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Top 5 Issues Clinicians Should Know About Ketamine Therapy

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Top 5 Issues Clinicians Should Know About Ketamine Therapy Top 5 Issues Clinicians Should Know about Ketamine Therapy Sanjay J. Mathew, MD Marjorie Bintliff Johnson and Raleigh White Johnson, Jr. Vice Chair for Research Professor of Psychiatry and Behavioral Sciences Menninger Department of Psychiatry and Behavioral Sciences Baylor College of Medicine Michael E. Debakey VA Medical Center Houston, Texas Faculty Disclosure • Dr. Mathew: Consultant—Alkermes, Allergan, Clexio Biosciences, Intracellular Therapies, Janssen, Perception Neurosciences, Sage Therapeutics; Grant/Research Support—Biohaven, VistaGen Therapeutics. Disclosure • The faculty have been informed of their responsibility to disclose to the audience if they will be discussing off-label or investigational use(s) of drugs, products, and/or devices (any use not approved by the US Food and Drug Administration). – Ketamine does not have an FDA-approved indication for any psychiatric disorder. • Applicable CME staff have no relationships to disclose relating to the subject matter of this activity. • This activity has been independently reviewed for balance. Learning Objectives • Assess the clinical trials literature on the use of ketamine and esketamine for treatment-resistant depression • Describe leading hypotheses as to how ketamine and esketamine is working in the brain • Apply this learning to the individual patient in order to assess the risks vs the benefits of this therapy Outline #1. FDA Approval of Intranasal Esketamine for TRD #2. Methods to Prolong and Extend the Short-Lived Effect #3. Comparative Effectiveness in TRD #4. Mechanism of Action #5. Where do we need more data? TRD = treatment-resistant depression. #1: The FDA approved intranasal esketamine spray for TRD in March 2019 Indicated, in conjunction with an oral antidepressant, for the treatment of TRD in adults TRD: In the current episode, patient has not responded adequately to at least 2 different antidepressants of adequate dose and duration Ketamine Metabolic Pathways CYP2B6, CYP3A4; CYP2C9, CYP2C19 (lesser) Cl Cl NH NH2 (2S,6S)-HNK Cl O O (S)-Ketamine * NH (0.30 μM) (S)-Norketamine (1.7 μM) O Cl Ketamine (racemate) Cl Cl (0.53 μM for NMDAR) NH2 NH NH 2 O O O OH (R)-Ketamine (R)-Norketamine (2R,6R)-HNK (1.40 μM) (13 μM) (> 10 μM) HNK = hydroxynorketamine; NMDAR = N-methyl-D-aspartate receptor. Zanos P, et al. Nature. 2016;533(7604):481-486. Pharmacokinetics of Intranasal Esketamine • Time to maximum plasma concentration (Tmax): 20 to 40 minutes after last nasal spray • Bioavailability: 48% • Mean terminal half-life (t1/2): 7 to 12 hours, rapid decline in initial 2 to 4 hours • No sex differences • No effect of body weight (> 39–170 kg) US Food and Drug Administration. Drugs@FDA: FDA Approved Drug Products. www.accessdata.fda.gov/scripts/cder/daf/. Janssen Research & Development, LLC. Advisory Committee Briefing Document. January 16, 2019. www.fda.gov/media/121377/download. Accessed July 1, 2019. Phase 2 Trial of Intranasal Esketamine in TRD Placebo nonresponders re-randomized 56 mg and 84 mg produced plasma levels = IV esketamine 0.2 mg/kg N=67. CADSS = Clinician Administered Dissociative States Scale; MADRS = Montgomery–Åsberg Depression Rating Scale. Daly EJ, et al. JAMA Psychiatry. 