; American College of Clinical Pharmacology, vol. 53, Issue 9, Sep. 2013, pp. 996-998 (5pages).
[cited by applicant]
Sharpe et al., “Major depression in outpatients attending a regional cancer centre: screening and unmet treatment needs”, British Journal of Cancer, 2004, vol. 90, pp. 314-320.
[cited by applicant]
Shirawi et al., Journal of Clinical Psychopharmacology, Oral Ketamine in Treatment-Resistant Depression, vol. 37, No. 4, Aug. 2017, pp. 1-4, 464-467.
[cited by applicant]
Shiroma et al., “Augmentation of response and remission to serial intravenous subanesthetic ketamine in treatment resistant depression”, Journal of Affective Disorders, vol. 155, 2014, pp. 123-129.
[cited by applicant]
Singh et al., “Intravenous Esketamine in Adult Treatment-Resistant Depression: A Double-Blind, Double-Randomization, Placebo-Controlled Study”, Biological Psychiatry, 2016, vol. 80, pp. 424-431.
[cited by applicant]
Smith-Apeldoorn et al., BMC Psychiatry; “Oral esketamine for treatment-resistant depression: rationale and design of a randomized controlled trial”, BMC Psychiatry, vol. 19:375, No. 1, Nov. 2019, pp. 1-9.
[cited by applicant]
Snaith et al., “Doctors and overpopulation,” British Medical Journal, vol. 292, Feb. 1986, p. 344.
[cited by applicant]
Snaith et al., “The hospital anxiety and depression scale”, 1986, vol. 292, 6516, p. 344.
[cited by applicant]
Sofia et al., “Evaluation of Ketamine HCI for Anti-Depressant Activity”, Arch. Int. Pharmacodyn. Ther., 1975, vol. 214, No. 1, pp. 68-74.
[cited by applicant]
Spravato esketamine nasal spray, Approved Product Monograph, Canada, May 19, 2020, pp. 1-59.
[cited by applicant]
Spravato Prescribing Information, Section 2.2, Mar. 2019.
[cited by applicant]
Striebel et al., “(Being with a Buddha): A Case Report of Methoxetamine Use in a United States Veteran with PTSD' Case Reports”, Psychiatry, 2017, Article ID 2319094, pp. 1-5.
[cited by applicant]
Thomas et al., “Rapid effectiveness of intravenous ketamine for ultraresistant depression in a clinical setting and evidence for baseline anhedonia and bipolarity as clinical predictors of effectiveness”, J Psychopharma…
[cited by applicant]
Toyama et al., “Genotoxic Effects of N-nitrosoketamine and Ketamine as Assessed by In Vitro Micronucleus Test in Chinese Hamster Lung Fibroblast Cell Line”, Environ. Health Prev. Med., May 2006, vol. 11, pp. 120-127.
[cited by applicant]
Vallesenor et al., “A pilot study of plasma metabolomic patterns from patients treated with ketamine for bipolar depression: evidence for a response-related difference in mitochondrial networks”, Br J Pharmacology, 2014…
[cited by applicant]
Van de Loo, et al., “The effects of intranasal esketamine (84 mg) and oral mirtazapine (30 mg) on on-road driving performance: a double-blind, placebo-controlled study”, Psychopharmacology, 2017, vol. 234, pp. 3175-3183.
[cited by applicant]
Vesierra Label, Jan. 2018, 12 pages.
[cited by applicant]
Wallace et al: Randomized, double-blind, placebo-controlled, dose-escalation study: Investigation of the safety, pharmacokinetics, and antihyperalgesic activity of 1-4-chlorokynurenine in healthy volunteer, Scandinavian…
[cited by applicant]
Wasteson et al., “Depression assessment and classification in palliative cancer patients: a systematic literature review”, Palliative Medicine, 2009, vol. 23, No. 8, pp. 739-753.
[cited by applicant]
White et al., “Comparative Pharmacology of the Ketamine Isomers”, Brit. Journal Anaesth., 1985, vol. 57, pp. 197-203.
[cited by applicant]
White, et al., “Pharmacology of Ketamine Isomers in Surgical Patients”, Anesthesiology, 1980, vol. 52, pp. 231-239.
[cited by applicant]
Wilkinson et al., “A Survey of the Clinical, Off-Label Use of Ketamine as a Treatment for Psychiatric Disorders”, Am. J. Psychiatry, Jul. 2017, vol. 174, No. 7, pp. 695-696.
