Outline • Background on Ketamine The Promise and Perils of Ketamine • The Promise – Single Infusion Therapy for TRD, Suicidal in Psychiatric Practice Ideation, PTSD – Continuation Therapy Sanjay J. Mathew, MD • The Perils Professor of Psychiatry & Behavioral Sciences • Ketamine in Clinical Practice: Towards Best Johnson Family Chair for Research in Psychiatry Practice Patterns for Off-label Use Menninger Department of Psychiatry & Behavioral Sciences Baylor College of Medicine Staff Physician, Michael E. Debakey VA Medical Center Houston, Texas TRD = treatment-resistant depression; PTSD = posttraumatic stress disorder. Case Study: Ms. B • Age 31, first depressive episode age 24 in law school • 2 episodes/year, with loss of function, marked anhedonia, and suicidal ideation • Past adequate trials of antidepressants: – Sertraline (200 mg) – Venlafaxine XR (300 mg) – Bupropion XL (450 mg) – Vortioxetine (20 mg) • Adjunctive lithium and aripiprazole not well tolerated • ECT effective but suffered severe memory impairment WOULD YOU CONSIDER A TRIAL OF KETAMINE? ECT = electroconvulsive therapy. Nichols SD, et al. Current Psychiatry . 2015;15(5):48-51. Ketamine and NMDA Receptor Ketamine: History • Synthesized in 1962 by Calvin Stevens, a Parke-Davis • Dissociative anesthetic (2–3 mg/kg — 2000–3000 ng/mL chemist seeking an alternative anesthetic to PCP peak plasma concentrations) • FDA approved for human use since 1970 (Schedule III) • Uncompetitive high-affinity • Approved indications NMDAR antagonist – “ …the sole anesthetic agent for diagnostic and surgical • Binds to PCP “angel dust” site procedures that do not require skeletal muscle relaxation. ” within ion channel – “ …the induction of anesthesia prior to the administration of • Membrane depolarization other general anesthetic agents. ” relieves Mg block, and with co-agonist binding, Ca2+ and Na+ enters cell – “ …to supplement low-potency agents, such as nitrous oxide. ” NMDA = N-methyl-D-aspartate. PCP = phencyclidine. Du J, et al. Dialogues Clin Neurosci . US Food and Drug Administration. www.accessdata.fda.gov/scripts/cder/daf/. 2004;6(2):143-155.
Antidepressant Mechanism of Action of NMDA Receptor Modulators Murrough JW, et al. Nat Rev Drug Discov . 2017;[Epub ahead of print]. Are the Antidepressant Actions of Ketamine Metabolic Pathways of Ketamine Independent of NMDA Receptor Activity? Zanos P, et al. Nature . 2016;533(7604):481-486. Malinow R. Nature . 2016;533(7604):477-478. Zarate CA Jr, et al. Mol Psychiatry . 2017;22(3):324-327. Single Ketamine Infusion is Superior to Psychoactive Single Ketamine Infusion (0.5 mg/kg over 30 minutes) Control in TRD: Baylor/Mt Sinai Study (N = 72) Rapidly Effective in TRD: Replication Study (N = 17) Ketamine dose = .5 mg/kg Reduction in MADRS score 24 hours after infusion was the primary outcome measure and 70–200 ng/mL peak plasma concentration. was significantly greater for the ketamine group than for the midazolam group ( P ≤ .002). * P ˂ .05; ** P ˂ .01; *** P ˂ .001. HAM-D = Hamilton Rating Scale for Depression; SSRI = selective serotonin reuptake inhibitor; TRD = treatment-resistant depression. MADRS = Montgomery-Åsberg Depression Rating Scale. Zarate CA Jr, et al. Arch Gen Psychiatry . 2006;63(8):856-864. Murrough JW, et al. Am J Psychiatry . 2013;170(10):1134-1142.
Single Infusion of Ketamine – Short-Term Effect Sizes Efficacy in TRD (N = 147) for Single Infusion Ketamine At 1 day At 1 week Newport DJ, et al. Am J Psychiatry . 2015;172(10):950-966. Bobo WV, et al. Depress Anxiety . 2016;33(8):698-710. Effect of Ketamine on Suicidal Ideation: Add-on Trial of Ketamine in Treatment-Resistant Bipolar Depression Individual Patient Meta-Analysis Dose: 0.5 mg/kg ketamine ** ** *** *** Depressive symptoms significantly improved in participants receiving ketamine compared with placebo * P < .001; † P < .01. Wilkinson S, et al. Presented at: Society of Biological Psychiatry – 72nd Annual Meeting; May 18–20, Diazgranados N, et al. Arch Gen Psychiatry . 2010;67(8):793-802. 2017; San Diego, CA. Single Dose Efficacy in PTSD Double-Blind, Placebo-Controlled, Dose-Ranging Trial of Intravenous Ketamine as Adjunctive Therapy in TRD Ms. A: “I feel good, I want to get out and do things, like get a haircut. I haven’t felt like this in a year. I tried to SCREEN think about (the assault) but couldn’t. That was strange… I feel more RANDOMIZE connected to others, less afraid.” Mr. B: “I feel much better, the sirens outside on the street no longer bother Ketamine Midazolam DAY Ketamine Ketamine Ketamine me. I called several friends that I hadn’t .5 mg/kg .045 mg/kg 0 .1 mg/kg .2 mg/kg 1.0 mg/kg spoken with in a while. I feel calm, not n = 18 n = 20 n = 22 n = 20 n = 19 so jumpy.” DAY PRIMARY ENDPOINT ASSESSMENTS 3 Ms. C: “I feel energetic, not stressed out or anxious, I feel good, refreshed. I enjoyed going outdoors briefly for a DAY smoke. I haven’t dwelled on thoughts 30 STUDY COMPLETION about (the trauma) , I let it go. I feel happy, upbeat, my mind is clear. Interacting with others no longer takes so much effort, I don’t feel like I have to Fava M, et al. Presented at: American Society of Clinical Psychopharmacology Annual Meeting; May fake.” Feder A, et al. JAMA Psychiatry . 2014;71(6):681-688. 29–June 2, 2017; Miami, FL.
