Top 5 Issues Clinicians Should Know about 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 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.

#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 , for the treatment of TRD in adults

TRD: In the current episode, patient has not responded adequately to at least 2 different 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)- (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 discontinued Primary AD + 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. Drugs@FDA: FDA Approved Drug Products. www.accessdata.fda.gov/scripts/cder/daf/. Esketamine Risk Evaluation and Mitigation Strategy (REMS) • Controlled distribution for use only in certified health care settings

• Patient self-administration under direct observation of a health care provider

• Monitoring for least 2 hours after drug administration

• All patients must be enrolled in REMS Best Practices for Treatment Setting

• Private setting with minimal stimulation

• Means for patient to recline head at 45° during dosing

• Able to monitor cardiovascular function (EKG, blood pressure) and O2 saturation

• PRN – Nausea: ondansetron 8 mg SL or metoclopramide (10 mg po or IV or IM) – Agitation: short-acting benzodiazepine

US Food and Drug Administration. Drugs@FDA: FDA Approved Drug Products. www.accessdata.fda.gov/scripts/cder/daf/. #2: How to Prolong and Extend the Short-Lived Effect? Twice or Thrice-Weekly Ketamine Infusions in TRD

Response rate = 71%; 18 days until relapse

Murrough JW, et al. Biol Psychiatry. 2013;74(4):250-256. Singh JB, et al. Am J Psychiatry. 2016;173(8):816-826. Single, Repeated, and Maintenance IV Ketamine for TRD

Phillips JL, et al. Am J Psychiatry. 2019;176(5):401-409. SUSTAIN-2 Trial: Long-Term Efficacy Results

• 48-week open-label maintenance trial for patients responding to 4- week induction course of esketamine (N=802)

• Dosing frequency decreased from twice weekly during induction phase to weekly or every Day 28 Week 48 other week in the 48-week (N=688) (N=139) optimization/maintenance Response, n (%) 581 (84.4%) 124 (89.2%) phase Remission, n (%) 349 (50.7%) 95 (68.3%)

Janssen Research & Development, LLC. Advisory Committee Briefing Document. January 16, 2019. www.fda.gov/media/121377/download. Accessed July 1, 2019. Riluzole Not Effective in Preventing Relapse after IV Ketamine • 2 negative placebo-controlled studies for relapse prevention following IV ketamine

n=21 n=21

HAM-D = Hamilton Rating Scale for Depression. Mathew SJ, et al. Int J Neuropsychopharmacol. 2010;13(1):71-82. Ibrahim L, et al. Neuropsychopharmacology. 2012;37(6):1526-1533. Continuation Therapy following IV Ketamine in TRD

Mean lithium level at endpoint = 0.61 mEq/L (SD = 0.19). Costi S, et al. Neuropsychopharmacology. 2019 Mar 11; [Epub ahead of print]. Cognitive-Behavioral Therapy following IV Ketamine

CBT = cognitive-behavioral therapy; YBOCS = Yale–Brown Obsessive Compulsive Scale. Wilkinson ST, et al. Psychother Psychosom. 2017;86(3):162-167. Rodriguez CI, et al. J Clin Psychiatry. 2016;77(3):408-409. Interleaved Administration of IV Ketamine and ECT

• Standard ECT 3×/week • 2 ketamine (or placebo) infusions/week

ECT = electroconvulsive therapy. Altinay M, et al. Psychopharmacol Bull. 2019;49(1):8-16. #3: How Does Ketamine Compare to Current (and Potential Future) Therapies in TRD? Current Options for Difficult-to-Treat Depression

• ECT • Repetitive transcranial magnetic stimulation (rTMS) • Vagal nerve stimulation • / combination (FDA-approved) • Adjunctive treatment (FDA-approved) – – (XR) – • Augmentation (off-label) – Lithium – Thyroid (T3 or T4) – Ziprasidone MADRS CFB for Recent Approved Antidepressants MADRS LS Mean MADRS LS Mean Baseline MADRS Indication Antidepressant CFB at Primary Endpoint CFB Difference from Score Range Placebo/Active Control MDD -13 to -20 -2.8 to -7.1 31 to 34

Vilazodone -9.7 to -13 -2.5 to -3.2 31 to 32

Levomilnacipran -14 to -17 -1.3 to -4.9 30 to 36 Adjunctive MDD Aripiprazole -8.5 to -8.8 -2.8 to -3.0 31 to 32 Brexpiprazole -7.7 to -8.5 -1.3 to -3.1 33 to 35

Quetiapine XR -14 to -17 -1.6 to -4.1 28 to 32

Olanzapine + TRD Fluoxetine (fixed-dose -8.6 to -14 n/a 23 to 30 combination)

Fluoxetine (vs Olanzapine + -1.2 to -11 -1.4 to -12 “ Fluoxetine)

Olanzapine (vs -2.8 to -10 -0.8 to -11 Olanzapine + Fluoxetine) “

37 to 38 adult, Esketamine -10.1 to -20.8 -3.2 to -4.1 35 geriatric CFB = change from baseline. Janssen Research & Development, LLC. Advisory Committee Briefing Document. January 16, 2019. www.fda.gov/media/121377/download. Accessed July 1, 2019. TRD Patient Referred for ECT

