and Other Putative Rapid-Acting Medications: What Have They Taught Us about Neurobiology

Gerard Sanacora, MD, PhD George D. Gross and Esther S. Gross Professor of Psychiatry Yale University School of Medicine Director, Yale Depression Research Program Co-Director, Yale New Haven Hospital Interventional Psychiatry Service New Haven, Connecticut 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). – The off-label use of ketamine, , hydroxynorketamine, and D- cylcoserine for the treatment of depression will be discussed.

• Applicable CME staff have no relationships to disclose relating to the subject matter of this activity. • This activity has been independently reviewed for balance. Overview

• Discuss the History underlying the development of Ketamine

• Cover the range and evolution of thoughts related to ketamine’s mechanism(s) of antidepressant action

• Consider the implications for clinical use of the drug and future drug development Motivating the Development of Novel Antidepressant Treatments • Growing awareness that Depression is a major contributor to the overall global burden of disease • Failure to show improvement in rates of death by Suicide • Increased awareness of high rates of non-response and treatment-resistant depression • Lag times of several weeks to months prior to meaningful clinical change with existing Understanding the Pathogenic and Pathophysiological Processes Underlying Mood Disorders Understanding the Cellular Pathophysiology Underlying Mood Disorders Altered Excitatory (glutamate) and Inhibitory Cortisol (GABA) Neurotransmission Altered 5-HT/NE/DA Function

Altered Neurotrophic Factor Function Inflammatory BDNF, etc… Cytokines

A Gene Expression M BDNF = brain-derived neurotrophic factor; GABA = gamma-aminobutyric acid; 5-HT = serotonin; NE = norepinephrine. Sanacora G. J Clin Psychiatry. 2008;69 Suppl 5:22-27. Sapolsky RM. Biol Psychiatry. 2000;48(8):755-765. Moghaddam B. Biol Psychiatry. 2002;51(10):775-787. Virgin CE Jr, et al. J Neurochem. 1991;57(4):1422-1428. Structural Neuroimaging Studies in MDD Show Evidence of Volume Reductions

Drevets WC, et al. Nature. 1997;386(6627):824-827.

Normal Depression Bremner JD, et al. Am J Psychiatry. 2000;157(1):115-118. Sheline YI, et al. Am J Psychiatry. 2003;160(8):1516-1518.

MDD = major depressive disorder. Glial Density and Number are Reduced in the Brains of Patients with Depression Anterior Cingulate Cortex

Glial (GFAP) Immunoreactivity in the Prefrontal Cortex Control (27 years old) MDD (32 years old)

Control Bipolar MDD Cotter D, et al. Arch Gen Psychiatry. 2001;58(6):545-553. Miguel-Hidalgo JJ, et al. J Affect Disord. 2010;127(1-3):230-240. Miguel-Hidalgo JJ, et al. J Psychiatr Res. 2003;37(5):411-420. Miguel-Hidalgo JJ, et al. Biol Psychiatry. 2002;52(12):1121-1133. Miguel-Hidalgo JJ, et al. Biol Psychiatry. 2000;48(8):861-873. GFAP = glial fibrillary acidic protein. Rajkowska G, et al. CNS Neurol Disord Drug Targets. 2007;6(3):219-233. Rajkowska G, et al. Biol Psychiatry. 1999;45(9):1085-1098. Ongür D, et al. Proc Natl Acad Sci U S A. 1998;95(22):13290-13295. Si X, et al. Neuropsychopharmacology. 2004;29(11):2088-2096. Altshuler LL, et al. Bipolar Disord. 2010;12(5):541-549. Gittins RA, et al. J Affect Disord. 2011;133(1-2):328-332. Occipital GABA Concentrations are Especially Decreased in Melancholic and/or TRD Subtype

Study Measure Field MDD Class Samples Effect Size

Sanacora G, et al. Arch 2.1 T Primarily inpatient, 14 MDD vs Gen Psychiatry. GABA/Cr d=2.28 [1.42–3.25] 57% TRD 18 HV 1999;56(11):1043-1047. Sanacora G, et al. Arch GABA/Cr Primarily outpatient, 33 MDD vs Gen Psychiatry. 2.1 T d=.64 [.13–1.08] 24% TRD 38 HV 2004;61(7):705-713. Bhagwagar Z, et al. Int J GABA/Cr Fully remitted, 15 MDD vs Neuropsychopharmacol. 3 T d= .89 [.14–1.58] recurrent 18 HV 2008;11(2):255-260. Price RB, et al. Biol Outpatient, Psychiatry. 15 TRD vs GABA/H2O 3 T categorized as TRD d=1.32 [.59 –2.01] 2009;65(9):792-800. 24 HV or nTRD by ATHF