[cited by applicant]
Witkin Jeffrey M et al: “Rapid-Acting Antidepressants”, Current Pharmaceutical Design, vol. 24, No. 22, Jun. 27, 2018 (Jun. 27, 2018), pp. 2556-2563.
[cited by applicant]
Womble, “Effects of Ketamine on Major Depressive Disorder in a Patient With Posttraumatic Stress Disorder”, AANA Journal, Apr. 2013, vol. 81, No. 2, pp. 118-119.
[cited by applicant]
Yanagihara et al., “Plasma Concentration Profiles of Ketamine and Norketamine After Administration of Various Ketamine Preparations to Healthy Japanese Volunteers”, Biopharmaceutics & Drug Disposition, 2003, vol. 24, No…
[cited by applicant]
Yang et al., “R-ketamine: A Rapid-Onset and Sustained Antidepressant Without Psychotomimetic Side Effects”, Transl. Psychiatry, Sep. 2015, 11 pages.
[cited by applicant]
Yehuda et al., “What I have changed my mind about and why”, European Journal of Psychotraumatology, 2016, vol. 7, pp. 1-9.
[cited by applicant]
Zanos Panos, et al: “Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms”, Pharmacological Reviews, vol. 70, No. 3, Jun. 2018, pp. 621-660.
[cited by applicant]
Zarate et al., “Replication of Ketamine's Antidepressant Efficacy in Bipolar Depression: A Randomized Controlled Add-on Trial”, Biol. Psychiatry., 2012, vol. 71, No. 11, pp. 939-946.
[cited by applicant]
Zhang et al., “R(-)-ketamine Shows Greater Potency and Longer Lasting Antidepressant Effects Than S (+)-ketamine”, Pharmacology, Biochemistry and Behavior, Jan. 2014, vol. 116, pp. 137-141.
[cited by applicant]
Zhao et al., Simultaneous population pharmacokinetic modelling of ketamine and three major metabolites in patients with treatment-resistant bipolar depression, BJCP, 2012, vol. 74, No. 2, pp. 304-314.
[cited by applicant]
Zigmond et al., “The Hospital Anxiety and Depression Scale,” Acta psychiatr. scand., vol. 67, 1983, pp. 361-370.
[cited by applicant]
Zulresso FDA Label, Full Prescribing Information, Sep. 30, 2019, 21 pages.
[cited by applicant]
Ebert et al., “Norketamine, the Main Metabolite of Ketamine, is a non-competitive NMDA Receptor Antagonist in the Rat Cortex and Spinal Cord”, European Journal of Pharmacology, 1997, vol. 333, pp. 99-104.
[cited by applicant]
EMCDDA, Report on the Risk Assessment of Ketamine in the Framework of the Joint Action on New Synthetic Drugs, 2002, 120 pages.
[cited by applicant]
European Monitoring Centre for Drug and Drug Addition's 2002 risk assessment report of Ketamine, pp. 49-50.
[cited by applicant]
Fanta et al., “Population Pharmacokinetics of S-ketamine and Norketamine in Healthy Volunteers After Intravenous and Oral Dosing”, Eur. J. Clin. Pharmacol., Mar. 1, 2015, vol. 71, No. 4, pp. 441-447.
[cited by applicant]
Fava et al: “Opioid Modulation With Buprenorphine/Samidorphan as Adjunctive Treatment for Inadequate Response to Antidepressants: A Randomized Double-Blind Placebo-Controlled Trial”, Am. J. Psychiatry, May 2016, vol. 17…
[cited by applicant]
Fava, et al., “Major Depressive Disorder”, Neuron, Nov. 2000, vol. 28, pp. 335-341.
[cited by applicant]
Feder et al., “Efficacy of Intravenous Ketamine for Treatment of Chronic Posttraumatic Stress Disorder”, JAMA Psychiatry, 2014, vol. 71, No. 6, pp. 681-688.
[cited by applicant]
Fond et al' Ketamine's effectiveness in unipolar versus bipolar depression1 Psychopharmacology (2014) 231:4417-4418.
[cited by applicant]
Geisslinger et al., “Pharmacokinetics and Pharmacodynamics of Ketamine Enantiomers in Surgical Patients Using a Stereoselective Analytical Method”, British Journal of Anesthesia, 1993, vol. 70, pp. 666-671.
[cited by applicant]
Gershon, “Adjustment Disorders,” Trauma and Stressor Related Disorders, Nov. 17, 2022, pp. 286-289.
[cited by applicant]
Gershon, “Depressive Disorder Due to Another Medical Condition,” Depressive Disorder, Nov. 17, 2022, pp. 180-183.