HAM-D-6 Scores for Different HAM-D-6 Response Rates IV Ketamine Doses vs Midazolam Fava M, et al. Presented at: American Society of Clinical Psychopharmacology Annual Meeting; May Fava M, et al. Presented at: American Society of Clinical Psychopharmacology Annual Meeting; May 29–June 2, 2017; Miami, FL. 29–June 2, 2017; Miami, FL. Take-Home Message: Continuation and Maintenance Therapy Dose-Response Trial of IV Ketamine in TRD • Repeated ketamine infusions • Both low dose (0.1 mg/kg) and higher doses (0.5 mg/kg and 1 mg/kg) of IV ketamine superior to active placebo • Maintenance ketamine protocols in combination • Limitations: with drugs, ECT, or psychotherapy – Lack of racial diversity in study sample – Unclear reasons for failure of 0.2 mg/kg dose arm – No assessment of response durability beyond 72 hours or speed of response at 4 hours Fava M, et al. Presented at: American Society of Clinical Psychopharmacology Annual Meeting; May 29–June 2, 2017; Miami, FL. Thrice-Weekly Ketamine Infusions in TRD: Thrice-Weekly Ketamine Infusions in TRD: Minneapolis VA Sample (N = 14) Mt Sinai Sample (N = 24) 92% responded; 67% remitted Mean time to relapse = 16 days 18 days until relapse Dose = 0.5 mg/kg over 40 minutes Murrough JW, et al. Biol Psychiatry . 2013;74(4):250-256. Shiroma PR, et al. J Affect Disord . 2014;155:123-129.
Repeated Ketamine Infusions in TRD: 12-Month Naturalistic Observation of 3 Patients Mayo Clinic Sample (N = 12) Receiving Ketamine Infusions for TRD Patient 1’s response to ketamine infusions Patient 2’s response to ketamine infusions Patient 3’s response to ketamine infusions 58% responded, 42% remitted Thrice-weekly up to 6 infusions Dose = 0.5 mg/kg over 100 minutes Vande Voort JL, et al. J Affect Disord . 2016;206:300-304. Szymkowicz SM, et al. J Affect Disord . 2013;147(1-3):416-420. Twice-Weekly Dosing as Effective as RCT of the NMDA Receptor Partial Agonist Thrice-Weekly Dosing in TRD D-Cycloserine (1 g/day) Augmentation for TRD Enrolment, randomization, withdrawals and completion of the study (N = 26). 47 Assessed Ket: 69% responded, 38% remitted (CONSORT flow diagram.) for eligibility PBO: 15% responded; 7.7% remitted Enrolment 26 Randomized Proportion of responders [≥ 50% 13 Placebo 13 D-cycloserine 1 Discontinued 3 Discontinued study Ket: 54% responded; 23% remitted improvement on 21-item HAMD] study due to 1 Hearing discomfort during 6 week adjuvant treatment PBO: 6% responded; 0% remitted chest pain 1 Non-compliance with D-cycloserine (n = 13) and 1 Tiredness placebo (n = 13). * P = .039 Analyzed Analyzed 13 Intent to treat 13 Intent to treat 12 Completers 10 Completers RCT = randomized controlled trial. Singh JB, et al. Am J Psychiatry . 2016;173(8):816-826. Heresco-Levy U, et al. Int J Neuropsychopharmacol . 2013;16(3):501-506. NRX-101 for the Treatment of Acute Suicidal D-Cycloserine for Relapse Prevention Post-IV Ketamine in Treatment-Resistant Bipolar Depression Ideation and Behavior in Bipolar Depression • NRX-101: Fixed dose combination of DCS + lurasidone • Primary outcome of Phase 2b Trial : – Time to relapse following IV ketamine infusion • Randomized Arms following single IV Ketamine infusion: – NRX-101 (DCS + lurasidone) – Lurasidone + placebo DCS = D-cycloserine. Kantrowitz JT, et al. J Clin Psychiatry . 2015;76(6):737-738. ClinicalTrials.gov Identifier: NCT02974010.
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