Gabbay V, et al. Arch Gen 20 MDD vs Med-free depressed Psychiatry. GABA/H2O 3 T 21 HV adolescents 2012;69(2):139-149. adolescents

TRD = treatment-resistant depression; HV = healthy volunteer; nTRD = nontreatment-resistant MDD. Amino Acid Neurotransmitter Metabolism: A Tightly Coupled System

Chowdhury GM, et al. Biol Psychiatry. 2012;71(11):1022-1025. GABA and Glutamate Levels in Patients with MDD

Sanacora G, et al. Arch Gen Psychiatry. 2004;61(7):705-713. 13C-MRS Demonstrates Abnormal Glutamate Metabolism in Patients with MDD

13 13 C-MRS = C-magnetic resonance spectroscopy; VTCAN = neuronal tricarboxylic acid cycle. Abdallah CG, et al. Am J Psychiatry. 2014;171(12):1320-1327. Modulation of Glutamate Release

Altered Trafficking Altered Glutamate Clearance

Popoli M, et al. Nat Rev Neurosci. 2011;13(1):22-37. Using Ketamine to Target the System in the Pursuit of Novel Antidepressant Treatments Potential Glutamate Targets

a. Glutamate release

b. Group II and III mGluRs

c. Group I mGluRs

d. NMDARs

e. AMPARs

f. Glucocorticoid receptors

g. Excitatory amino acid transporters and exchangers

h. Endocannabinoid receptors

mGluR = metabotropic glutamate receptor; NMDAR = N-methyl-D-aspartate receptor; AMPAR = α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor. Popoli M, et al. Nat Rev Neurosci. 2011;13(1):22-37. Trullas R, et al. Eur J Pharmacol. 1990;185(1):1-10. Adaptive Changes in the NMDA Receptor Complex after Chronic Treatment with and 1-aminocyclopropanecarboxylic Acid

Abstract Chronic (14 daily injections) treatment of mice with the prototypic antidepressant imipramine significantly alters ligand binding to the N-methyl-D-aspartate (NMDA) receptor complex. These effects were compared to a chronic regimen of 1-aminocyclopropanecarboxylic acid, a high-affinity partial agonist at strychnine-insensitive receptors which mimics the effects of imipramine in preclinical models predictive of antidepressant action. Changes in the NMDA receptor complex after chronic, but not acute treatment with imipramine were manifested as: 1) a reduction in the potency of glycine to inhibit [3H]5,7- dichlorokynurenic acid binding to strychnine-insensitive glycine receptors; 2) a decrease in the proportion of high-affinity glycine sites inhibiting [3H]CGP 39653 binding to NMDA receptors; and 3) a decrease in basal [3H]MK-801 binding (under nonequilibrium conditions) to sites within NMDA receptor-coupled cation channels which was reversible by the addition of glutamate. These effects were observed in cerebral cortex, but not in hippocampus, striatum or basal forebrain. Chronic treatment with 1-aminocyclopropanecarboxylic acid resulted in changes which paralleled those of imipramine on ligand binding to the NMDA receptor complex, but the reduction in basal [3H]MK-801 binding did not achieve statistical significance. These findings indicate that adaptive changes in the NMDA receptor complex could be a feature common to chronic treatment with structurally unrelated antidepressants.

Nowak G, et al. J Pharmacol Exp Ther. 1993;265(3):1380-1386. Antidepressants for the New Millennium

Despite a remarkable structural diversity, most conventional antidepressants may be viewed as ‘monoamine based’, increasing the synaptic availability of serotonin, norepinephrine, and/or dopamine. Both preclinical and recent clinical studies indicate that compounds which reduce transmission at N- methyl-D-aspartate (NMDA) receptors are antidepressant. Moreover, chronic administration of antidepressants to mice alters both the mRNA levels encoding N-methyl-D-aspartate receptor subunits and radioligand binding to these receptors within circumscribed areas of the central nervous system. It is hypothesized that these two different treatment strategies converge to produce an identical functional endpoint: a region-specific dampening of NMDA receptor function. The pathways leading to this convergence provide a rudimentary framework for discovering novel antidepressants.