ECT vs Ketamine in Patients with TRD Patient Screened Treatment-Resistant Depression N=600–800

Randomize N=400 Treatment Phase Acute Treatment Responders Follow-up Phase

ECT Arm; 9 Treatments N=200 (3×/week)

1 3 6 18 Days Month Months Months

Ketamine Arm; 6 Treatments N=200 (2×/week)

Projected Attrition 20% QIDS-SR = Quick Inventory of Depressive Symptomatology (Self-Report). Primary Efficacy ClinicalTrials.gov Identifier: NCT03113968. Endpoint (QIDS-SR) AXS-05 ( + ): Change in MADRS Total Score 0

-2 AXS-05 Bupropion

-4

-6

Score -8 Baseline -10 P=.169

Total Total -12 from -14

-16 P=.024 MADRS MADRS -18 P=.003 Change -20 P=.007 P=.013 -22 Baseline 1 2 3 4 5 6 Week AXS-05 Bupropion P-Value Primary Endpoint Change in MADRS Total Score over 6-week Period (averaged) -13.7 -8.8 <.001 Change in MADRS Total Score at Week 6 -17.2 -12.1 .013 Gorman C, et al. AXS-05: A Mechanistically Novel Oral Therapeutic in Development for Neuropsychiatric Disorders. Presented at: American Psychiatric Association Annual Meeting; May 18–22, 2019; San Francisco, CA. Rapastinel: Phase 2a Single-Dose Study

0

Placebo -5 from

17 GLYX-13: - 1 mg/kg -10 5 mg/kg HDRS

Baseline 10 * mg/kg

Difference -15 * 30 mg/kg

0 1 3 7 14 Day after Dosing

Effect sizes: DUBLIN, March 6, 2019 /PRNewswire/ -- Allergan plc (NYSE: AGN) today announced topline results from three pivotal studies of rapastinel as an 5 mg/kg dose = 0.41–0.49 adjunctive treatment of Major Depressive Disorder (MDD). In three acute 10 mg/kg dose = 0.43–0.58 studies (RAP-MD-01, -02, -03), the rapastinel treatment arms did not . differentiate from placebo on the primary and key secondary endpoints. In addition, an interim analysis of the rapastinel relapse prevention study (RAP- MD-04) suggests the primary and key secondary endpoints will not be met. HDRS-17 = 17-item Hamilton Rating Scale for Depression. Preskorn S, et al. J Psychiatr Pract. 2015;21(2):140-149. #4: Ketamine’s Antidepressant Mechanism of Action is Complex (and the Story Continues to Evolve) Depression ≠ Simple “Chemical Imbalance” of Serotonin

• Glutamate and Cortico-Limbic Circuits – Glutamate  Main information thoroughfare of the brain

– Impairments in neuroplasticity (ability to grow and change)

– Impairments in synaptic connectivity

Adapted from: Krystal JH, et al. Neuron. 2019;101(5):774-778. Ketamine is an NMDA Receptor Channel Blocker

Role of NMDA Receptor: “To sense the simultaneous presence of glutamate and a range of other (chemical, metabolic, physical) cues and to respond by gating a Ca2+ rich cationic current that integrates and reflects this information”

Ketamine binds to the PCP site within the ionotropic channel pore

NMDA = N-methyl-D-aspartate. Duman RS. F1000Res. 2018;7. Iacobucci GJ, et al. Nat Rev Neurosci. 2017;18(4):236-249. Proposed Antidepressant Mechanism of Action of Ketamine (Simple Version)

“GO” pathway

“Stop” pathway

Murrough JW, et al. Nat Rev Drug Discov. 2017;16(7):472-486. Proposed Mechanisms of Ketamine Action as an Antidepressant (Complex Version)

Zanos P, et al. Mol Psychiatry. 2018;23(4):801-811. Prefrontal Spinogenesis is Required for Sustaining, But Not Inducing, Ketamine’s Effects on Behavior and Circuit Function

Moda-Sava RN, et al. Science. 2019;364(6436). Opioid Receptor Antagonism Attenuates Antidepressant Effects of Ketamine • 12 patients with TRD received 2 ketamine infusions (0.5 mg/kg), separated by about 30 days

• Pretreatment with naltrexone (50 mg) or placebo (45 minutes pre-ketamine)

• 24-hour post ketamine—significant differences in HAM-D reduction – Nal+ KET: ⬇ 5.6 pts (0/7 remission) – PBO+ KET: 22.3 pts (5/7 remission) ⇓ ⬇ ⇓ • No significant differences in acute dissociative response

Williams NR, et al. Am J Psychiatry. 2018;175(12):1205-1215. Are ketamine clinics “nothing more than modern opium dens”? Counterevidence • Williams et al. study limitations – Nocebo effects? (58% nausea in naltrexone group vs 25% placebo) – Lack of control arms (oral placebo + IV saline; naltrexone + IV saline) – Small subsample • No typical signs or symptoms associated with μ-agonism (pupillary constriction, constipation, etc.) • SNP in OPRM1 (rs1799971), known to affect response to endogenous opioids, did not impact antidepressant response to esketamine in 2 short-term studies • Lack of MOR stimulation at clinically used ketamine/esketamine doses – Binding affinities were 10- to 20-fold weaker at MORs than at NMDARs