[cited by applicant]
Giorgetti, et al., “Effects of ketamine on psychomotor, sensory and cognitive functions relevant for driving ability”, Forensic Science International, 2015, vol. 252, pp. 127-142.
[cited by applicant]
Grady et al., Ketamine for the treatment of major depressive disorder and bipolar depression: A review of the literature1 Ment Health Clin [Internet], 2017, vol. 7, No. 1, pp. 16-23.
[cited by applicant]
Grant et al., “Pharmacokinetics and Analgesic Effects of I.M. and Oral Ketamine”, British Journal of Anesthesia, 1981, vol. 53, pp. 805-810.
[cited by applicant]
Hagelberg et al., “Clarithromycin, a potent inhibitor of CYP3A, Greatly Increases Exposure to Oral S-ketamine”, European Journal of Pain, 2010, pp. 625-629.
[cited by applicant]
Han et al., “Oral scopolamine augmentation for major depression”, Expert Rev. Neurother, 2013, vol. 13, No. 1, pp. 19-21.
[cited by applicant]
Hartberg, et al., Psychopharmacology, Impact of oral ketamine augmentation on hospital admissions in treatment-resistant depression and PTSD: a retrospective study, 2018, pp. 393-398.
[cited by applicant]
Hartvig et al., “Central Nervous System Effects of Subdissociative Doses of (S)-ketamine are Related to Plasma and Brain Concentrations Measured with Positron Emission Tomography in Healthy Volunteers”, Clin. Pharm. & T…
[cited by applicant]
Hashimoto et al., “R-ketamine: A Rapid-Onset and Sustained Antidepressant Without Risk of Brain Toxicity”, Psychological Medicine, Aug. 2016, vol. 46, pp. 2449-2451.
[cited by applicant]
Hasin et al., “Epidemiology of Major Depressive Disorder”, Arch. Gen. Psychiatry, 2005, vol. 62, pp. 1097-1106.
[cited by applicant]
Himmelseher et al., “Ketamine for Perioperative Pain Management”, Anesthesiology, Jan. 2005, vol. 102, pp. 211-220.
[cited by applicant]
Hintzsche, “Subanesthetic-Dose Ketamine to Decrease Emergence Delirium in the Surgical Patient With Posttraumatic Stress Disorder”, AANA Journal, Jun. 2018, vol. 86, No. 3, pp. 220-224.
[cited by applicant]
Horn et al., “Understanding resilience: New approaches for preventing and treating PTSD”, Experimental Neurology, 2016, vol. 284, pp. 119-132.
[cited by applicant]
Hou et al., “Applying ketamine to alleviate the PTSD-like effects by regulating the HCNI-related BDNF”, Progress in Neuropsychopharmacology & Biological Psychiatry, 2018, vol. 86, pp. 313-321.
[cited by applicant]
Huge et al., “Effects of low-dose intranasal (S)-ketamine in patients with Neuropathic pain”, European Journal of Pain, 2010, pp. 387-394.
[cited by applicant]
Ihmsen et al., “Stereoselective pharmacokinetics of ketamine: R(-)-Ketamine inhibits the elimination of S(+)-ketamine”, Clinical Pharmacology & Therapeutics, 2001, vol. 70, pp. 431-438.
[cited by applicant]
Irwin 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 Trail”, Journal of Palliative Medicine, 2013, vol. 16, No. 8, pp. 9…
[cited by applicant]
Jafarinia, et al., Journal of Affective Disorders, Efficacy and safety of oral ketamine versus diclofenac to alleviate mild to moderate depression in chronic pain patients: A double-blind, randomized, controlled trial 2…
[cited by applicant]
Janssen Announces Results of Esketamine Nasal Spray Phase 3 Study in Patients with Treatment-Resistant Depression, Innovation, Sep. 21, 2018, 6 pages.
[cited by applicant]
Janssen Study For NCT03808259, A Study to Investigate the Different Modes of (S) Ketamine Administration in Healthy Participants, Last Updated Sep. 12, 2019.
[cited by applicant]
Janssen Submits Esketamine Nasal Spray New Drug Application to U.S. Fda for Treatment-Resistant Depression, Sep. 4, 2018 [Retrieved from internet https://www.prnewswire.com/news-releases/janssen-submits-esketamine-nasal…
[cited by applicant]
Jarventausta et al., “S-ketamine for the Treatment of Depression”, Psychiatria Fennica, 2015, vol. 46, pp. 11-20.