Skolnick P. Eur J Pharmacol. 1999;375(1-3):31-40. Cognition Perception Anxiety

Krystal JH, et al. Arch Gen Psychiatry. 1994;51(3):199-214. Antidepressant Actions of Ketamine

Ketamine Treatment (0.5 μg/kg Single Infusion) 5 Placebo Treatment

0

-5

-10 HDRS/ Depression Severity Depression HDRS/ Δ -15

Mean Mean 0 60 120 180 240 24 48 72 Time (Min) Time (Hour) Ketamine treatment was a 0.5 mg/kg single infusion. HDRS = Hamilton Rating Scale for Depression. Berman RM, et al. Biol Psychiatry. 2000;47(4):351-354. Ketamine Produces an Acute Antidepressant Response in Unipolar Depression

Zarate CA Jr, et al. Arch Gen Psychiatry. 2006;63(8):856-864. Never a Truly “New Idea”

Khorramzadeh E, et al. Psychosomatics. 1973;14(6):344-346. Sofia RD, et al. Arch Int Pharmacodyn Ther. 1975;214(1):68-74. Antidepressant Effects of Glutamatergic Drugs

DCS Treatment “It is difficult to explain why n=18 psychiatric benefits should have 100% occurred almost immediately n=25 following drug administration…” n=14 75%

50% All Responses

Excluding Temporary Response 25%

0% Depression Insomnia Anorexia

DCS = D-cylcoserine. Crane GE. Compr Psychiatry. 1961;2(1):51-59. IV Ketamine: Efficacy in TRD

At 1 day

At 1 week

Newport DJ, et al. Am J Psychiatry. 2015;172(10):950-966. The Quest to Better Understand Ketamine’s Mechanism of Antidepressant Action Effects of NMDA Antagonists on Glutamate Neurotransmission GABA Neuron Glutamate Neuron Toxicity Desensitization

Metabotropic Glutamate Receptors

EAATs Glutamate NMDA Receptor Glutamine Na+ channel

EAAT = excitatory amino acid transporter. Glia The Role of AMPA in Generating the Antidepressant-Like Response

GABA Neuron

Glutamine NBQX

Glutamate

Glutamine

Maeng S, et al. Biol Psychiatry. 2008;63(4):349-352. Subanesthetic Doses of Ketamine Increase While Anesthetic Doses of Ketamine Decrease or Have No Effect on Extracellular Levels of Glutamate in the Prefrontal Cortex

*Significant differences as compared with saline-treated group. Moghaddam B, et al. J Neurosci. 1997;17(8):2921-2927. Dose-Response Effects of Ketamine on 2-DG Uptake in Rodents

Duncan GE, et al. Brain Res. 1998;787(2):181-190. Dose Dependence of Ketamine Effects

adjP≤.05 Dunnett test. Chowdhury GM, et al. Biol Psychiatry. 2012;71(11):1022-1025. Dose-Dependent Ketamine Effects on Cycling and Behavior

Chowdhury GM, et al. Mol Psychiatry. 2017;22(1):120-126. Time Course of Ketamine’s Effects on Cycling

Ketamine (30 mg/kg) 10, 30, and Ketamine (10 mg/kg) 24 hour 60 mins Post-Injection Time Response Post-Injection Time Response

{NS}

Chowdhury GM, et al. Mol Psychiatry. 2017;22(1):120-126. Double-Blind, Placebo-Controlled, Dose-Ranging Trial of Intravenous Ketamine as Adjunctive Therapy in TRD

Differences in HAM-D-6 Scores between Doses of Ketamine and Midazolam (Primary Outcome) Pairwise Comparisons of MADRS Changes between Ketamine Doses and Midazolam

Estimated Group Day MADRS Change Raw P Adj. P Cohen’s d Difference

2-Group Comparison Ketamine comb. 1

Ketamine comb. 3 -5.47 0.04 0.04 -0.60 5-Group Comparison ketamine 0.1 mg/kg 1 ketamine 0.2 mg/kg 1 ketamine 0.5 mg/kg 1 ketamine 1.0 mg/kg 1 ketamine 0.1 mg/kg 3 -5.15 0.16 0.33 -0.48 ketamine 0.2 mg/kg 3 -2.16 0.53 0.53 -0.20 ketamine 0.5 mg/kg 3 -9.85 0.00 0.02 -1.03 ketamine 1.0 mg/kg 3 -7.72 0.03 0.08 -0.70 RAPID Trial. MADRS = Montgomery–Åsberg Depression Rating Scale. Fava M, et al. Mol Psychiatry. 2018; In Press. mTOR = mammalian target of rapamycin. Li N, et al. Science. 2010;329(5994):959-964. Dose Dependence of Ketamine Effects

FST Phosphorylation

**P<.01, ANOVA. FST = forced swim test. Li N, et al. Science. 2010;329(5994):959-964. Ketamine Increases Dendritic Spine Density

Control

Ketamine

Liu RJ, Aghajanian GK. Proc Natl Acad Sci U S A. 2008;105(1):359-364. Li N, et al. Biol Psychiatry. 2011;69(8):754-761. Ketamine’s Effects on Plasticity and Behavior

GABA Neuron

Glutamate Neuron BDN Protein F Akt/ER K Synthesis

mTOR

ERK = extracellular-regulated kinase. Li N, et al. Science. 2010;329(5994):959-964. eEF2 = eukaryotic elongation factor 2. Autry AE, et al. Nature. 2011;475(7354):91-95. Monteggia LM, et al. Biol Psychiatry. 2013;73(12):1199-1203. Ketamine’s Effects on Plasticity and Behavior GABA Neuron