MOR = mu opioid receptor; SNP = single nucleotide polymorphism. George MS. Am J Psychiatry. 2018;175(12):1157-1158. Zanos P, et al. Pharmacol Rev. 2018;70(3):621-660. Hibar D, et al. Effect of Mu Opiate Receptor Gene Polymorphism, rs1799971 (A118G), on the Perceptual and Antidepressant Actions of Esketamine and Placebo. Presented at: American College of Neuropharmacology Annual Meeting; December 9–13, 2018; Hollywood, Fl. However, Naltrexone Injection May Not Blunt Antidepressant Response to IV Ketamine in MDD/AUD

AUD = use disorder. Yoon G, et al. JAMA Psychiatry. 2019 Jan 9; [Epub ahead of print]. #5: Where is More Data Needed?

Other Routes of Administration Dose Late-life Depression Clinical Predictors of Effectiveness Long-term Safety Titrated Subcutaneous Ketamine in Older Patients with TRD

Mean age = 65.6 (5.7) George D, et al. Am J Geriatr Psychiatry. 2017;25(11):1199-1209. NIMH RAPID Trial Confirms Rapid Antidepressant Efficacy of 0.5 mg/kg and Shows New Evidence of Efficacy of 1.0 mg/kg Dose

1 mg/kg

midazolam 0.5 mg/kg 0.2 mg/kg

0.1 mg/kg

1 mg/kg 0.5 mg/kg

RR = response rate. RR at Day 1: KET: 31%, 21%, 59%, 53% MID: 11% Fava M, et al. Mol Psychiatry. 2018 Oct 3; [Epub ahead of print]. RR at Day 3: KET: 47%, 37%, 57%, 37% MID: 33% Esketamine Nasal Spray Trial in Patients with TRD > 65 Years

LS Mean Baseline LS Mean Change Difference 1-Sided MADRS Treatment Arm N from Baseline from Placebo P-value Total Score (95% CI) at Week 4 (95% CI) at <.025 (SD) Week 4

Placebo + Oral AD 65 34.8 (6.4) -6.5 (-9.4 to -3.6) -- -- -3.6 (-7.2 to .029 Esketamine + Oral AD 72 35.5 (5.9) -10.1 (-13.1 to -7.1) 0.07)

Janssen Research & Development, LLC. Advisory Committee Briefing Document. January 16, 2019. www.fda.gov/media/121377/download. Accessed July 1, 2019. Ochs-Ross R, et al. Efficacy and safety of esketamine nasal spray plus an oral antidepressant in elderly patients with treatment-resistant depression. Presented at: American Society of Clinical Psychopharmacology Annual Meeting; May 29–June 1, 2018; Miami Beach, FL. Esketamine Patient Subgroups and Pharmacokinetics

65–74 Age Group

≥ 75 Age Group

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. Differential Efficacy in Males?

NIMH RAPID Trial of IV Ketamine in TRD Janssen Research & Development, LLC. Advisory Committee Briefing Document. January 16, 2019. www.fda.gov/media/121377/download. Accessed July 1, 2019. Freeman MP, et al. J Psychiatr Res. 2019;110:166-171. Clinical Predictors or Mediators of Efficacy

• Anhedonia (+)

• Family history of AUD (+)

• Early, rapid response (+)

• Dissociative side effects (+/-)

• Early infusion-related anxiety (-)

• Hopelessness (-)

5D-ASC = 5-Dimensional Altered States of Consciousness. Thomas RK, et al. J Psychopharmacol. 2018;32(10):1110-1117. Niciu MJ, et al. J Affect Disord. 2018;232:310-315. Aust S, et al. Eur Neuropsychopharmacol. 2019;29(4):529-538. High Baseline Anxiety Did Not Impact Antidepressant Response to IV Ketamine in TRD • N=45 participants with anxious Day 1 TRD • N=54 participants without anxious TRD

• No statistically significant interaction effect between treatment group assignment Day 3 and anxious/nonanxious status on HAM-D-6 score

Salloum NC, et al. Depress Anxiety. 2019;36(3):235-243. Side Effects Associated with Ketamine Use in Depression: A Systematic Review • 288 published reports

• Acute side effects are generally transient and resolve spontaneously

• Insufficient data on side effects of repeated dosing and long-term risks – Urological – Hepatic – Craving/dependence – Cognitive

Short B, et al. Lancet Psychiatry. 2018;5(1):65-78. Conclusions

• We finally have an FDA-approved non-monoamine-based drug for depression

• Unmet needs include preventing relapse following acute response, treating elderly patients, and identifying response predictors

• The effectiveness and safety/tolerability of esketamine in real world clinical practice awaits further study

• Understanding the mechanism of action of ketamine and esketamine is critical for future antidepressant and anxiolytic drug development