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Ketamine in Psychiatric Practice: Taking the Long-Term View

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Ketamine in Psychiatric Practice: Taking the Long-Term View Ketamine in Psychiatric Practice: Taking the Long-Term View Sanjay J. Mathew, MD Professor of Psychiatry & Behavioral Sciences Johnson Family Chair for Research in Psychiatry Menninger Department of Psychiatry & Behavioral Sciences Baylor College of Medicine Staff Physician, Michael E. Debakey VA Medical Center Houston, Texas 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. Outline of Talk • Background on Ketamine • Update on Recent Clinical Trials – Treatment-Resistant Depression – Suicidal Ideation and Behavior – Anxiety and PTSD • Ketamine in Clinical Practice • Relapse prevention and maintenance approaches • The Future I. Background on Ketamine Ketamine: History • Synthesized in 1962 by an industry chemist seeking alternative anesthetic to PCP • FDA approved for human use since 1970 – “…the sole anesthetic agent for diagnostic and surgical procedures that do not require skeletal muscle relaxation.” – “…the induction of anesthesia prior to the administration of other general anesthetic agents.” – “…to supplement low-potency agents, such as nitrous oxide.” • DEA Schedule III agent PCP = phencyclidine; DEA = US Drug Enforcement Agency. Ketamine is an NMDA Receptor Channel Blocker NMDA = N-methyl-D-aspartate Duman RS. F1000Res. 2018;7. Iacobucci GJ, et al. Nat Rev Neurosci. 2017;18(4):236-249. R- and S-Ketamine Pathways and HNK Metabolite 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 NMDA-R) NH2 NH NH 2 O O O OH (R)-Ketamine (R)-Norketamine (2R,6R)-HNK (1.40 μM) (13 μM) (> 10 μM) HNK = hydroxynorketamine. Zanos P, et al. Nature. 2016;533(7604):481-486. Comparison of Ketamine Administration Routes Intravenous Intramuscular Intranasal Oral Onset of Action 30 sec 3–4 min 10 min 30 min Duration 5–10 min 12–25 min 60 min 4–12 hr Time to Peak - 5–30 min 10–14 min 30 min Bioavailability 100% 93% 35%–50% 20%–30% Excretion Urine 91%, feces 3% Metabolism Hepatic (2B6, 2C9, 3A4) Half-life Alpha 10–15 min, Beta 2.5 hrs Lexicomp Online®. Hudson, Ohio: Lexi-Comp, Inc.; March 2, 2018. Ketamine for Depression: Studies by Route of Administration No. of No. of No. of Patients Patients Published Receiving Receiving Studies Multiple Ketamine Doses Intravenous 49 737 214 Oral 6 72 66 Intramuscular 3 7 7 Subcutaneous 4 25 25 Intranasal 2 18 1 Sublingual 1 26 26 Transmucosal 1 17 17 TOTAL 902 356 Short B, et al. Lancet Psychiatry. 2018;5(1):65-78. II. Update on Recent Clinical Trials Treatment-Resistant Depression Single Dose Ketamine Infusion Trials in TRD Ketamine (0.5 mg/kg over 40 minutes) Rapidly Ketamine Superior to Psychoactive Control: Effective vs Saline Placebo: Replication Study (N=17) Baylor/Mt Sinai NIMH funded Study (N=72) Ketamine dose = .5 mg/kg TRD = treatment-resistant depression; HAMD = Hamilton Rating Scale for Depression. 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 Meta-Analytic Efficacy in TRD At 1 day At 1 week N=147. Newport DJ, et al. Am J Psychiatry. 2015;172(10):950-966. Double-Blind, Placebo-Controlled, Dose-Ranging Trial of IV Ketamine as Adjunctive Therapy in TRD SCREEN RANDOMIZE DAY Ketamine Ketamine Ketamine Ketamine Midazolam 0 0.1 mg/kg 0.2 mg/kg 0.5 mg/kg 1.0 mg/kg 0.045mg/kg n=18 n=20 n=22 n=20 n=19 DAY PRIMARY ENDPOINT ASSESSMENTS 3 DAY 30 STUDY COMPLETION NIMH RAPID Trial, N=99. Fava M, et al. Mol Psychiatry. 2018; In Press. RAPID Trial: IV Ketamine Dose-Response A. 2-Group Comparison B. 5-Group Comparison Fava M, et al. Mol Psychiatry. 2018; In Press. RAPID Trial: Time Course over 30 Days Fava M, et al. Mol Psychiatry. 2018; In Press. RAPID Trial: Dose-Related Dissociative Side Effects CADSS 25 20 15 CADSS 10 5 0 0 25 50 75 100 125 Minute ketamine 0.1 mg/kg ketamine 0.2 mg/kg ketamine 0.5 mg/kg ketamine 1.0 mg/kg midazolam 0.045 mg CADSS = Clinician-Administered Dissociative States Scale. Fava M, et al. Mol Psychiatry. 2018; In Press. Phase 2 Trial of Adjunctive Intranasal Esketamine in TRD N=67. Daly EJ, et al. JAMA Psychiatry. 2018;75(2):139-148. Thrice-Weekly Ketamine Infusions in TRD Response rate = 71%; 18 days until relapse N=24. Murrough JW, et al. Biol Psychiatry. 2013;74(4):250-256. Multi-Infusion Ketamine Trials in TRD Thrice-Weekly Ketamine Infusions in TRD: Twice-Weekly Dosing as Effective as Minneapolis VA Sample (N=14) Thrice-Weekly Dosing in TRD (N=67) Ketamine: 69% responded 38% remitted PBO: 15% responded 7.7% remitted Ketamine: 54% responded 23% remitted PBO: 6% responded 0% remitted Shiroma PR, et al. J Affect Disord. 2014;155:123-129. Singh JB, et al. Am J Psychiatry. 