Glutamate

Neuron eEF- 2K Protein P Synthesis/

BDNF

Autry AE, et al. Nature. 2011;475(7354):91-95. Zanos P, et al. Nature. 2016;533(7604):481-486. NMDA Independent Effects of HNK

GABA Neuron

Glutamate Neuron BDN Protein F Akt/ER K Synthesis

mTOR

Ketamine HNK HNK = HydroxynorKetamine. Zanos P, et al. Nature. 2016;533(7604):481-486. Yang Y, et al. Nature. 2018;554(7692):317-322. Are Structural Changes in the Brain Important to the Mechanism of Drug Action?

Red = anterodorsal hippocampus; Blue = posterodorsal hippocampus; Green = subiculum/dentate gyrus; Yellow = ventral hippocampus.

Gass N, et al. Neuropsychopharmacology. 2014;39(4):895-906. Coman, et al. Unpublished Data. Abdallah CG, et al. Neuropsychopharmacology. 2017;42(6):1210-1219. Animal Studies Suggest Repeated Administration of Ketamine May Have Toxic Effects

Featherstone RE, et al. Neurobiol Dis. 2012;47(3):338-346. Schobel SA, et al. Neuron. 2013;78(1):81-93. Other Potential Mechanisms Monoaminergic Effects?

Fukumoto K, et al. Psychopharmacology. 2014;231(11):2291-2298. Yamamoto S, et al. Neuropsychopharmacology. 2013;38(13):2666-2674. Anti-inflammatory Effects ?

Dale O, et al. Anesth Analg. 2012;115(4):934-943. Opioid Effects?

Williams NR, et al. Am J Psychiatry. 2018 Aug 29;[Epub ahead of print]. Gupta A, et al. J Neurochem. 2011;119(2):294-302. Non-Specific Effects of the Treatment

• Hope

• Unique Psychological / Spiritual Experience

• Positive Social Interactions Compound, Pharmacology Sponsor Phase Route of Administration Ketamine, Non-selective, non-competitive NMDA receptor Multiple -- various antagonist Esketamine, Non-selective, non-competitive NMDA receptor Janssen III IN antagonist / AZD-6765, Low trapping NMDAR antagonist AstraZeneca / Biohaven IIb IV / CP-101,606, NMDAR antagonist at NR2B subunit Pfizer II IV EVT-101 NMDAR antagonist at NR2B subunit Evotec / La Roche II

Rislenemdaz / CERC-301 / MK-0657, NMDAR antagonist at NR2B subunit Cerecor II oral AVP-786, Non-selective antagonist of NMDAR Avanir / Otsuka II oral AXS-05, Non-selective antagonist of NMDAR Axsome III oral / GLYX-13, Partial functional agonist at glycine site of NMDA Allergan III IV receptor

Apimostinel / NRX-1074 / AGN- Reported to be a functional antagonist at Glycine B 241660, Allergan II site of the NMDA receptor oral Compound, Pharmacology Sponsor Phase Route of Administration

AV-101, Selective agonist at glycine site of NMDA receptor VistaGen II oral NR1 subunit NRX-100 / NRX-101, Partial NMDAR agonist at glycine-site NeuroRx III oral / RO4917523, NAM of mGluR Hoffmann-La Roche IIb oral 5

Decoglurant / RG1578 / RO4995819 NAM of mGluR2/3 Hoffmann-La Roche II Tulrampator / CX-1632 / S-47445 PAM of AMPA receptor RespireRx II

NIMH Riluzole, Glutamate release inhibitor/uptake facilitator Tehran University of Medical II oral Sciences

Brexanolone / SAGE-547, PAM of GABA receptor Sage III IV A Ganaxolone, PAM of GABA receptor Marinus II IV A SAGE-217, PAM of GABA receptor Sage II oral A Collaborators

• Psychiatry • MR CENTER • Sam Wilkinson – Kevin Behar • Chadi Abdallah – Golam Chowdhury • Rachel Katz – Graeme Mason • Robert Ostroff – Doug Rothman • John Krystal – Molecular Psychiatry • BMS • Mounira Banasr – Linda Bristow, Eric Schaeffer – Ashley Lepack • Ron Duman • MGH, Maurizio Fava • George Aghajanian • Baylor, Sanjay Mathew • NIMH, Carlos Zarate NIMH, NARSAD, VA REAP, CT DMHAS Donaghue • Rockefeller University, Bruce McEwen Foundation, VA REAP, Merck, Bristol-Myers • University of Milan, Maurizio Popoli Squibb • SUNY Buffalo, Zhen Yan