[cited by applicant]
Jazayeri et al., “Comparison of therapeutic effects of omega-3 fatty acid eicosapentaenoic acid and fluoxetine, separately and in combination, in major depressive disorder”, Aust Nz J Psychiatry, Mar. 2008 vol. 42, No. …
[cited by applicant]
Kelley et al., “Open-Label Placebo for Major Depressive Disorder: A Pilot Randomized Controlled Trial,” Psychotherapy and Psychosomatics, vol. 81, No. 5, Aug. 2012, pp. 312-314.
[cited by applicant]
Kelmendi et al., “PTSD: from neurobiology to pharmacological treatments”, European Journal of Psychotraumatology, 2016, vol. 7, 31858, pp. 1-11.
[cited by applicant]
Ketamine as a Rapid Treatment for Post-Traumatic Stress Disorder, Grant No. W81XWH-08-1-0602, U.S. Army Medical Research and Material Command, Oct. 2011.
[cited by applicant]
Ketamine INN, Update Review Report Agenda Item 6.1, Expert Committee on Drug Dependence, WHO, 37th Meeting, Geneva, Nov. 2015, pp. 1-46.
[cited by applicant]
Kharasch et al., “Metabolism of Ketamine Stereoisomers by Human Liver Microsomes”, Anesthesiology, 1992, vol. 77, pp. 1201-1207.
[cited by applicant]
Kim, “Ketamine for Treatment-Resistant Depression or Post-Traumatic Stress Disorder in Various Settings: A Review of Clinical Effectiveness, Safety, and Guidelines”, CADTH Rapid Response Report, Mar. 2017, pp. 1-30.
[cited by applicant]
Kishimoto et al., “Compliance and persistence with daily, weekly, and monthly bisphosphonates for osteoporosis in Japan: analysis of data from the CISA”, Arch Osteoporos, 2015, vol. 10, No. 27, pp. 1-6.
[cited by applicant]
Kraus et al ‘Administration of ketamine for unipolar and bipolar depression’ Int J Psychiatry Clin Pract. Mar. 2017, vol. 21, No. 1, pp. 2-12.
[cited by applicant]
Krystal et al., “Synaptic Loss and the Pathophysiology of PTSD: Implications for Ketamine as a Prototype Novel Therapeutic”, Curr. Psychiatry, Rep., Apr. 2018, vol. 19, No. 10, 74, pp. 20.
[cited by applicant]
Lara et al., “Antidepressant, mood stabilizing and procognitive effects of very low dose sublingual ketamine in refractory unipolar and bipolar depression”, International Journal of Neuropsychopharmacology, 2013, vol. 1…
[cited by applicant]
Lavretsky et al., “Methylphenidate Augmentation of Citalopram in Elderly Depressed Patients”, Am J Geriatr Psychiatry 2001 Summer, vol. 9, No. 3, pp. 298-303.
[cited by applicant]
Livingston et al., “Influence of age and sex on the duration of action ketamine in the rat [proceedings]”, Br J Pharmacol., Jan. 1977, vol. 59, 491P.
[cited by applicant]
Lloyd-Williams et al., “A pilotrandomisedcontrolledtrialtoreducesufferingandemotional distress in patients with advanced cancer”, J Affect Dis 2013, vol. 148, pp. 141-145.
[cited by applicant]
Lloyd-Williams et al., “Antidepressant medication in patients with advanced cancer-an observational study”, QJM, Nov. 2013, vol. 106, No. 11, pp. 995-1001.
[cited by applicant]
Loebel et al., “Lurasidone Monotherapy in the Treatment of Bipolar 1 Depression: A Randomized, Double-Blind, Placebo-Controlled Study”, Am J Psychiatry, 2014, vol. 171, pp. 160-168.
[cited by applicant]
Ionescu et al., “A single infusion of ketamine improves depression scores in patients with anxious bipolar depression”, Bipolar Disord. Jun. 2015, vol. 17, No. 4, pp. 438-443.
[cited by applicant]
Malinosky et al., “Ketamine and Norketamine Plasma Concentrations after i.v., Nasal and Rectal Administration in Children”, British Journal of Anaesthesia, 1996, vol. 22, pp. 203-207.