2016;173(8):816-826. First Placebo-Controlled Randomized Trial of Oral Ketamine as Adjunct to SSRI in MDD • Primary outcome: Change in HDRS at 2 weeks – Early improvement in 85.4% vs Oral ketamine dose = 25 mg BID 42.5% in sertraline + placebo group • Response rate at Week 6 – sertraline + ketamine 85.4% – sertraline + placebo 57.5% • No difference in remission at Week 6 (22% vs 15%) N=90. HDRS = Hamilton Rating Scale for Depression; SSRI = selective serotonin reuptake inhibitor; MDD = major depressive disorder. Arabzadeh S, et al. J Affect Disord. 2018;235:236-241. Suicidal Ideation and Behavior Ketamine and Suicidal Ideation: Individual Patient Meta-Analysis *p<0.05. **p<0.01. ***p<0.001. Wilkinson ST, et al. Am J Psychiatry. 2018;175(2):150-158. IV Ketamine for Rapid Reduction of Suicidal Thoughts in MDD Day 1 (24 hours postinfusion): Ketamine: 55% response; Midazolam: 30% response SSI = Scale for Suicidal Ideation. Grunebaum MF, et al. Am J Psychiatry. 2018;175(4):327-335. Intranasal Esketamine and Suicide Risk in MDD: Proof-of-Concept Trial 25 Canuso CM, et al. Am J Psychiatry. 2018 Apr 16;[Epub ahead of print]. Intranasal Esketamine and Suicide Risk in MDD: Proof-of-Concept Trial Proportion of patients achieving resolution of suicide risk (CGI-SR Score 0 or 1) at Day 1 (4 hours postdose) and Day 2 CGI-SR = Clinical Global Impression – Suicide Risk. (~24 hours postdose) LOCF Canuso CM, et al. Am J Psychiatry. 2018 Apr 16;[Epub ahead of print]. Summary: Ketamine for Suicidal Ideation and Behavior • Ketamine’s rapid effects on suicidal ideation may be independent of its impact on depression • Intranasal Esketamine granted Breakthrough Therapy Designation from FDA for MDD “with imminent risk for suicide” • More data needed on longer term outcomes and prevention of suicide attempts Anxiety Disorders and PTSD Ketamine for Social Anxiety Disorder • Significant reduction in social phobia symptoms on the LSAS, but not on the VAS (N=18) • Significant carryover effects observed in patients who received ketamine first, even with a washout period of 4 weeks LSAS = Liebowitz Social Anxiety Scale; VAS = visual analog scale. Taylor JH, et al. Neuropsychopharmacology. 2018;43(2):325-333. Subcutaneous Ketamine in Treatment-Refractory Anxiety • Single ascending dose, administered subcutaneously in weekly intervals • 0.25 mg/kg, 0.50 mg/kg, 1.0 mg/kg • 10 of 12 patients (83%) reported > 50% reduction in HAM-A and/or FQ scales after the 0.5 or 1 mg/kg doses • Only minor changes were noted at 0.25 mg/kg dose N=12. HAM-A = Hamilton Rating Scale for Anxiety; FQ = Fear Questionnaire. Glue P, et al. J Psychopharmacol. 2017;31(10):1302-1305. 3 Months of Weekly Maintenance Ketamine for Treatment-Refractory GAD and SAD N=20, open-label study Dose: 1 mg/kg subcutaneous injection 1–2 treatments/week GAD = generalized anxiety disorder; SAD = social anxiety disorder. Glue P, et al. J Psychopharmacol. 2018 Mar 1;[Epub ahead of print]. Repeated IV Ketamine in PTSD and TRD 41 days 20 days N=15. PTSD = posttraumatic stress disorder. Albott CS, et al. J Clin Psychiatry. 2018;79(3). III. Ketamine in Clinical Practice Rapid Growth in Ketamine Providers over the Past Decade *February 2018— > 140 ketamine providers in ≈30 states Most common off-label indications— MDD (72%), bipolar (15%), PTSD (6%) Wilkinson ST, et al. Am J Psychiatry. 2017;174(7):695-696. “While ketamine may be beneficial to some patients with mood disorders, it is important to consider the limitations of the available data and the potential risk associated with the drug when considering the treatment option.” . Sanacora G, et al. JAMA Psychiatry. 2017;74(4):399-405. Consensus Statement • Patient Selection • Informed consent process • Clinician experience and training • Treatment delivery • Post-infusion monitoring and discharge • Safety Measures and Continuation of Treatment Sanacora G, et al. JAMA Psychiatry. 2017;74(4):399-405. VA National Protocol Guidance (December 2017) Inclusion Criteria Exclusion Criteria • Current diagnosis of Unipolar MDD by • Current or past history of schizophrenia, DSM-5 schizoaffective disorder, or bipolar • Patient has failed to achieve full response to disorder 2 adequate therapeutic trials of • Dementia antidepressants, including augmentation when appropriate or psychotherapy • Current or recent (within 7 days) delirium • Psychiatrist evaluated patient and • Current Uncontrolled hypertension (SBP documented qualification for ketamine > 160 mmHg or DBP > 90 mmHg) treatment • Severe cardiac decompensation • PHQ-9 score of ≥ 15 (moderate or severe) • Pregnant or lack of birth control in women • Patient or legal representative able to of childbearing age provide verbal informed consent • Positive UDS or current or previous • Patient has transportation and an adult to abuse of ketamine accompany them arranged and • Allergy or previous serious adverse documented effects to ketamine PHQ-9 = Patient Health Questionnaire; SBP = systolic blood pressure; DBP = diastolic blood pressure; UDS = urine drug screen.
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