2018;75(2):139-148. Study Design for Short-Term Phase 3 Trials MDD Participants SUSTaIN-1 (3003) Esketamine or (nonresponse to ≥ 1 Nasal Spray Primary AD AD Primary discontinued + SUSTaIN-2 (3004) oral AD treatments New Oral Or in current Non- OL AD SoC without Esketamine depressive episode Continuation responders or and currently taking Follow-up Phase of Same Response? a different oral AD Note: Responders for at least the Oral AD were ineligible for Active Nonresponders previous 2 weeks, at randomization Comparator or above minimum (New Oral therapeutic dose) OL AD) + Follow-up Phase Intranasal PBO Screening / Observational Phase Double-Blind Induction Phase Follow-Up Phase 4 weeks 4 weeks: IN dose frequency Up to 24 weeks 2×/week AD = antidepressant; MDD = major depressive disorder; OL = open-label; PBO = placebo. Presented at: American Psychiatric Association Annual Meeting; May 5–9, 2018; New York, NY. American Society of Clinical Psychopharmacology Annual Meeting; May 29–June 1, 2018; Miami Beach, FL. Results of Short-Term Studies of Esketamine* *In Study 3001, the lower dose could not be tested for statistical significance because the higher dose failed. CI = confidence interval; ESK = esketamine; MADRS = Montgomery–Åsberg Depression Rating Scale (scores range from 0–60, with higher scores indicating more severe depression). Data are from the US Food and Drug Administration. Plus–minus values are means ±SD. †One-sided P values are compared with P=.025. Kim J, et al. N Engl J Med. 2019 May 22; [Epub ahead of print]. Phase 3 Adjunctive Intranasal Esketamine in TRD Flexible dose 56 mg/84 mg (2×/week) vs Placebo N=227 randomized Median age = 47 response rate: 62% female 69.3% vs. 52% (NNT =6) 93% Caucasian remission rate: 5% black -4.0 in 52.5% vs. 31.0% MADRS (NNT =5) (effect size Failed up to 5 0.30) previous AD trials European and US sites Two-thirds of patients were on 84 mg dose at end of treatment period. Popova V, et al. Am J Psychiatry. 2019;176(6):428-438. Key Secondary Efficacy Endpoints Esketamine + AD AD + Placebo Early Onset of Sustained Clinical Response N 114 109 Yes, n (%) 9 (7.9%) 5 (4.6%) Generalized Cochran-Mantel-Haenszel test 2-sided P-value 0.321 Odds ratio (95% CI) 1.79 (0.57; 5.67) Sheehan Disability Scale Total Score Baseline N 111 104 Mean (SD) 24.0 (4.07) 24.2 (4.38) MMRM analysis Difference of LS means (SE) -4.0 (1.17) 95% CI on difference -6.28; -1.64 Effect size (95% CI) 0.48 (0.17, 0.78) Patient Health Questionnaire Total Score Baseline N 114 109 Mean (SD) 20.2 (3.63) 20.4 (3.74) Change from baseline to day 28 N 104 100 Mean (SD) -13.0 (6.42) -10.2 (7.80) MMRM analysis Difference of LS means (SE) -2.4 (0.88) 95% CI on difference -4.18; -0.69 Effect size (95% CI) 0.34 (0.06, 0.61) Popova V, et al. Am J Psychiatry. 