[cited by applicant]
Marcus et al., “Antipsychotic Adherence and Rehospitalization in Schizophrenia Patients Receiving Oral Versus Long-Acting Injectable Antipsychotics Following Hospital Discharge”, JMCP, Sep. 2015, vol. 21, No. 9, pp. 1-7…
[cited by applicant]
Mathai et al., “The relationship between subjective effects induced by a single dose of ketamine and treatment response in patients with major depressive disorder: A systematic review”, Journal of Affective Disorders, 2…
[cited by applicant]
Mathew et al., “A Randomized, Double-Blind, Placebo-Controlled, Sequential Parallel Comparison Design Trial of Adjunctive Riluzole for Treatment-Resistant Major Depressive Disorder”, Neuropsychopharmacology. Dec. 2017, …
[cited by applicant]
Mathew et al., “Ketamine for Treatment-Resistant Unipolar Depression: Current Evidence”, CNS Drugs, Mar. 1, 2012, vol. 26, No. 3, pp. 189-204.
[cited by applicant]
McGhee et al., “The correlation between ketamine and posttraumatic stress disorder in burned service members”, The Journal of Trauma: Injury, Infection and Critical Care, Feb. 2008, vol. 64, Issue 2, pp. S195-S199.
[cited by applicant]
Mikics et al., “The role of GluN2B-containing NMDA receptors in short- and long-term fear recall”, Physiology & Behavior, 2017, vol. 177, pp. 44-48.
[cited by applicant]
Mion et al., “A retrospective study of ketamine administration and the development of acute or post-traumatic stress disorder in 274 war-wounded soldiers”, Anaesthesia, 2017, vol. 72, pp. 1476-1483.
[cited by applicant]
Mischoulon et al., “A double-blind dose-finding pilot study of docosahexaenoic acid (DHA) for major depressive disorder”, European Neuropsychopharmacology, 2008, vol. 18, pp. 639-645.
[cited by applicant]
Mischoulon et al., “A Double-Blind Randomized Controlled Trial of Ethyl-Eicosapentaenoate (EPA-E) for Major Depressive Disorder”, J Clin Psychiatry Dec. 2009, vol. 70, No. 12, pp. 1636-1644.
[cited by applicant]
Mischoulon et al., A Double-Bline, Randominzed Controlled Clinical Trial comparing Eiocosapentaenoic Acid Versus docosahexanenoic Acid for Drepression, J Clin Psychiatry Jan. 2014, vol. 76, No. 1, pp. 54-61.
[cited by applicant]
Molero et al., “Antidepressant Efficacy and Tolerability of Ketamine and Esketamine: A Critical Review”, CNS Drugs, May 2018, 10 pages.
[cited by applicant]
Morrison, “Effect of intranasal esketamine on cognitive functioning in healthy participants: a randomized, double-blind, placebo-controlled study”, Psychopharmacology, Feb. 2018, vol. 235, pp. 1107-1119.
[cited by applicant]
Mrazek et al., “A Review of the Clinical, Economic, and Societal Burden of Treatment-Resistant Depression: 1996-2013”, Psychiatric Services, Aug. 2014, vol. 65, No. 8, pp. 977-987.
[cited by applicant]
Musazzi et al., “What Acute Stress Protocols Can Tell Us About PTSD and Stress-Related Neuropsychiatric Disorders”, Frontiers in Pharmacology, Jul. 2018, vol. 9, Article 758.
[cited by applicant]
Nair et al., “A Simple Practice Guide for Dose Conversion between animals and human”, Journal of Basic and Clinical Pharmacy, 2016, vol. 7, No. 2, pp. 27-31.
[cited by applicant]
NCT01998958, Oct. 29, 2015.
[cited by applicant]
NCT02133001, Mar. 18, 2016.
[cited by applicant]
NCT02343289, Jan. 21, 2015.
[cited by applicant]
NCT02417064, Apr. 10, 2015.
[cited by applicant]
NCT02418585, Apr. 13, 2015.
[cited by applicant]
NCT02422186, Apr. 16, 2015.
[cited by applicant]
NCT02493868, Jul. 7, 2015.
[cited by applicant]
NCT02497287, Jun. 10, 2015.
[cited by applicant]
NCT02782104, May 25, 2016.
[cited by applicant]
NCT02918318, Sep. 27, 2016.
[cited by applicant]
NCT03039192, Feb. 1, 2017.
[cited by applicant]
NCT03097133, Mar. 27, 2017.
[cited by applicant]
NCT03185819, Jun. 12, 2017.
[cited by applicant]
NCT03434041, Feb. 18, 2018.
[cited by applicant]
NCT03965871 trial protocol as accessed Jul. 25, 2019.
[cited by applicant]
Netherlands Pharmacovigilance Centre report, Esketamine and hepatotoxicity, May 2013, 7 pages.
[cited by applicant]
Noppers et al., “Drug-induced liver injury following a repeated course of ketamine treatment for chronic pain in CRPS type 1 patients: A report of 3 cases”., Pain, vol. 152, 2011, pp. 2179-2178.
[cited by applicant]
Norrholm et al., “Fear Extinction in Traumatized Civilians with Posttraumatic Stress Disorder: Relation to Symptom Severity”, Biol Psychiatry, 2011, pp. 69556-69563.
[cited by applicant]
Nugent et al., “Neural correlates of rapid antidepressant response to ketamine in bipolar disorder”, Bipolar Disord. Mar. 2014, vol. 16, No. 2, pp. 119-128.
[cited by applicant]
Och-Ross et al., “Efficacy and Safety of Intranasal Esketamine Plus and Oral Antidepressant in Elderly Patients with Treatment-Resistant Depression”, 2018 Annual Meeting of the American Psychiatric Association (APA), Ma…
[cited by applicant]
Ostuzzi et al., “Antidepressants for the treatment of depression in people with cancer,” Cochrane Database of Systematic Reviews, 2018, Issue 4, Art. No. CD011006, pp. 1-51.
[cited by applicant]
Ostuzzi et al., “Cochrane Database of Systematic Reviews, Antidepressants for the treatment of depression in people with cancer (Review)”, 2018, pp. 1-78.
[cited by applicant]
Oye et al., “Effects of Ketamine on Sensory Perception: Evidence for a Role of N-Methyl-D-Aspartate Receptors”, Journal of Pharmacology and Experimental Therapeutics, Mar. 1992, vol. 260, No. 3, pp. 1209-1213.
[cited by applicant]
Papakostas et al., “The Nature of Placebo Response in Clinical Studies of Major Depressive Disorder”, J. Clin. Psychiatry, 2015, vol. 76, No. 4, pp. 456-466.
[cited by applicant]
Paslakis et al., “Oral Administration of the NMDA Receptor Antagonist S-Ketamine as Add-On Therapy of Depression: A Case Series”, Pharmacopsychiatry, Jan. 2010, 43(1), 33-35.
[cited by applicant]
Patent and Exclusivity for: N211243, Product 001, Esketamine Hydrochloride (Spravato) Spray EQ 28mg Base, Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations, [Retrieved from internet on Apr. 4,…
[cited by applicant]
Peltoniemi et al., “Ketamine: A Review of Clinical Pharmacokinetics and Pharmacodynamics in Anesthesia and Pain Therapy”, Clin Pharmacokinet 2016, vol. 55, pp. 1059-1077.
[cited by applicant]
Peltoniemi et al., “Rifampicin has a Profound Effect on the Pharmacokinetics of Oral S-Ketamine and Less on Intravenous S-Ketamine”, Basic & Clinical Pharmacology, 2012, vol. 111, pp. 325-332.
[cited by applicant]
Peltoniemi et al., “S-ketamine concentrations are greatly increased by grapefruit juice,” European Journal of Clinical Pharmacology, vol. 68, No. 6, Jan. 2012, pp. 979-986.
[cited by applicant]
Pfenninger et al., “Cognitive Impairment after Small-dose Ketamine Isomers in Comparison to Equianalgesic Racemic Ketamine in Human Volunteers”, Anesthesiology, 2002, vol. 96, pp. 357-366.
[cited by applicant]
Pradhan et al., “D-Serine is a potential biomarker for clinical response in treatment of posttraumatic stress disorder using (R,S)-ketamine infusion and Timber Psychotherapy: A Pilot Study”, BBA—Proteins and Proteomics,…
[cited by applicant]
Preskorn et al., “Randomized Proof of Concept Trial of GLYX-13, an N-Methyl-D-Aspartate Receptor Glycine Site Partial Agonist, in Major Depressive Disorder Nonresponsive to a Previous Antidepressant Agent”, Journal of P…
[cited by applicant]
Qi et al., “Prevention of Post-Traumatic Stress Disorder After Trauma: Current Evidence and Future Directions”, Curr Psychiatry Rep., 2016, vol. 18, pp. 1-11.
[cited by applicant]
Declaration of Elena Kagan for U.S. Appl. No. 17/789,631 titled Dosage Regime With Esketamine for Treating Major Depressive Disorder dated Jul. 14, 2024, 415 Pages.
[cited by applicant]
Declaration of Tal Birnberg for U.S. Appl. No. 16/592,930 titled Method of Treating Major Depressive Disorder dated Nov. 24, 2022, 46 Pages.
[cited by applicant]