2019;176(6):428-438. Dosing Schedule for Intranasal Esketamine Spray Nasal Spray Device Indicator Induction One device contains 2 sprays. Weeks 1–4 Dosage Tip (1 spray for each nostril) Phase 2 green dots (0 mg delivered) Administer Day 1 starting: 56 mg Nose rest twice per Subsequent Doses: 56 mg week or 84 mg Device full Indicator Maintenance 1 green Weeks 5–8 Finger rest dot Phase 1 spray Administer 56 mg or 84 mg delivered once weekly Weeks 9+ No green dots Plunger Administer 56 mg or 84 mg 2sprays (28mg) delivered every 2 Device empty weeks or Each device delivers 2 sprays containing a total of once weekly 28 mg of esketamine. US Food and Drug Administration. Drugs@FDA: FDA Approved Drug Products. www.accessdata.fda.gov/scripts/cder/daf/. Phase 3 Esketamine Maintenance Trial Time to Relapse for Patients in Stable Remission SUSTAIN-I Study Design Esketamine Nasal Spray + Oral AD (N=705) 16 weeks Esketamine Stable Remitters & Stable Responders (N=297, 42%) Esketamine Placebo Esketamine Arm Arm Weeks Risk of relapse 26.7% for esketamine vs 45.3% for PBO (P=.003) The median number of days to relapse in stable remitters who received placebo was 273 days. The hazard ratio (95% CI) of esketamine + oral AD relative to placebo nasal spray + oral AD was 0.49 (95% CI: 0.29, 0.84). Daly EJ, et al. JAMA Psychiatry. 2019 Jun 5; [Epub ahead of print]. Esketamine Side Effects • Warnings and Precautions – Sedation: 49% to 61% – Dissociation: 61% to 75% – Abuse and misuse (Schedule III controlled substance) – Suicidal thoughts and behaviors – Increase in blood pressure – Cognitive impairment – Impaired ability to drive and operate machinery – Ulcerative or interstitial cystitis – Embryo-fetal toxicity • Contraindications – Aneurysmal vascular disease or arteriovenous malformation – History of intracerebral hemorrhage US Food and Drug Administration. Drugs@FDA: FDA Approved Drug Products. www.accessdata.fda.gov/scripts/cder/daf/. Adverse Reactions Occurring in ≥ 2% of Patients with TRD Esketamine + Oral AD Placebo + Oral AD N=346 N=222 Tachycardia 6 (2%) 1 (0.5%) Vertigo 78 (23%) 6 (3%) Constipation 11 (3%) 3 (1%) Diarrhea 23 (7%) 13 (6%) Dry mouth 19 (5%) 7 (3%) Nausea 98 (28%) 19 (9%) Vomiting 32 (9%) 4 (2%) Feeling abnormal 12 (3%) 0 (0%) Feeling drunk 19 (5%) 1 (0.5%) Blood pressure increased 36 (10%) 6 (3%) Dizziness 101 (29%) 17 (8%) Dysarthria 15 (4%) 0 (0%) Dysgeusia 66 (19%) 30 (14%) Headache 70 (20%) 38 (17%) Hypoesthesia 63 (18%) 5 (2%) Lethargy 37 (11%) 2 (1%) Mental impairment 11 (3%) 2 (1%) Sedation 79 (23%) 21 (9%) Tremor 12 (3%) 2 (1%) Anxiety 45 (13%) 14 (6%) Dissociation 142 (41%) 21 (9%) Euphoric mood 15 (4%) 2 (1%) Insomnia 29 (8%) 16 (7%) Pollakiuria 11 (3%) 1 (0.5%) Nasal discomfort 23 (7%) 11 (5%) Oropharyngeal pain 9 (3%) 5 (2%) Throat irritation 23 (7%) 9 (4%) Hyperhidrosis 14 (4%) 5 (2%) US Food and Drug Administration. Drugs@FDA: FDA Approved Drug Products. www.accessdata.fda.gov/scripts/cder/daf/. Dissociative Side Effects over Time CADSS > 4 threshold Popova V, et al. Am J Psychiatry. 2019;176(6):428-438. Increases in Blood Pressure Patients < 65 years Patients ≥ 65 years Esketamine + Esketamine + Placebo + Oral AD Placebo + Oral AD Oral AD Oral AD N=346 N=222 N=72 N=65 Systolic Blood Pressure ≥ 180 mmHG 9 (3%) – 2 (3%) 1 (2%) ≥ 40 mmHG increase 29 (8%) 1 (0.5%) 12 (17%) 1 (2%) Diastolic Blood Pressure ≥ 110 mmHG 13 (4%) 1 (0.5%) – – ≥ 25 mmHG increase 46 (13%) 6 (3%) 10 (14%) 2 (3%) US Food and Drug Administration.
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